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Injections That Could Ease Your Joint Pain Cleveland Clinic

If youre one of the 30 million adults in the United States who live with joint pain, you know its often debilitating. It cankeep you from staying active and even make daily chores seem impossible. What you might not know is that your doctor can treat you with more than pills or surgery.

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Depending on the severity of your pain, injections can be another option for easing your joint pain andget you moving again, sayssports and medical orthopaedist Jason Genin, DO.

In many cases, we use these injections to try to reduce inflammation and pain in your joints, Dr. Genin says. With some treatments, you often can experience fewer symptoms for several months.

There are several injectable options to help treat knee pain. The injections range from corticosteroids, which have been around for decades, to newer cellular therapies like platelet-rich plasma (PRP), he says.

Your physician will decide which one is best based on your individual needs, says sports and medical orthopaedist Dominic King, DO.

Not every injection is right for every patient, Dr. King explains. We take a lot of time to understand your specific issues and create an injectable plan that works with your entire knee care path. This can include weight loss, exercise, stretching, activity modification, anti-inflammatory medications, as well as injection therapy.

Traditional injections, such as corticosteroids (cortisone), can be effective particularly in the late stages of arthritis, as a way to get past a sudden increase in pain and delay the need for surgery.

Hyaluronic acid (HA) injections often are used when corticosteroid injections dont work. But they usually are approved only for use in the knee.

In some instances, doctors consider HA injections first if you dont have obvious signs of inflammation. HA also is a better option if you have diabetes, as corticosteroids can raise blood sugar levels.

Also known as gel injections, HA injections are chemically similar to your natural joint fluid.

When you have osteoarthritis, joint fluid becomes watery. So, this injection helps to restore the fluids natural properties and works as a lubricant and a shock absorber.

HA is a cushion or a buffer against inflammatory cells in the joint, Dr. Genin says. In some cases, it can stimulate the knee to start producing more natural HA. Some physicians also believe that HA helps reduce pain by coating nerve endings within the joint.

One treatment, which may consist of between one and three injections, usually offers symptom relief for four to five months, but sometimes up to one year. However, pain and stiffness will return. Most insurance companies only approve one HA injection every six months.

Platelet-rich plasma (PRP) injectionsare a newer alternative to treat osteoarthritis joint pain. Cells from the patients own blood are processed in a centrifuge to remove red blood cells and most white blood cells, concentrating the platelets. A growing body of evidence has shown that PRP can be as effective or more effective than anti-inflammatory medications or cortisone, particularly in the early stages of arthritis, Dr. Genin adds.

Side effects include a very low risk of infection and pain at the injection site. You also must stop taking oral anti-inflammatory medications for a short amount of time if you get a PRP injection, Dr. Genin says.

Often, many of these injections are effective in reducing or stopping your joint pain, but its important to remember that they may not keep the pain from returning, Dr. King notes. In fact, theyre most effective when used with other therapies. And we consider surgical options only if other treatment options have failed.

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Injections That Could Ease Your Joint Pain Cleveland Clinic

Treatment of diabetic foot ulcer in France | CEOR

Introduction

Chronic non-healing ulcer is a major health problem and its prevalence in the world ranges from 1.9 to 13.1%.1,2 The incidence of chronic ulcers is expected to increase as the population ages and the risk factors for atherosclerotic occlusion such as smoking, obesity and diabetes are increasing. One of the main causes of non-healing ulcer is diabetes. Diabetic foot ulcer (DFU) is diagnosed in 1218% of patients with type 2 diabetes and in 0.62% of patients with type 1 diabetes.3 In addition, 70% of these patients are diagnosed with peripheral neuropathy.4,5 Diabetic chronic wounds lead to pain, discomfort, infection, consultations, dressings, hospitalizations, sequelae, sick leave, and poor quality of life. Individuals with diabetic foot ulcers are susceptible to infection and the healing process is complicated by diabetic neuropathy leading to chronic non-healing ulcers. Consequently, an estimated 12% of individuals with diabetic foot ulcer require lower extremity amputation.3,8,9

Moreover, chronic ulcers also represent a substantial financial burden for the patient and the healthcare system.6,7 The Eurodiale study analysed the direct and indirect annual costs in several European countries (in 14 European centres including Spain, France, the UK, Czech Republic, Germany, Denmark, Sweden and Italy) with a total of 821 patients with DFU. The mean annual cost per patient was 10,091, hospitalization being the most relevant direct cost.10 In the UK, the mean NHS cost of wound care over 12 months was estimated at 7800 per DFU (of which 13% was attributable to amputations), ranging from 2140 to 8800 per healed and unhealed DFU, respectively, and 16,900 per amputated wound.11 The main element (around 20%) of total spending is complications related to DFU.12 In the US, DFU accounted for 83% and 96% of all major and minor amputations related to foot ulcers, respectively, and significantly increased cost of care (DFU: $1.38 vs non-DFU: $0.13 billion/year; p <0.001).13 Therefore, it is important to evaluate strategies that can ensure better prevention and management of this type of wound to lower the number of amputations.

The goal of ulcer treatment is to obtain wound closure as expeditiously as possible. Conventional treatment for non-healing ulcers includes wound cleansing, necrotic tissue debridement, prevention, diagnosis, and, if necessary, treatment of infection, mechanical off-loading, management of blood glucose levels and local ulcer care with dressing application.3,14 Therapeutic procedures to manage DFU are fundamentally based on an adequate covering of the wound, early treatment of the infection, and relief of pressure, with a probability of healing being close to 60% in 1 year. Despite treatment, many chronic ulcers fail to heal or persist for months/years and/or recur after healing, requiring additional advanced wound care therapies for adequate healing. At 31 months follow up, diabetic foot ulcers have around a 40% of recurrence and 12.3% were not healed at the end of the follow-up period.1517 Moreover, at 3 years there is evidence of a 10% to 20% rate of amputations.15,18,19,44

It has been demonstrated that plasma growth factor (PGF) such as platelet derived growth factor (PDGF) significantly shortens treatment duration and leads to healing in approximately 80% of wounds.2024 Many authors2024 found that platelet release has improved healing rates if compared with standard remedies. On the other hand, other studies20,21 found no major difference in healing outcome of leg ulcers, between treatment groups with platelet release and control groups (placebo). An extensive review was performed by Picard et al 2015. They carried out a PubMed and Cochrane search (19782015) including all studies assessing the clinical effect of platelet-rich plasma (PRP) on the healing of diabetic chronic wounds. The screening retrieved 7555 articles and 12 studies were included. Of six randomized studies included, five found significant benefits for the use of PRP on diabetic chronic foot ulcers. The authors concluded that 87.5% of controlled studies found a significant benefit for the adjunction of PRP to treat chronic diabetic wounds. As PRP may be beneficial, they suggest using it on diabetic ulcers which remain unhealed after standard treatment.25 The most recent meta-analyses and review articles have highlighted the therapeutic potential of PRP in chronic wounds with demonstrated benefits in several clinical outcomes, notably complete wound closure, wound surface reduction, scar reduction, and a lowering of incidence of infections.2634

The clinical results of PRP effectiveness in the treatment of DFU are promising considering, however, that the costs associated with treating DFUs with PRP are presumably higher than using standard therapy. Therefore, the implementation of this therapeutic approach in health systems should be based on its cost-effectiveness. Only a few studies have directly dealt with the relationship between the costs and the results of PRP versus standard care and, in addition, no economic evaluations in parallel with clinical studies have been reported. Two studies prior to 2014 found PRP treatment being cost-effective or even dominant compared with usual care.22,35,36 Recently, Linertov et al found that, in a 5-year time horizon, PRP treatment for DFU could be considered a cost-effective or even a cost-saving alternative in Spanish healthcare settings, depending on the method of obtaining the PRP (commercial kit versus manual method) and, to a large extent, on the price of the kit used. As a consequence, these authors called for future studies on the effectiveness and costs of specific devices or methods to be used as inputs for more specific cost-effectiveness models.37 The objective of this study is to close the gap through a cost-effectiveness analysis, with a 1-year time horizon, of a specific PRP preparation procedure for the treatment of DFU versus standard of care accounting for cost using a micro-costing approach. In order to collect detailed data on resource use, material costs and professional time spent on care, our analysis was conducted alongside a clinical study (Le Creusot study, France).38 This paper provides more specific evidence and insights for clinical and managerial decision making exploiting a French setting.

A randomized controlled trial to evaluate the safety and efficacy of autologous platelet-rich plasma (PRP) gel for stimulating wound healing in chronic deep diabetic foot ulcers (3 A stage according to UT classification) was performed at the Fondation Htel-Dieu hospital in Le Creusot, France. N=86 diabetic patients were randomized either to best standard of care (SoC) alone or PRP treatment combined with SoC. Good standard of care was used when appropriate and included debridement, infection control, comorbidities management and off-loading. The two arms were comparable at baseline for age, presence of a neuropathy, antiaggregant treatment, and depth and surface of wounds.38

In PRP treatment, gel is obtained from patients blood by getting a platelet-rich, leukocyte-poor plasma using Regenkit (RegenLab, Switzerland). The commercial kit consists of 3 tubes (2 BCT and 1 ATS) that are used to produce a PRP gel.

This is an outpatient clinical protocol: after a 2-week run-in period, if no reduction of wound surface >20% was observed, patients were randomized (PRP gel application or control SoC treatment). Patients were treated for 6 weeks maximum (less in case of wound closure). PRP gel arm patients could receive more than one gel application upon investigator decision. Primary efficacy endpoint for wound closure was measured at 6 weeks. Efficacy was also evaluated at follow-up visits at 9 and 12 weeks.

For the PRP arm, only protective compress change was done at home once weekly, while for the control group the dressing change was performed at home once daily.

Forty-six patients were randomized to the PRP gel treatment and 40 to the SoC alone arm. All patients were neuropathic, with deep ulcers mostly located on toe and metatarsal, but also heel and plantar vault. Chronic wound duration was on average more than 6 months.

In terms of results observed at 6 weeks after initiation of treatment, PRP arm shows a complete wound closure in 56.5% of patients versus 20.0% in control group, with a statistically significant difference (p 0.001). Similarly, PRP arm reaches 77.3% wound closure at 12 weeks versus 35.7% for SoC control group. During the study, data on resource use and costs were collected. In particular, the authors picked for both arms material usage, professional time spent on care and costs for each activity.

The cost-effectiveness analysis was performed using a Markov model, with a hypothetical cohort of patients with chronic DFU (duration of >3 weeks) with high orthopaedic risk and with ulcers graded 3A (UT classification), meaning deep ulcers down to the bone, including tunnelling and perforating wounds.

Using a decision-analytical model, we defined a structure and within it could insert evidence from this specific clinical study's outcomes (Le Creusot study) as well as from the literature to generalize the results. The advantage of using Markov model is that it is flexible, particularly adapted for modelling chronic diseases spreading over months or years, and deals with ongoing risks and events that might happen more than once over time (recurrence).

The first step was to define DFUs in terms of mutually exclusive states, including all relevant health outcomes, with movement between these states based on transition probabilities. In this study, the Markov model contained six possible health states (2 temporary states, 3 standard states, 1 absorbing state): (1) DFU (first) complete treatment; (2) persistent DFU; (3) completely healed DFU; (4) amputation; (5); post-amputation; and (6) death from any cause and because of surgery (see Figure 1). At the beginning of the model, patients with DFUs would receive the first treatment according to one of the following strategies: PRP combined with best SoC or Soc alone. Hypothetical patients started in state 1 and moved into predefined health states. Each clinical state had an associated cost and effectiveness estimate. Hypothetical patients accumulated costs and QALYs associated with the time spent in each clinical state during the simulated 3-month period. The cycle length was 1 week and the time horizon was 1 year.

Figure 1 Markov model of diabetic foot ulcer. States are identical for usual and PRP care.

In the first state, patients receive their first complete treatment. The first state is a temporary state, therefore patients receive value of cost and utilities for the first treatment and then go with a 100% probability to the second state. In state 2 (persistent DFU), they receive the weekly care. For PRP treatment, there is a certain probability of needing a new complete treatment that is more costly than the weekly care. We modelled the necessity of some patients having more than one complete treatment using a transient event rather than a state. Therefore, we used transition rewards so that a one-time cost was associated with a patient having a second treatment. Although the need of a new treatment is not a state itself, and it has no effect on state transition, it may have costs (and/or disutilities) associated with it. For traditional care, this possibility is not allowed since the dressing change is performed daily until the wound is healed.

In state 2, for PRP arm, the home nurse opens the dressing and checks the cleanliness of the primary dressing (according to Le Creusot study protocol, this is performed once a week in the absence of complications). If the dressing is clean, the nurse will operate the simple replacement of the secondary dressing. Otherwise, a second complete treatment is planned. State 2, for usual treatment arm, draws the complex dressing (dressing change) performed by a home nurse every day who carries out the cleaning and dressing procedure 5 days per week.

In state 3, patients receive costs and utility of a complete healing of their ulcer. As scientific evidence shows, there is some probability that diabetic patients can have a new occurrence, thus they can move from the state complete wound disclosure, through relapse, to the necessity of new medications. State 6 is the absorbing state and collects individuals dying from any cause (life table) and because of surgery. Results are reported in terms of incremental cost-effectiveness ratio (ICER).

All costs associated with health states and transition costs in the Markov model were measured in euros for 2019, as presented in Table 1. Costs were estimated through a micro-costing approach alongside the resources used in Le Creusot study. These costs are from the perspective of the French healthcare system.

Table 1 Data Used in the Model: Costs

For the cost of dressings, we have made a few estimations to get the average price of a simple dressing (PRP group) and a complex dressing (SoC group). Simple dressing made use of Jelonet, Adaptic, Grassolind plus secondary dressing as serum. Complex dressing, depending on wound characteristics, made use of different families of products. From Le Creusot study we have a rate of utilization of 70% of hydrocellular dressing (Mepilex, Ialuset, Urgotull), 20% on superabsorbant hydrocellular dressing (Cutimed, Wilsabord, Sorbact) and 10% using Urgostart. In Appendix Table 1, we summarize the main parameters used. The details of the calculations on the materials used are included in the Excel file Couts Materiels Hopital.

In state 1, PRP cost is due to: the use of regenkit BCT-1 (X2) and ATS (X1) + cleaning procedure + the medication + nurse time. The cost of comparator is due to the cost of complex dressing + cleaning procedure + nurse time (state 1: DFU complete treatment: PRP arm: 186; comparator: 12.6). In state 2, PRP cost of 7.3 is due to the repair of the medication + nurse time. The cost of comparator is due to the cost of complex dressing + cleaning procedure + nurse time multiplied 5 times per week (state 2: persistent DFU (PRP: 7.3; comparator: 63).

Quality of life assessments for six possible health states (see model description) were based on general health status profiles, which are less sensitive than illness-specific scales but allowed us to analyse and compare results outside the context of a certain disease. A variety of generic preference-based measures have been developed; the most used questionnaires include the EuroQol EQ-5D, the Short Form 6D (SF-6D) and the Health Utilities Index (HUI). Once completed, the questionnaires generate a score using an algorithm based on values that have been obtained from a sample of the general public.40 The values are the health-related quality of life (HRQoL) and measure the utility from living in a specific health state. Health states assume HRQoL values between 0 (dead) and 1 (perfect health); negative values are possible when the health status is considered worse than death. QALYs are assessed by combining the weights calculated for health states alongside the time spent in those health states. QALYs represent the number of years lived in perfect health. The advantage of their use is the possibility to compare results among pathologies and among willingness to pay thresholds for health outcomes.

In this analysis, quality of life assessments for the six possible health states were based on the generic EuroQol instrument and obtained from a previous published study, as presented in Table 2.41 Redekop et al used a time trade-off method to estimate the utility weights associated with a range of health states related to DFUs and their complications. This source was also used previously to provide the quality-of-life estimates for a cost-effectiveness analysis of a negative pressure device for the treatment of DFUs. QALYs were calculated by multiplying the quality-of-life utility weight for one health state by the number of years staying in that state.

Table 2 Data Used in the Model: Effectiveness (at 3 Months)

Probabilities of healing were informed by the proportion of ulcers completely healed at the 12-week time point (Le Creusot study data), 77.3% for PRP care and 35.1% for usual care. Whereas Le Creusot study showed strong results in favor of PRP, in our cost-effectiveness analysis we decided to use a conservative approach. The model parameters were from a recent meta-analysis based on five existing clinical trials; the healing success was 58.33% for PRP and 50.31% for usual care28 (see Table 3).

Table 3 Data Used in the Model: Probability of Healing (at 3 Months)

In Le Creusot study, a total of 27 patients had one injection, 17 had two injections and 2 patients had 3 PRP applications. On average, patients received 1.46 PRP treatments. Therefore, we modelled a conservative probability of 0.5 per cycle to receive a second complete treatment (from Le Creusot study, the probability of having a second complete treatment is 0.2).

To generalize the model, the risk of amputation and relapse were included. Amputation is a temporary state leading to the post-amputation state. The probability of amputation was taken from the Moulik study18 and adjusted according to the model cycles (1 week). The new occurrence probability was taken from the Eurodiale study.44

All annual and three-month probabilities were transformed to weekly probabilities by the formula proposed by Briggs:39

where tp1 is the weekly transition probability we wish to estimate and tpt is the overall probability over time, t.

Deterministic sensitivity analysis has been conducted to assess the impact of the uncertainty of the parameters used in the model on the results. Deterministic sensitivity analyses are useful to deal with different uncertainties, whereby: (i) model uncertainty means every model is a simplification of the reality, (ii) parameter uncertainty is an estimation of costs and effectiveness, and (iii) heterogeneity is the individual variability between patients. Therefore, the sensitivity analyses have been run for the most important parameters of the model (Tables 13). Deterministic sensitivity analysis (DSA) has been run for every minmax scenario of any parameters. In detail, one-way DSA and tornado analysis have been run for every parameter where a min and max scenario is reported.

Probabilistic sensitivity analysis (PSA) was performed through a Monte Carlo simulation, performing 10,000 cases, to assess the uncertainty around the ICER and the probability of the PRP therapy to be cost-effective at different willingness to pay thresholds. A probability distribution was assigned at each model input parameter to describe the different values the parameter can have with different probabilities. The effectiveness and probabilities have been modelled with beta distributions; costs were represented as Gamma distributions as recommended in literature.45 For the parameters cited in literature where it was not estimated standard error, it was assumed a general standard error of 25% of the mean value.39

All analyses were perfomed using TreeAge Pro 2021.

In the base case scenario PRP treatment results in cost savings. The average cost per QALY is around 188 for comparator and 181 for PRP, respectively. The ICER of PRP treatment is 613/QALY, which, being lower than zero, indicates the dominance of the PRP therapy.

In order to know how each parameter influences the results, a one-way sensitivity analysis was performed for the main parameters. The tornado analysis shows the collection of one-way sensitivity analyses for the main parameters (see Figure 2). The DSA results are consistent with the base case scenario. However, for some parameters the PRP treatment is not cost-saving but having a positive ICER can be cost-effective according to the willingness to pay thresholds used.

Figure 2 Tornado analysis.

The most sensitive parameters are the PRP arm probability of needing a new complete treatment and the number of weekly medications carried out for both. The analysis shows that the main difference in costs is due to the daily nurse visits and dressing changes for the comparator therapy, while for PRP therapy we have only one visit per week. The PRP therapy cost is higher in the first week (186) due to the expense for medical devices and nurse time, but it decreases at few euros over the following weeks because only 50% of patients per week need a new complete medication. Therefore, the PRP branch needs less nurse time and a reduced use of materials resulting in a cost saving in respect of the standard of care (SoC) alone. Initially, PRP treatment is more costly but at each cycle the cumulative costs become lower than for usual care and from week 7 the comparator become the most expensive. This trend is due mainly to less frequency of medications for PRP and to a better healing probability (Figure 3).

Figure 3 Cumulative cost per week of the two therapies.

Changing the PRP arm's probability of needing a new complete treatment from 0.5 to 0.7 leads PRP strategy to be no longer cost-saving, with an ICER of 732/QALY. Including a lowest number of SoC weekly medications (from 5 to 3) leads to a 622/QALY, while increasing PRP weekly medication (from 1 to 4) has an ICER of 732/QALY. Considering common thresholds of around 20/30,000, PRP is a cost-effective option.

Other sensitive parameters that lead PRP therapy to be cost-effective and not cost-saving are the cost of the kit used and the total cost of the complete procedure.

The probabilistic sensitivity analysis was performed through a Monte Carlo simulation considering 10,000 scenarios (or cases). All the parameters and variables of the model vary according to the assigned distribution. Figure 4 shows the corresponding acceptability curve with the WTP thresholds. For every WTP threshold, the percentage of cases in favor of PRP or HA is shown, where the percentage of cost-effective iterations is derived from a probabilistic sensitivity analysis performed through the Monte Carlo simulation. For example, at 10,000/QALY there is a 77% probability for PRP treatment to be cost-effective.

Figure 4 Cost-effectiveness acceptability curve of PRP vs SoC under various WTP thresholds.

The present study evaluates the cost-effectiveness of PRP treatment compared with usual management of DFU patients in patients with chronic DFU (duration of >3 weeks) with high orthopaedic risk and ulcers graded 3A (UT classification). This work was conducted along with a clinical study (Le Creusot study) allowing a micro-costing approach in the assessment of resource utilization. Conservative data on effectiveness obtained from a recent meta-analysis were considered (the healing success was 58.33% for PRP and 50.31% for usual care).28 Under these assumptions, the PRP therapy resulted in cost-savings in the base case scenario.

The number of weekly medications for both treatments and the PRP arm probability of needing a new complete treatment influence the results because the PRP, after the first complete medication, needs only one intervention per week in comparison to five for usual care. PRP has higher cost for the complete medication but, in the absence of complications (nurse checks once weekly), only the change of secondary dressing is needed. In the absence of healing signs, the physician can schedule a second PRP application. The probability used in the model for a second PRP complete treatment is 50% weekly. Therefore, PRP has the potential to involve lower consumption of resources (both nurse time and materials). As shown in sensitivity analysis, considering three medications per week (instead of five) for usual care, PRP is no longer the cost-saving therapy but with a 622/QALY is cost-effective (ICER inferior to the threshold of 30,000/QALY). Our results confirm the findings of identified economic evaluations3537 which found the PRP treatment being cost-effective or even dominant compared with usual care. The three works before 2014 have limited methodological quality and do not provide sufficient details of the evaluated procedures. A recent study from a Spanish setting found that, in a 5-year time horizon, PRP treatment for DFU could be considered a cost-effective or even a cost-saving alternative. However, there are few economic evaluations probably because of the scarcity of robust clinical trials and for the wide heterogeneity of the population enrolled in the studies.

This work is not free from limitations. It used cost data specific to the French setting because it is rooted in Le Creusot study. It helps to give more details regarding the PRP vs SoC procedure and allows a micro-costing approach, but it can be less generalizable to other contexts. For example, even if the tornado analysis showed consistent results, the number of PRP complete treatments may influence the outcome of the model and thus calls for further analysis. Moreover, the results need to be interpreted in light of a limited level of evidence complicated by heterogeneity in the characteristics of the patients treated and adding to these factors also the procedures used for PRP/usual care therapies such as, for example, the number of medications and the type of materials used. Therefore, more high-quality randomized controlled trials, possibly with longer term follow up, are required.

In conclusion, considering limitations, the PRP treatment for DFU could be considered a cost-effective or even a cost-saving alternative in the French setting.

This study does not contain human/animal test subjects.

The paper is the advancement of a previous working paper published on the website of Department of Management, University C Foscari Venice: Salvatore Russo & Stefano Landi, 2020. Cost-effectiveness analysis for the treatment of diabetic foot ulcer in France: PRP vs standard of care, Working Paper n.4/2020, August 2020, ISSN:2239-2734. This research was supported by University Ca Foscari Venezia through a grant provided by Regenlab SA to SL. Salvatore Russo and Stefano Landi are co-first authors for this study.

All authors made a significant contribution to the work reported. In detail, all authors worked on the conception, study design, and interpretation. SC worked on acquisition of data, SL and SR on execution and analysis. All authors took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

SC formerly worked for Regen Lab as external consultant. The authors report no other conflicts of interest in this work.

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27. Hirase T, Ruff E, Surani S, Ratnani I. Topical application of platelet-rich plasma for diabetic foot ulcers: a systematic review. World J Diabetes. 2018;9(10):172179. doi:10.4239/wjd.v9.i10.172

28. Del Pino-Sedeo T, Trujillo-Martn MM, Andia I, et al. Platelet-rich plasma for the treatment of diabetic foot ulcers: a meta-analysis. Wound Repair Regen. 2019;27(2):170182. doi:10.1111/wrr.12690

29. Hsieh TS, Chiu WK, Yang TF, Wang HJ, Chen C. A meta-analysis of the evidence for assisted therapy with platelet-rich plasma for atrophic acne scars. Aesthetic Plast Surg. 2019;43(6):16151623. doi:10.1007/s00266-019-01471-w

30. Shen Z, Zheng S, Chen G, et al. Efficacy and safety of platelet-rich plasma in treating cutaneous ulceration: a meta-analysis of randomized controlled trials. J Cosmet Dermatol. 2019;18(2):495507. doi:10.1111/jocd.12853

31. Ding H, Fu XL, Miao WW, Mao XC, Zhan MQ, Chen HL. Efficacy of autologous platelet-rich gel for diabetic foot wound healing: a meta-analysis of 15 randomized controlled trials. Adv Wound Care (New Rochelle). 2019;8(5):195207. doi:10.1089/wound.2018.0861

32. Li Y, Gao Y, Gao Y, et al. Autologous platelet-rich gel treatment for diabetic chronic cutaneous ulcers: a meta-analysis of randomized controlled trials. J Diabetes. 2019;11(5):359369. doi:10.1111/1753-0407.12850

33. Xia Y, Zhao J, Xie J, Lv Y, Cao DS. The efficacy of platelet-rich plasma dressing for chronic nonhealing ulcers: a meta-analysis of 15 randomized controlled trials. Plast Reconstr Surg. 2019;144(6):14631474. doi:10.1097/PRS.0000000000006281

34. Hu Z, Qu S, Zhang J, et al. Efficacy and safety of platelet-rich plasma for patients with diabetic ulcers: a systematic review and meta-analysis. Adv Wound Care (New Rochelle). 2019;8(7):298308. doi:10.1089/wound.2018.0842

35. Dougherty EJ. An evidence-based model comparing the cost-effectiveness of platelet-rich plasma gel to alternative therapies for patients with nonhealing diabetic foot ulcers. Adv Skin Wound Care. 2008;21(12):568575. doi:10.1097/01.ASW.0000323589.27605.71

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37. Linertov R, Del Pino-Sedeo T, Prez LG, et al. Cost-effectiveness of platelet-rich plasma for diabetic foot ulcer in Spain [published online ahead of print, 2020 Feb 10]. Int J Low Extrem Wounds. 2020;1534734620903239. doi:10.1177/1534734620903239.

38. Clavel S, Albache N, Labrut H, Robu E, Denizot C. Autologous platelet gel: an help in chronic deep diabetic foot ulcers treatment in 2019 Diabetic Foot Conference Abstracts. J Diabetes Sci Technol. 2020;14(3):601678. doi:10.1177/1932296819897643

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Treatment of diabetic foot ulcer in France | CEOR

Trends Shaping The Future Of Beauty And Cosmetics In 2022

The Global beauty industry is currently valued at $532 billion. However, like every other industry, the global beauty industry is also prone to constant change and growth. The ongoing pandemic also took a massive toll on this industry. This is why you need to understand the ongoing trends that will have a huge impact on the future of beauty and cosmetics in 2022. This will allow us to understand better the direction in which the global beauty industry is moving. Here are the top trends that are expected to dominate the future of beauty and cosmetics.

The ongoing pandemic has taught everyone the importance of hygiene and cleanliness in our everyday lives. The professionals expect this trend to continue in the future, even when the pandemic is finally over. Everyone was looking for hand sanitizer and hand soaps during the pandemic. This has slowly encouraged beauty brands to enter this arena, and they have started offering luxurious and beauty-oriented hand soaps and sanitizers.

People will stay loyal to their favorite beauty brands, and professionals expect them to buy hand sanitizers and other hygiene items from their favorite beauty brands. This way, we will see a revolution in the hygiene department.

People love and demand transparency from their favorite brands. We no longer live in an era when people were unaware of the ingredients used in their favorite products. This is why people want to know what they are putting on their skin. This demand has encouraged beauty brands to sign up with third-party labs to offer complete transparency regarding skincare items. This trend will change the future of beauty and cosmetics in 2022.

Transparency will be among the top priorities of different brands. The customers want to know what they are using, and these brands are willing to offer them a detailed report of all the ingredients and chemical formulas used in the products. This will allow the customers to understand whether their product is sustainable and organic.

The ongoing pandemic has forced us to live inside the confines of our homes. This gave us a chance to digitize every aspect of our life. People who were previously unwilling to adopt technology into their lives completely rely on digital technology to continue their daily activities.

This dependence on technology also increased our exposure to blue light. Blue light is known to have damaging effects on the skin. This is where beauty brands jumped in and started working on innovative ingredients to minimize blue lights damaging impact on our skin.

Blue light protection is one of the most anticipated and biggest trends that we will see in the future. The customers want to take care of their skin, and beauty companies are here to help you slow down the process of skin aging. We will see ingredients such as turmeric and algae in our favorite products.

This may sound odd at first. However, hundreds of different beauty companies are constantly trying to transform solid makeup items into liquid makeup. When customers spend a lot of money on beauty products, they expect those products to stay on for a while. We have already seen waterproof mascara and lipstick items in the past. 2022 will be the year where the consumers finally see liquid lipsticks and liquid items expected to stay on the skin throughout the day.

This trend was quite popular even before the pandemic. However, minimalist makeup is expected to make a comeback in the upcoming years. People want to feel beautiful and independent even without the use of makeup accessories. In addition to this, complicated makeup routines also take up a lot of time, and many customers do not have enough time for such routines. This is why we will see our rise in minimalist makeup accessories and routines.

Slow beauty and natural skincare are all the rage right now. Therefore, many people are trying to understand how to make their skin glow up without foreign elements. They want to say goodbye to foreign elements and embrace a healthier way of achieving beautiful skin daily. This is why we will see minimalist makeup practices in the future.

As the entire world slowly shifted towards online video calls and meetings for daily chores, some people were worried about their outlook and face in virtual meetings. A lot of people were worried about how they looked online. This is why skin surgeons and dermatology experts saw an immense boost in the number of people who wanted to learn more about the different cosmetic procedures for facial concerns.

The number of people who investigated different procedures for eye area treatments was higher than ever. This trend is expected to continue down the road, and people will slowly move towards facial treatments and cosmetic surgeries to look better and more beautiful on video calls and virtual chat rooms.

We may not feel it or see it, but our fingers are home to a whole host of bacteria. In addition to this, there are also colonies of viruses that live on our skin. Similarly, an average person touches their hair more than 40 times a day.

We may not see it, but there is an exchange of bacteria and viruses between your hair and fingers. This takes a negative toll on the health of your hair. This is why scientists and professionals have been trying to develop innovative solutions to take care of hair.

2022 may be the year when we finally see antibacterial haircare. Many different beauty companies are already working on creating antibacterial haircare products that are safe for customers, such as cleaning sprays, antibacterial shampoos, and antibacterial moisturizers. These items are expected to fight against any bacteria or virus and offer antimicrobial disinfecting agents that will offer maximum protection for your hair throughout the day.

Another arena that will see a massive improvement in 2022 is the scalp area. People slowly understand the importance of taking care of their scalp. This is why we will see a boost in the number of people who will move towards scalp treatments to reduce hair loss and improve hair health. Platelet-rich Plasma (PRP) injections are becoming more and more common among people.

Another important trend that you can see in the year 2022 is that people will try to move towards organic and plant-based skincare items. Some people are already trying to minimize their impact on the environment. Skincare is the next arena that will see a massive evolution in minimizing the carbon footprint on the environment.

People are trying to move towards plant-based skincare items for multiple reasons. One of the reasons is to minimize the impact on the surrounding environment. Another important reason is that people want to stay away from harsh chemicals and introduce naturally occurring ingredients into their daily skincare routine.

A lot of people are trying to investigate the benefits of using hemp-based or CBD creams. We will see a massive increase in consumers who will try to move towards plant-based skincare items.

In the past, people used to spend a lot of money on getting different hairstyles and artificially augmenting their natural hair. However, we will see a decrease in this trend as people have started to believe in low maintenance power.

Similarly, people are also quite happy to embrace themselves as they are. This will change the

future of beauty and cosmetics in 2022. We will see more and more people embrace their natural hair and stay away from hair straightening or hair curling activities. In addition to this, customers are also worried about hair loss and hair damage. This is why we will see many people embrace air-drying and the natural texture of their hair. They will try to stay away from chemicals and intense heat for hair straightening activities.

People will slowly try to move towards low-maintenance and natural hair care routines. They will also try to find organic and natural shampoos for the daily hair care routine. Therefore, we will see people embracing their natural texture and natural hair more often.

Here are the top 10 statistics that you must know to understand the future of beauty and cosmetics in 2022.

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Trends Shaping The Future Of Beauty And Cosmetics In 2022

Knee and Hip Arthritis: Self-Assessment and Management – Baptist Health South Florida

Could the pain you are feeling be arthritis? Francisco J. Garcia, physician assistant at the arthritis clinic at Miami Orthopedics & Sports Medicine Institute, answered this commonly asked question when he addressed the self-assessment and management of knee and hip arthritis at a recent virtual community health discussion.

The symptoms of knee and hip arthritis can impede your ability to exercise, participate in social activities and go on vacation, and this decrease in activity can lead to muscle weakness, obesity, falls and, ultimately, depression, Mr. Garcia said.

Arthritis may be classified as osteoarthritis, inflammatory arthritis or posttraumatic arthritis, Mr. Garcia explained.

Osteoarthritis involves the degeneration of hyaline cartilage the hard, slippery tissue that covers the ends of bones where they form a joint. The condition is usually caused by the wear and tear over time. The joints most commonly affected include the knees, hips, neck, lumbar spine and hands, Mr. Garcia says. Osteoarthritis is genetic- and age-related, with early signs manifesting around age 50.

Inflammatory arthritis is triggered by an autoimmune disease that attacks the lining of the joint capsule, most commonly in the wrists, hands, fingers, toes and knees. The inflammatory process can eventually destroy cartilage and bone within the joint, Mr. Garcia explains. The most common types are rheumatoid arthritis, gout, lupus and psoriatic arthritis. These diseases have a genetic component, can occur at any age and affect women more than men.

Post-traumatic arthritis is caused by a physical injury that damages the cartilage and/or bone and changes the mechanics of the joint, making it wear out more quickly. The injury can be from sports or a vehicle accident, fall or military injury.

Since the knees and hips bear weight, they are among the most common joints affected by arthritis.

Knee Arthritis

Arthritis in the knee occurs when the cushion between the femur and tibia has deteriorated. When self-assessing your knee health, consider these symptoms of knee arthritis:

Hip Arthritis

Arthritis in the hip occurs when the cartilage in the joint gradually wears away and the protective joint space between the bones decreases. In addition to osteoarthritis, inflammatory arthritis and post-traumatic arthritis, this degeneration can be caused by hip dysplasia a genetic condition in which the hip socket does not fully cover the ball portion of the upper thighbone.

When self-assessing your hip health, Mr. Garcia recommends that you consider these symptoms of hip arthritis:

Conservative Treatments

To reduce the effect of arthritis on your quality of life, Mr. Garcia recommends seeing a specialist to evaluate your condition and initiate a non-surgical management plan to reduce your symptoms. Your conservative care plan may include:

Injections can lubricate the joint and reduce pain and inflammation, Mr. Garcia explained. For the knee, a cortisone injection can provide two to three months of relief while a hyaluronic acid injection is effective for three to six months. Injections in the hip give short, mild relief but do not last as long as knee injections.

Surgical Treatments

When conservative treatments fail and pain affects your quality of life, surgical management may be warranted. Partial knee replacements and total knee replacements are performed under spinal anesthesia and sedation. Some patients will stay one night in the hospital while other qualified patients will be discharged home on the same day. Mr. Garcia recommends that all patients attend physical therapy for six to eight weeks to achieve the best outcome.

Patients undergoing hip replacement surgery also may stay one night in the hospital or be discharged the same day. The orthopedic surgeons at Miami Orthopedics & Sports Medicine Institute use the anterior approach, which protects soft tissue from damage, rather than the posterior or lateral approach, which has a longer recovery and increases the risk of dislocation and leg length discrepancy. Patients will be ambulating on the day of surgery and start physical therapy immediately.

For most people, joint replacement surgery is a game changer, providing pain relief, improved mobility and a better quality of life, Mr. Garcia says.

Tags: arthritis, hip arthroscopy, knee pain

Continued here:
Knee and Hip Arthritis: Self-Assessment and Management - Baptist Health South Florida

JAWS and the 2022 Hall of Fame Ballot: Carl Crawford – FanGraphs

The following article is part of Jay Jaffes ongoing look at the candidates on the BBWAA 2022 Hall of Fame ballot. For a detailed introduction to this years ballot, and other candidates in the series, use the tool above; an introduction to JAWS can be found here. For a tentative schedule and a chance to fill out a Hall of Fame ballot for our crowdsourcing project, see here. All WAR figures refer to the Baseball-Reference version unless otherwise indicated.

Content warning: This piece contains details about alleged domestic and gun violence. The content may be difficult to read and emotionally upsetting.

2022 BBWAA Candidate: Carl Crawford

SOURCE: Baseball-Reference

The new millennium hasnt exactly been a banner one for the stolen base. Between soaring home run rates and the influence of analytics on front offices, the tactic has gone out of style, and per-game rates have fallen. As one-run strategies go, teams seem content to wait for a player to knock a ball over a wall rather than manufacture a run. During the first decade of the 2000s, as home runs kept flying, Carl Crawford stood out for his electrifying speed and skill on the basepaths.

In the first eight full seasons of his 15-year career (2002-16), Crawford led the American League in stolen bases four times, finished second once and third twice, stealing at least 46 bases in each of those seasons. He topped an 80% success rate in the first five of those seasons, and led the league in triples three times as well. Crawfords wheels as well as his midrange power and strong defense helped him make four All-Star teams and win a Gold Glove while starring for the Rays first two playoff teams.

Alas, Crawford hit free agency, signed a massive seven-year deal with the Red Sox, and almost immediately went into the decline phase of his career due to injuries. After totaling 35.6 WAR with Tampa Bay from 2002-10, he managed just 3.5 WAR over his final six seasons spent with Boston and the Dodgers while missing substantial time due to Tommy John surgery, plus wrist, finger, oblique, and hamstring woes. He was released by Los Angeles with a year and a half still to go on his contract, and never played again.

Since retiring, Crawford has made grim headlines, including one for a 2020 arrest for domestic assault against his ex-girlfriend, and another for the drowning of a 5-year-old boy and 24-year-old woman during a party at his home and a subsequent lawsuit alleging negligence. If Crawford were a serious candidate for election, on the level of Omar Vizquel, such matters might cost him the support of voters. As it is, they complicate his legacy.

Crawford was born on August 5, 1981 in Houston, Texas, and grew up in the Fifth Ward. His grandfather, Roy Burns, ran a legendary barbecue restaurant, Burns Original BBQ, in Houston, and his father Steve went into the family business. Later, so did Carls brother, Cory, and Crawford used some of his career earnings to help finance the restaurants rebirth.

As a child, the left-handed Crawford pitched and played first base for the Smokey Jasper Park Angels, a Little League team coached by Ray Bourn, whose son Michael yes, Michael Bourn was 16 months younger than Crawford. The younger Bourn played 11 years in the majors (2006-16), won three stolen base titles and made two All-Star teams but was not included on this years Hall of Fame ballot despite being eligible. The team was very good, but due to a lack of money for travel, We didnt even get a chance to play in (the Little League World Series), Crawford recalled in 2014. I mean we beat everybody else. We scrimmaged one of those teams that went and blew em out. The situation led Crawford to help fund the travel of the national title-winning Jackie Robinson West team from Chicago.

At Jefferson Davis High School, Crawford lettered in football, basketball, and baseball. While lore has it that UCLA offered him a basketball scholarship to play point guard, Crawford later debunked that story. He did sign a letter of intent to go to the University of Nebraska on scholarships for football and baseball, but when the Devil Rays chose him in the second round of the 1999 draft (the 52nd pick overall), he soon signed for a $1.245 million bonus.

When he began his career with the Devil Rays Princeton affiliate in the Appalachian League in 1999, Crawford was still just 17 years old and comparatively inexperienced at baseball, given his interests in other sports. Nonetheless, he hit .319/.350/.404 and stole 17 bases in a league where he was 2.7 years younger than the average player, then hit .319/.350/.404 with league-leading totals of 170 hits and 55 steals, not to mention 11 triples, as an 18-year-old in the South Atlantic League. Baseball America placed him 72nd on their Top 100 Prospects list in the spring of 2001 while noting that the Devil Rays rave about Crawfords ability to take instruction and put it to use. His enthusiasm is apparent, and he never seems intimidated [even if] his inexperience sometimes shows.

Despite hitting a more modest .274/.323/.352 with 36 steals at Double-A Orlando in 2001, Crawford moved up to number 59 on BAs list because hed held his own as a 19-year-old. From his prospect capsule:

He has great speed, quick wrists and a good idea of how to hit. His superior work ethic rivals that of any player in the system, and hes considered the Devil Rays most coachable prospect. Crawfords arm is his lone below-average tool. His baseball instincts, such as taking the correct routes on fly balls, should get better with experience. His pitch recognition and ability to work counts need improvement, and his swing could use some refinement.

After spending the first half of the 2002 season at Triple-A Durham, Crawford was called up to make his major league debut. He went 1-for-4 with a two-run single off the Blue Jays Brian Bowles on July 20, 2002, 16 days short of his 21st birthday. On a team that lost 106 games, Crawford hit just .259/.290/.371 for a 77 OPS+ in 278 PA, but his baserunning and defense still boosted his value to 1.0 WAR. His hitting was only slightly better the following year (.281/.309/.362, 81 OPS+), but he did steal an AL-high 55 bases in 65 attempts; between his baserunning, double play avoidance and 11 Defensive Runs Saved, he was worth 2.3 WAR, a respectable showing for an age-21 season.

Crawford broke out in 2004, making his first All-star team, hitting .296/.331/.450 (105 OPS+) with league bests in triples (19) and steals (59), and 4.9 WAR. That began a four-year run during which he hit for a 112 OPS+ (.304/.341/.467) while averaging 14 homers, 15 triples, 53 steals, and 4.5 WAR. He made the AL All-Star team again in 2007, led the league in triples in 05 and 06, and in steals in 06 and 07; from 2005-07, he was successful on 85% of his stolen base attempts. In April 2005, he signed a four-year, $15.25 million extension that included club options for 2009 and 10.

The Devil Rays remained a bad ballclub in this span, losing fewer than 95 games only in 2004. But the times they were a-changin in Tampa Bay. Manager Lou Piniella and general manager Chuck LaMar were replaced by Joe Maddon and Andrew Friedman after the 2005 season, and the Devil Rays became the Rays after 07. With rookie third baseman Evan Longoria joining Crawford, B.J. Upton, and a stable of young pitchers led by James Shields and Matt Garza, the team turned the corner in 2008, winning 97 games and the AL East. Crawford was not at his best, however; between a four-game suspension for his part in a brawl against the Red Sox, a minor hamstring injury, and surgery to repair a subluxation of his right middle finger tendon, he played in just 109 games and hit for an 89 OPS+ with just 25 steals and 2.5 WAR.

Despite not making a single major league plate appearance after August 9 due to injuries, Crawford reclaimed his starting left field job at the outset of the 2008 postseason, and hit .290/.333/.468 as the Rays beat the White Sox and Red Sox before losing to the Phillies in a five-game World Series. His biggest contribution came in Game 4 of the ALCS, when he went 5-for-5 with two doubles and a triple, scoring three runs and driving in two in a 13-4 win. He homered off both Cole Hamels and Joe Blanton in the World Series, albeit both in games that the Rays lost.

The Rays picked up Crawfords options in each of the next two seasons, and he responded with performances that netted him All-Star berths in both years. He hit .305/.364/.452 (116 OPS+) with 15 homers and career highs of 60 steals including an AL record-tying six in one game on May 3 and 5.0 WAR in 2009, and was the MVP of the All-Star Game for his robbery of a potential go-ahead home run by Brad Hawpe.

Crawford topped that with a career year, hitting .307/.356/.495 with highs in slugging percentage, homers (19), OPS+ (135) and WAR (7.0, good for sixth in the league) while stealing 47 bases and boasting a league-high 13 triples. Though his 8 DRS wasnt his best, he did bring home his only Gold Glove that year as well. The Rays won the AL East again, but lost a five-game Division Series to the Rangers; Crawford went just 3-for-21, though two of his hits and his only homer came in Tampa Bays Game 3 win.

That big season carried the 29-year-old Crawford into free agency, where his speed, athleticism, defensive ability, and budding power attracted the attention of the Red Sox, who had missed the playoffs for the first time since 2006. When fellow free agent Jayson Werth signed a seven-year, $126 million deal with the Nationals, Crawford and his agents, Greg Genske and Brian Peter, got a boost. He signed with the Red Sox for seven years and $142 million, choosing them over the Angels, who were reportedly offering the same package. The deal was the games 11th-largest at the time, and the sixth-largest of any free agent to that point, after those of Alex Rodriguez ($275 and $252 million), Mark Teixiera ($180 million), CC Sabathia ($161 million), and Manny Ramirez ($160 million).

Crawfords time in Boston was a disaster. He hit .155/.204/.227 in April 2011, missed a month from mid-June to mid-July due to a hamstring strain, and declined in every phase of his game, hitting just .255/.289/.405 (85 OPS+) with 11 homers and 18 steals his lowest total since his rookie season in 130 games. The Red Sox nonetheless carried the ALs best record into September, but went just 7-20 the rest of the way. Still, they entered the final night of the season at 90-71, tied with the Rays for the AL Wild Card spot, and headed to the ninth inning of their season finale up 3-2 on the lowly Orioles. After striking out the first two batters in the ninth, closer Jonathan Papelbon gave up back-to-back doubles to Chris Davis and Nolan Reimold, tying the game. With pinch-runner Kyle Hudson on second base, Robert Andino lined a ball to left field, where Crawford tried unsuccessfully to make a sliding catch, then threw home too late to prevent the winning run from scoring. It made for an enduring image not just of the teams season, but of the left fielders tenure in Boston.

The Red Sox lost that game, but they werent eliminated until the Rays erased a 7-0 deficit against the Yankees in the eighth and ninth innings, then won in the 12th.

In January, Crawford underwent surgery to repair cartilage in his left wrist. Initially, the Red Sox explained he had begun experiencing soreness during his offseason hitting workouts, but by Opening Day, it emerged that hed dealt with wrist pain for years and had received painkilling injections to manage the problem in 2011. Just as he neared his return in late March, he sprained his left UCL and received an injection of platelet-rich plasma. He didnt make his season debut until July 16, 2012, and it soon became apparent both that his elbow was still a problem and that the Red Sox were going nowhere, so he underwent Tommy John surgery in late August.

On August 25, two days after that surgery, the Red Sox shocked the baseball world by trading Crawford, Josh Beckett, Adrian Gonzalez, Nick Punto, and $258 million cash all but $12 million of what remained on the players respective contracts to the Dodgers for a five-player package.

Crawford was surprised by the trade,and relieved. When he reported to spring training, he spoke of Bostons toxic environment and his inner struggles. I just didnt see a light at the end of the tunnel, he told the Los Angeles Times Dylan Hernandez. It puts you in kind of a depression stage. You just dont see a way out. A year and a half later, he admitted that he hadnt done his research on Boston or spoken to a single player who had played there about his experience.

Crawfords return to action was solid but unspectacular. He hit .283/.329/.407 (107 OPS+) with 15 stolen bases and 1.5 WAR in 116 games, missing just over a month due to a hamstring strain. He came up big in the Division Series against the Braves, going 6-for 17 with three homers in a four-game victory; he hit a three-run shot off Julio Teheran in Game 3, then homered twice of Freddy Garcia in Game 4. Though he collected hits in all six games of the Dodgers NLCS loss to the Cardinals, he scored just twice and drove in one run, that via a solo homer off Joe Kelly in a Game 5 win.

Crawfords 2014 season was his best as a Dodger, not that it was a complete one. The 32-year-old left fielder hit .300/.339/.429 (118 OPS+) with 23 steals in 29 attempts, and 2.4 WAR, but he missed six weeks due to a left ankle sprain. Though he went 5-for-17 against the Cardinals in the Division Series, the Dodgers fell in four games.

From there, the returns diminished. Crawford was the Dodgers Opening Day left fielder in both the 2015 and 16 seasons, but slipped below replacement level and was increasingly unavailable due to injuries. He missed 12 weeks in 2015 due to an oblique strain, and played in just 69 games, finishing with -0.2 WAR, then played in just 30 games, missing time due to a lower back strain. On June 5, a point at which he was a full win below replacement level in just 87 PA, the team designated him for assignment, then released him while still owing him $35 million. Despite the fact that he would have cost just the league minimum, he never played again. The Rays reportedly expressed at least some interest in bringing him back in late June of 2016 when their outfield was depleted by injuries, and he mulled a comeback over the following winter, but that was it for his career.

Crawfords career total of 480 stolen bases ranks only 43rd all-time, but its fourth among those since the year 2000, behind only Juan Pierre (614), Jos Reyes (517), and Ichiro Suzuki (509), with 2022 ballot newcomer Jimmy Rollins (470) fifth, and current candidate Bobby Abreu seventh (347 of his 400). Similarly, Crawfords 81.5% success rate ranks sixth among players with at least 300 stolen base attempts in that span, with Carlos Beltrn first (87.3%, nearly a point higher than his overall 86.4% dating back to 1998) and Rollins (81.7%) fourth. Crawfords total of 83 runs for baserunning and double play avoidance also ranks fourth for the span behind Ichiro (118), Johnny Damon (95, from his career total of 125 dating back to 1995), and Pierre (85).

Alas, all of that is at least somewhat overshadowed not only by the dud that was Crawfords contract but by his post-career legal issues. In 2017, he founded 1501 Certified Entertainment, a music label. Rapper Megan Thee Stallion signed with the label in early 2018 and soon found success, but when she signed a management deal with Jay-Zs label Roc Nation in September 2019, 1501 blocked her from releasing new music. In response, she sued 1501 and Crawford, calling the contract unconscionable and the label purposefully and deceptively vague in paying her; the case is ongoing.

More tragically, on May 16, 2020, two people, 5-year-old Kasen Hersi and 25-year-old Bethany Lartigue, drowned in the backyard swimming pool during a party at his house in Houston. The woman had been staying at Crawfords home while filming music videos; she jumped in to save the boy but neither one survived after being administered CPR. The boys father soon sued Crawford for $1 million for negligence, claiming that he had failed to take reasonable and necessary steps to prevent the boy from having access to the pool. Crawford publicly expressed remorse over the two deaths; the current status of that lawsuit is unknown.

On June 3, 2020, Crawford was arrested in Houston and charged with assault of a family member/impeding breathing, a felony. According to court documents, Crawford showed up at the Houston apartment of his ex-girlfriend, with whom he has a daughter who was one year old at the time, on May 8. The woman alleged that Crawford fired a semi-automatic handgun, threatened her at gunpoint, slammed her head against the wall and squeezed her neck. The emergence of the couples child distracted Crawford long enough for her to escape. Crawford also allegedly fled the scene, but left behind the handgun.

Crawford turned himself in and was freed on $10,000 bond. Via lawyer Rusty Hardin (who previously represented Roger Clemens in allegations related to the Mitchell Report), he denied the charges and his conduct. While further developments in the case were not publicly reported, according to Harris County court records, he was indicted by a grand jury in December 2020, but the case was dismissed the following March when his ex-girlfriend refused to cooperate with the prosecution.

Even without prosecution, such disturbing stuff would likely compromise a serious candidates chances for election to the Hall of Fame, and as it is, the litany makes even appreciating the high points of Crawfords uneven career a complicated matter.

Continue reading here:
JAWS and the 2022 Hall of Fame Ballot: Carl Crawford - FanGraphs

Nowakowski Considers CD19 Therapy in Transplant-Ineligible DLBCL – Targeted Oncology

During a Targeted Oncology live event, Grzegorz S. Nowakowski, MD, discussed the case of a patient treated with tafasitamab plus lenalidomide in the second line for diffuse B-cell lymphoma.

Targeted OncologyTM: What are the options for second-line therapy in this patient with DLBCL?

NOWAKOWSKI: The current NCCN [National Comprehensive Cancer Network] guidelines [for patients who are not candidates for transplant] have gemcitabine [Gemzar] plus oxaliplatin [Eloxatin] plus or minus rituximab as a preferred regimen.1

Polatuzumab vedotin [Polivy] plus bendamustine [Treanda] plus rituximab is also included in the NCCN guidelines. Tafasitamab [Monjuvi] plus lenalidomide [Revlimid], which is another option, is FDA approved for second-line therapy and beyond. A lot of us in the field, in patients who are not willing to go for more intensive regimens [such as] transplant or CAR [chimeric antigen receptor] T-cell therapy, are looking more into these chemotherapy combinations, particularly if the patient progresses after chemotherapy. The idea is its going to be a different mode of action. CAR T-cell therapy is [used in the third-line setting] as of now. Again, this may change in the future.

What is the rationale behind the patient receiving this combination?

The FDA granted accelerated approval for the combination of tafasitamab and lenalidomide for relapsed or refractory DLBCL based on [results from] the L-MIND study [NCT02399085].2

Tafasitamab has a cool concept where the antibody cells target CD19, just as in CAR T-cell therapy and loncastuximab tesirine [Zynlonta], which is another recently approved antibody. There were initial developments before studying [CD19] where we felt it could be a good target, but some antibodies didnt work so well. Now there is this renaissance of interest in CD19-targeting agents such as CAR T-cell therapy, tafasitamab, and loncastuximab.

The [tafasitamab] antibody is engineered to have this enhanced Fc function that increases ADCC [antibody-dependent cellular cytotoxicity], ADCP [antibody-dependent cellular phagocytosis], and cell death. It causes direct cell death because CD19 is important in B-cell receptor signaling and not only in the immune system, but it gives some antisignaling properties as well.3

Lenalidomide has the properties of immune activation and microenvironment function and there are dozens of papers postulating many mechanisms of action for lenalidomide. Its very pleiotropic, but it does immune activation, and we know from R2 [lenalidomide plus rituximab] and other antibody combinations that it tends to synergize with the antibodies very well. This preclinical idea led to the development of the combination of this naked antibody and lenalidomide in patients with relapsed or refractory DLBCL.

Which trial data supported the approval of tafasitamab/lenalidomide?

L-MIND was a single-arm, phase 2 study [that enrolled patients who had] 1 to 3 prior regimens and who were either relapsing after transplant or were not eligible for transplant. The primary refractory patients were to be excluded, but because of changing definitions, they accrued, to some degree, to the study, and had pretty good results anyway.4

Tafasitamab is an infusion, just like other antibodies. Its given on days 1, 8, 15, and 22, for 1 to 3 cycles. In cycles 4 to 12, it is given every 2 weeks. Lenalidomide is given at 25 mg daily on days 1 to 25, [just as] in multiple myeloma. This is a different dose [from the R2 regimen], which is 20 mg, but the 25 mg was well tolerated, and this was based on the initial [pilot study]. After 12 cycles of therapy, patients received tafasitamab until disease progression.3,4

Frequently [we are asked] why we would plan on continuing forever. I was involved in the design of the study, and the salvage options for patients were quite limited for those who were not transplant eligible and some of the investigators asked why we would want to stop if it is working. We gave investigators discretion to [decide] whether the patient was benefiting from the treatment and to continue until disease progression. The primary end point of the study was overall response rate [ORR], which has frequently been the most reliable end point for the activity of the combination in this setting because it tends to have less bias in patient selection. The secondary end points were PFS [progression-free survival], duration of response [DOR], overall survival [OS], and so forth.4,5

There were some lenalidomide dose reduction studies where patients were given doses of 25 mg down to 5 mg using step reductions.5

This was a study of the [safety] population, and 81 patients were accrued overall. The median age was 72. The IPI risk score, Ann Arbor stage, and LDH results were typical for refractory DLBCL. Patients with primary refractory disease were supposed to be excluded, but 19 of 81 patients had it and 44 of 81 patients were refractory to prior therapies. Relatively few patients had a prior stem cell transplant and the majority were not eligible for it due to comorbidities, unwillingness to do so, or not responding to salvage therapy. [Not responding] to previous therapies was a major reason [for not getting a transplant].5

How did patients do on the L-MIND trial?

The ORR for this combination was quite high at greater than 60%, which is comparable with what we see in CAR T-cell therapy or intensive chemotherapy. So this was quite significant and impressive at the time the [results were] published. The CR [complete response] rate was even more impressive at 43%. Again, this was in patients who were relapsed or refractory, not transplant eligible, or those relapsing after transplant, so a 43% CR rate is high.5,6

As clinicians, we care about the DOR, too. So if you are a regulator, say at the FDA, you only worry about response rates because its less about patient selection, but clinicians like responses to be durable. The median PFS was 12.1 months.5 The median PFS doesnt fully reflect the activity of this regimen because it plateaus just after the median. CAR T-cell therapy data look very similar, too. For a relatively well-tolerated combination, these were very impressive results at the time of presentation. The median OS was not reached and, as with the PFS results, the OS also plateaued. So these were very impressive results in terms of DOR.

The patients in CR were primarily driving this benefit, but even the patients in PR [partial response] had [an approximately] 30% sustained response.6 The treatment was active in the patients treated both with 1 prior or 2 or more prior lines of therapy. Responses, particularly the CR rates, were somewhat higher in the patients who were on second-line treatment. This would be the patients who were not eligible for transplant.

Do you feel comfortable using this regimen in patients with GCB [germinal center B-celllike] subtypes because they were underrepresented in the study?

There was a whole debate about it. We believe that the combination of the antibodies and lenalidomide works well in GCB subtypes as well. It is a little bit different with single agents because the data showed response rates and activity were better in ABC [activated B-cell] or nonGCB subtypes of DLBCL, but in combination, there appeared to be less of a differential by cell of origin.

But in the [forest plot] analysis, both subtypes benefited. There was a trend toward a little bit of a high response rate in patients with the ABC subtype, but overall, the response rate was high in patients with GCB patients as well. I believe it was approximately 45% to 50% in both subtypes.

What about the R2 regimen? Do you prefer not to use it in GCB subtypes?

Yes, I prefer not to use it in GCB subtypes. [Results of] the ECOG-ACRIN E1412 study [NCT01856192] were recently published in the Journal of Clinical Oncology and I was a PI [principal investigator] in it.7 This study was looking at all-comers, so it was the only randomized frontline phase 2 study, where lenalidomide was added to R-CHOP. This one was cell-of-origin agnostic, so they could have the GCB or ABC subtype. There was [approximately] a 12% difference in PFS in this study and a favorable hazard ratio.

Another study, the ROBUST study [NCT02285062], was focused on patients with the ABC subtype.8 It didnt show a difference using different lenalidomide scheduled doses, though there were other patient selection issues in the study. As a single agent, lenalidomide is more active in the ABC subtype and I use it myself in clinical practice more in ABC or nonGCB subtypes. In combination with the antibodies, or even chemotherapy, this may not be necessarily true. Because most of these patients are already exposed to rituximab, I think based on the R2 study [results], they didnt see much of a differential based on cell of origin, which is a little bit disappointing, because we were hoping we could [use it to] select the high responders, but that didnt pan out. REMARC [NCT01122472] was a study done by a French group that used lenalidomide maintenance after R-CHOP but didnt track the cell of origin.

In fact, the GCB subtype tended to benefit more, and an idea was that maybe some microenvironment influences played a role. In my clinical practice, in nonGCB subtypes, I use a single agent, but for combination of the antibodies, the activity seems to be agnostic to cell of origin.

How does an anti-CD19 antibody downregulate the CD19 receptor?

There is limited information, but they did a study looking at the CD19 expression after tafasitamab exposure in chronic lymphocytic leukemia and [there was no impact] and in DLBCL as well. The CD19 expression is just a part of the story because you worry that a part of the CD19 molecule could be mutated and then the CAR T-cell agents would not bind or that part of the molecule could be missed because of alternative splicing or losing one of the exons because of the evolutionary pressure of the treatment. We did whole exome and RNA sequencing and saw no abnormalities within the CD19 cells. It appears to be expressed after tafasitamab exposure, and there are no point mutations, exon deletions, or other changes that would affect the integrity of CD19, to the best of our knowledge.

Of course, the best data would come from clinical evidence if we note that CAR T-cell therapy is working. In this study, only 1 patient proceeded with CAR T-cell therapy and had good clinical benefit and was in remission last time I saw the data. So it appears that in anecdotal experiences CAR T-cell therapy will still work in those patients.

The opposite is true, too. There is a huge interest now in this combination and [whether] it will be active in post CAR T-cell relapses. Lenalidomide as a single agent is frequently used in this setting. How active will this combination be in postCAR T-cell relapse? We know that lenalidomide is active. A lot of patients with CAR T-cell relapses will still have CD19, so we believe that is also an option, but more data will be needed.

Do patients tolerate the 25-mg lenalidomide dose in combination with tafasitamab, or is the dose modified often?

[Approximately] 30% of patients will have to drop to 20 mg, particularly with subsequent cycles. The nice thing for lenalidomide is that you can use the growth factor support because it is primarily neutropenia that causes some of the dose reductions. Studies are different from real life, so in the real world we always have some patients who are already cytopenic from the previous therapy. I usually support them with a growth factor, and sometimes I start my patients at 20 mg. The dosing intensity of lenalidomide seems to be important, though.

I wouldnt very liberally decrease it because there appears to be some dose relation to the response, at least as a single agent in a refractory setting in DLBCL in contrast to follicular [lymphoma], but somewhere from 15 mg to 20 mg is the golden spot for response.

The 25 mg was used in those studies as a single agent, so, about one-third of patients did require dose reductions. If you use this combination, you follow the lenalidomide package inserts, and if you need to reduce because of creatinine clearance, you reduce the lenalidomide or if you see significant neutropenia despite the growth factor used, then you can reduce on a subsequent cycle to 20 mg, or interrupt and reduce to 20 mg.

Does patient preference weigh into the decision to choose finite therapy vs therapy until progression of disease in the second-line setting?

Yes, it comes down to the patients preference. I dont practice in the community, so I dont have more experience with this. We have this policy at Mayo Clinic that [any clinician] from around the world can call us at any time for advice about their patients. So, routinely, we are getting quite a few phone calls from those who are responsible for patients with lymphoma, or for any other disease type from outside, and practitioners call asking what to do.

I am always surprised by how many patients do not want to proceed with CAR T-cell therapy or stem cells or even clinical trials, which we often have here, because of the preference of being near the local center. Travel is not always possible and some patients want to stay where they are, which is a very reasonable option.

Are there trials comparing this with transplant or something lenalidomide alone?

We did 2 things to differentiate this from lenalidomide alone. A study called RE-MIND [NCT04150328] with close matching of the patients with real-world data showed that the combination was definitely much more active than lenalidomide alone. [We knew this] but wanted to double-check in a very close-matched cohort. A confirmatory study for this is [the frontMIND study (NCT04824092), which is a frontline study that compares] R-CHOP as standard therapy vs R2-CHOP plus tafasitamab.

I am the principal investigator globally for this study, and one of the reasons why we designed it this way was there was some activity already from randomized phase 2 studies using lenalidomide. It was safe and effective and also the doublet was already approved, so it was logical to move it forward.

However, the biggest [issue we had when] presenting this concept to some regulatory authorities was that we were a little bit naive in the past, thinking that adding 1 drug at a time is going to move the bar a whole lot. R-CHOP already has 5 different compounds, so I think the sixth one probably is not going to move the bar a whole lot. There are some studies that failed, I think, 1 drug at a time. So the ambitious plan here is to add a doublet. But the study is designed to capture very high-risk patients, [meaning] IPI 3 and above. Its looking at the highest-risk population and is adding doublet on top of R-CHOP. There are some study centers in the United States that are in the process of either opening or even have it open currently.

Could tafasitamab/lenalidomide be moved to the first-line setting with more targeted agents as chemotherapies are eliminated?

Yes. There is a pilot study led by my colleague Dr [Jason] Westin at [The University of Texas MD Anderson Cancer Center]. He is basically pioneering the so-called smart-start, or smart-stop now, where he is adding exactly this combination to R-CHOP. The question is: Can he strip some of the chemotherapy agents [such as anthracyclines]?

[The patient] tried to shorten and then to remove different cytotoxic drugs with the idea that maybe over time he can develop a chemotherapy-free regimen. [Results of] the initial pilot study have shown this combination plus ibrutinib [Imbruvica] is producing high response rates. He still added chemotherapy later because he was worried that he may miss the possibility of curing the patient, but after initial feasibility, he is slowly stripping chemotherapy. We may get there one day.

What are the similarities and differences of loncastuximab tesirine and tafasitamab?

I think cross-study comparisons are usually difficult. I am very cautious always when comparing different study results because the patient population is not always the same. I happen to be involved with the FDA in different reviews and I do believe that the response rate is what tends to reflect the most activity and is less dependent on patient selection, though not completely.

The ORR of loncastuximab is [approximately] 50% or very close to that. The DOR appears to be a little bit shorter, but this could be due to patient selection, so it looks very encouraging. It has a little bit of a different adverse event [AE] profile. At this point it doesnt have as strong a follow-up as this study, so we dont know if the same very encouraging plateaus in responding patients will be seen with it.

Maybe its going to happen, but it is more of a traditional cytotoxic therapy that is directed like polatuzumab. It works more on the immune microenvironment in immune activation. There is this renaissance of CD19 targeting and for CAR T-cell therapies, all the approved products target CD19, and now loncastuximab and tafasitamab.

I usually tell the industry to not develop any more agents targeting CD19. We have enough. There are some other good targets, too. Some of the CAR T-cell therapies are targeting different molecules on the surface.

How many of these patients on the L-MIND trial stopped therapy early? What is the safety profile of combination lenalidomide and tafasitamab?

The primary reason for stopping therapy early was disease progression because some patients just didnt respond. The toxicities were primarily hematologic, which is consistent with what you would see with lenalidomide. Nonhematologic AEs [included] fatigue and diarrhea, but nothing striking or unusual. Discontinuation of combination [therapy due to] AEs was seen in 12% of the patients [n = 10/81].5

A comparison of the AEs of combination therapy vs monotherapy showed the hematologic and other toxicities were driven by lenalidomide. Tafasitamab alone had [an approximate] 27% ORR and when combined with lenalidomide the response rate doubles, so theres a true synergy between those drugs.

The monotherapies are quite well tolerated. Some patients can develop neutropenia, as was seen in the monotherapy trials, but overall the toxicity is minimal for the antibody alone.

What is the rapidity of the response for this regimen? Who wouldnt be eligible for it?

The first evaluation was done after 2 cycles of therapy, so within 8 weeks the response was right there. The response is quite brisk. If I had any concern about putting [a patient] on lenalidomide, it would be for reasons such as it can cause some rashes as seen previously with lenalidomide combinations, so with previous hypersensitivity, I probably would not [use it].

If patients have very rapidly progressive symptoms, I may stabilize them with radiation or some other treatment first, maybe hydroxysteroids, rituximab, or something such as that just to remove the disease burden before I start this combination. I expected that the responses would be dipping over time, but the responses were brisk and happened after 2 cycles of therapy.

REFERENCES

Excerpt from:
Nowakowski Considers CD19 Therapy in Transplant-Ineligible DLBCL - Targeted Oncology

5 questions facing gene therapy in 2022 – BioPharma Dive

Four years ago, a small Philadelphia biotech company won U.S. approval for the first gene therapy to treat an inherited disease, a landmark after decades of research aimed at finding ways to correct errors in DNA.

Since then, most of the world's largest pharmaceutical companies have invested in gene therapy, as well as cell therapies that rely on genetic modification. Dozens of new biotech companies have launched, while scientists have taken forward breakthroughs in gene editing science to open up new treatment possibilities.

But the confidence brought on by such advances has also been tempered by safety setbacks and clinical trial results that fell short of expectations. In 2022, the outlook for the field remains bright, but companies face critical questions that could shape whether, and how soon, new genetic medicines reach patients. Here are five:

Food and Drug Administration approval of Spark Therapeutics' blindness treatment Luxturna a first in the U.S. came in 2017. A year and a half later, Novartis' spinal muscular atrophy therapy Zolgensma won a landmark OK.

But none have reached market since, with treatments from BioMarin Pharmaceutical and Bluebird bio unexpectedly derailed or delayed.

That could change in 2022. Two of Bluebird's treatments, for the blood disease beta thalassemia and a rare brain disorder, are now under review by the FDA, with target decision dates in May and June. BioMarin, after obtaining more data for its hemophilia A gene therapy, plans to soon approach the FDA about resubmitting an application for approval.

Others, such as CSL Behring and PTC Therapeutics, are also currently planning to file their experimental gene therapies with the FDA in 2022.

Approvals, should they come, could provide important validation for their makers and expand the number of patients for whom genetic medicines are an option. In biotech, though, approvals aren't the end of the road, but rather the mark of a sometimes challenging transition from research to commercial operations. With price tags expected to be high, and still outstanding questions around safety and long-term benefit, new gene therapies may prove difficult to sell.

A record $20 billion flowed into gene and cell therapy developers in 2020, significantly eclipsing the previous high-water mark set in 2018.

Last year, the bar was set higher still, with a total of $23 billion invested in the sector, according to figures compiled by the Alliance for Regenerative Medicine. About half of that funding went toward gene therapy developers specifically, with a similar share going to cell-based immunotherapy makers.

Driving the jump was a sharp increase in the amount of venture funding, which rose 73% to total nearly $10 billion, per ARM. Initial public offerings also helped, with sixteen new startups raising at least $50 million on U.S. markets.

Entering 2022, the question facing the field is whether those record numbers will continue. Biotech as a whole slumped into the end of last year, with shares of many companies falling amid a broader investment pullback. Gene therapy developers, a number of which had notable safety concerns crop up over 2021, were hit particularly hard.

Moreover, many startups that jumped to public markets hadn't yet begun clinical trials roughly half of the 29 gene and cell therapy companies that IPO'd over the past two years were preclinical, according to data compiled by BioPharma Dive. That can set high expectations companies will be hard pressed to meet.

Generation Bio, for example, raised $200 million in June 2020 with a pipeline of preclinical gene therapies for rare diseases of the liver and eye. Unexpected findings in animal studies, however, sank company shares by nearly 60% last December.

Still, the pace of progress in gene and cell therapy is fast. The potential is vast, too, which could continue to support high levels of investment.

"I think fundamentally, investment in this sector is driven by scientific advances, and clinical events and milestones," said Janet Lambert, ARM's CEO, in an interview. "And I think we see those in 2022."

The potential of replacing or editing faulty genes has been clear for decades. How to do so safely has been much less certain, and concerns on that front have set back the field several times.

"Safety, safety and safety are the first three top-of-mind risks," said Luca Issi, an analyst at RBC Capital Markets, in an interview.

Researchers have spent years making the technology that underpins gene therapy safer and now have a much better understanding of the tools at their disposal. But as dozens of companies push into clinical trials, a number of them have run into safety problems that raise crucial questions for investigators.

In trials run by Audentes Therapeutics and by Pfizer (in separate diseases), study volunteers have tragically died for reasons that aren't fully understood. UniQure, Bluebird bio and, most recently, Allogene Therapeutics have reported cases of cancer or worrisome genetic abnormalities that triggered study halts and investigations.

While the treatments being tested were later cleared in the three latter cases, the FDA was sufficiently alarmed to convene a panel of outside experts to review potential safety risks last fall. (Bluebird recently disclosed a new hold in a study of its sickle cell gene therapy due to a patient developing chronic anemia.)

The meeting was welcomed by some in the industry, who hope to work with the FDA to better detail known risks and how to avoid them in testing.

"[There's] nothing better than getting people together and talking about your struggles, and having FDA participate in that," said Ken Mills, CEO of gene therapy developer Regenxbio, in an interview. "The biggest benefit probably is for the new and emerging teams and people and companies that are coming into this space."

Safety scares and setbacks are likely to happen again, as more companies launch additional clinical trials. The FDA, as the recent meeting and clinical holds have shown, appears to be carefully weighing the potential risks to patients.

But, notably, there hasn't been a pullback from pursuing further research, as has happened in the past. Different technologies and diseases present different risks, which regulators, companies and the patient community are recognizing.

"We're by definition pushing the scientific envelope, and patients that we seek to treat often have few or no other treatment options," said ARM's Lambert.

Last June, Intellia Therapeutics disclosed early results from a study that offered the first clinical evidence CRISPR gene editing could be done safely and effectively inside the body.

The data were a major milestone for a technology that's dramatically expanded the possibility for editing DNA to treat disease. But the first glimpse left many important questions unanswered, not least of which are how long the reported effects might last and whether they'll drive the kind of dramatic clinical benefit gene editing promises.

Intellia is set to give an update on the study this quarter, which will start to give a better sense of how patients are faring. Later in the year the company is expecting to have preliminary data from an early study of another "in vivo" gene editing treatment.

In vivo gene editing is seen as a simpler approach that could work in more diseases than treatments that rely on stem cells extracted from each patient. But it's also potentially riskier, with the editing of DNA taking place inside the body rather than in a laboratory.

Areas like the eye, which is protected from some of the body's immune responses, have been a common first in vivo target by companies like Editas Medicine. But Intellia and others are targeting other tissues like the liver, muscle and lungs.

Later this year, Verve Therapeutics, a company that uses a more precise form of gene editing called base editing, plans to treat the first patient with an in vivo treatment for heart disease (which targets a gene expressed in the liver.)

"The future of gene editing is in vivo," said RBC's Issi. His view seems to be shared by Pfizer, which on Monday announced a $300 million research deal with Beam Therapeutics to pursue in vivo gene editing targets in the liver, muscle and central nervous system.

With more and more cell and gene therapy companies launching, the pipeline of would-be therapies has grown rapidly, as has the number of clinical trials being launched.

Yet, many companies are exploring similar approaches for the same diseases, resulting in drug pipelines that mirror each other. A September 2021 report from investment bank Piper Sandler found 21 gene therapy programs aimed at hemophilia A, 19 targeting Duchenne muscular dystrophy and 18 going after sickle cell disease.

In gene editing, Intellia, Editas, Beam and CRISPR Therapeutics are all developing treatments for sickle cell disease, with CRISPR the furthest along.

As programs advance and begin to deliver more clinical data, companies may be forced into making hard choices.

"[W]e think investors will place greater scrutiny as programs enter the clinic and certain rare diseases are disproportionately pursued," analysts at Stifel wrote in a recent note to investors, citing Fabry disease and hemophilia in particular.

This January, for example, Cambridge, Massachusetts-based Avrobio stopped work on a treatment for Fabry that was, until that point, the company's lead candidate. The decision was triggered by unexpected findings that looked different than earlier study results, but Avrobio also cited "multiple challenging regulatory and market dynamics."

Continue reading here:
5 questions facing gene therapy in 2022 - BioPharma Dive

What it’s like in academic family medicine: Shadowing Dr. Rouhbakhsh – American Medical Association

As a medical student, do you ever wonder what its like to specialize in academic family medicine? Meet AMA member Rambod A. Rouhbakhsh, MD, a featured academic family physician in the AMAsShadow Me Specialty Series, which offers advice directly from physicians about life in their specialties. Check out his insights to help determine whether a career in academic family medicine and preventive medicine might be a good fit for you.

The AMAsSpecialty Guidesimplifies medical students specialty selection process, highlight major specialties, detail training information, and provide access to related association information. It is produced byFREIDA, the AMA Residency & Fellowship Database.

Learn more with the AMA about family medicine and preventive medicine.

Shadowing Dr. Rouhbakhsh

Specialty: Family medicine; occupational and environmental medicine.

Practice setting: Academic family medicine residency; clinical research.

Years in practice:17.

A typical day and week in my practice: My days are split into discreet roles. Mondays are my teaching days. Tuesdays are recruitment and admin days. Wednesdays are program and institutional development days. Thursdays and Fridays are my clinical research days.

My day typically starts with a morning report at 7:30 a.m. and formally ends at 5 p.m. Informally, I find most of my meaningful work is done after hours. Now that I am in a leadership position, I rarely find quiet time to actually create a work product. As such, I tend to be most productive during my boys soccer practice when I can sit in my car and work on the computer.

How the year unfolds in my practice: When I began my career in academic family medicine, I started as clinical faculty, so my work revolved primarily around teaching residents in clinic. Now, as the program director, I spend more time doing administrative work, which translates to meetings, recruiting new residents, and developing faculty.

The year for us begins in July when we welcome our new residents. The interns spend much of July in orientation, during which we help them transition from medical student to resident physician. We organize orientation activities, compose introductory didactics, and help ease our interns into their new jobs. Also in July, we transition our new PGY-2 residents to senior residents who take on teaching and supervisory responsibilities for our new interns.

In August, we start prepping for recruitment season, which officially kicks off when we receive ERAS applications in September. We also tend to do outreach talks to our local medical schools in August and September. From early October through December, we interview prospective students and find matches for our residency program. We receive thousands of applications from medical students, but we only offer interviews to 60 applicants. To arrive at that point, we spend a significant portion of September reading applications.

October through December is dominated by the actual interviews. In pre-COVID times, these were more festive events with dinners and lunches. Now that they are virtual, it is less time-consuming, but also less fun. Throughout the fall and winter, we focus on our graduating PGY-3 residents to make sure they have met their requirements and assist them in finding jobs.

In January, faculty have more time to meet, and this is when we do cumulative evaluations of our residents and engage in program enhancement activities. We typically elect a chief resident for the upcoming year during this time. January through March is also when we spend extra time on research and academic projects.

Then in March we get our Match list. We welcome our incoming residents and start prepping them for orientation in July. Most of our focus in the spring is on our graduating senior residents. We organize wellness activities and plan for graduation. We also do our year-end cumulative evaluations for residents, faculty, and the program itself in late spring.

Interspersed throughout the academic year, we teach in clinic, in hospital, and during didactics. There are also myriad committee meetings and ad-hoc opportunities and issues that arise. For instance, new research collaborations frequently occur since we are literally across the street from the University of Southern Mississippi and across town from William Carey University. These opportunities are exciting, but sometimes they stretch our bandwidth.

The most challenging and rewarding aspects of academic family medicine: Teaching is fantastic, especially teaching residents. These young doctors are on the top tier of the education hierarchy. They are typically the smartest people I know, and I feel privileged to help them attain their post-graduate training. These are intelligent, motivated people who approach education with vigor and enthusiasm.

They are also inquisitive enough to challenge and grow my personal fund of knowledge. If there is something that we dont know collectively, residents will research it and come back to teach the entire group. These are high-powered education machines who can accomplish seemingly anything they put their minds to.

Academic family medicine is exceedingly rewarding, not just because it involves teaching, but because academic family medicine can be situated in community-based hospitals, allowing you greater flexibility to live where you wish. For example, if I had wanted to do academic neurosurgery or cardiology, I would have to be in the one medical school in Mississippi which is in Jackson.

Community-based family medicine residency programs are the bulk of academic family medicine. I am truly grateful for that because it allows me to live in a great place like Hattiesburg and not necessarily in a metropolitan area. Teaching is a remarkable joy, and I would encourage anyone who enjoys that to consider academic family medicine.

How life in academic family medicine has been affected by the global pandemic: Some of the societal effects of the pandemic have actually helped us. Being able to conduct virtual interviews with our program applicants has allowed us to draw more people and has provided us the opportunity to do more interviews in a less time-intensive and less costly way.

For example, we interviewed a woman from Ohio last year, and Im quite certain she wouldnt have flown to Mississippi for the interview. And she ended up being a match for our program, which has been fantastic for us. Also, we are now telemedicine-savvy practitioners, which is here to stay. Lastly, it has forced us to become better epidemiologists, virologists, and occupational hygienists.

How my lifestyle matches, or differs from, what I had envisioned: My life today is very different than my days as a clinical doctor. The hours are about the same, but the pace is different. My work is cognitively more challenging in academics, but it is less intense. When I was in clinic every day, I felt a rush of intensity that for me was requisite to be an efficient clinician. I dont feel that as often now. As a clinic doctor, I felt like a sprinter. Now, I feel a bit more like a marathon runnerespecially during meeting-heavy days.

Additionally, I do clinical research and run clinical trials for three half-days per week. As the principal investigator, I supervise sub-investigators, review charts, and see our trial patients. We have several ongoing trials, including COVID-19 vaccine trials, a meningococcal vaccine trial, a hypertension medication trial, a diabetes medication trial, and a pediatric migraine trial. Keeping all the protocols straight can be challenging, but it is not as intensive as a typical family medicine clinic day.

Books every medical student interested in family medicine should be reading:

The online resource students interested in family medicine should follow: My number one recommendation is UpToDate. It is the most comprehensive reference source I know of. I also suggest students sign up for recurring news that is delivered to their inbox regularly. My favorites are the New England Journal of Medicines Journal Watch, the AMAs Morning Rounds Daily, and the American Academy of Family Physicians Family Medicine Smart Brief.

Quick insights I would give students who are considering family medicine: The gift of family medicineand the curse to a degreeis its flexibility and its breadth. It can be daunting to feel like you havent mastered one aspect of the specialty. However, it is an evergreen challenge and provides enormous opportunities. It led me to preventive and occupational medicine and ultimately to academic family medicine. Family medicine is like a pluripotent stem cellit has limitless potential.

In family medicine, you can become whatever you want to become. It gives you sufficient background to discover your passions, which sometimes may be being a true generalist and having your hand in everything all the time. In that way, this specialty is extremely rewarding because it gives you the most tools to take care of the largest group of people in the most practical way.

When the pandemic broke out, my background in family medicine allowed me to dig deep into studying COVID-19. Again, its this type of training that allows you to go down these pathways with relative ease because you are so broadly trained.

Mantra or song to describe life in family medicine: At the beginning of my career, I would have to say Hustlin, by Rick Ross. Now, in midcareer, I cant think of a song. But I do have a mantra. I try to remind myself of the wisdom of impermanence: Everything changes.

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What it's like in academic family medicine: Shadowing Dr. Rouhbakhsh - American Medical Association

How Abu Dhabi’s ADQ is creating the UAE’s largest healthcare platform – Mobihealth News

Abu Dhabis ADQ has kicked off the new year with one of its biggest healthcare mergers yet.

The asset owner and investor considered one of the GCCs largest holding companies has announced that it has entered into an agreement to consolidate several companies within Pure Health, a UAE-based integrated healthcare solutions provider.

Companies set to become part of Pure Health include Abu Dhabi Health Services Company (SEHA), the National Health Insurance Company PJSC better known as Daman Tamouh Healthcare, Yas Clinic Group, and Abu Dhabi Stem Cell Center.

The merger which is subject to customary closing conditions, including regulatory approvals, ADQ confirmed will reportedly result in creating the largest healthcare provider in the UAE.

Pure Health will be instrumental in transforming the provision of healthcare as we consolidate several companies into the platform, said H.E. Mohamed Hassan Alsuwaidi, CEO of ADQ. We are further driving efficiencies to establish the UAEs largest healthcare network, underpinned by clinical excellence, through elevated services, optimised healthcare spend[ing], and improved efficiencies across the value chain.

Combining the strength of clinical powerhouses and the UAEs leading health insurer will develop a scalable healthcare platform for growth.

THE LARGER CONTEXT

Established in 2018, ADQs portfolio includes businesses in healthcare and pharma, energy and utilities, food and agriculture, and mobility and logistics.

Pure Health, meanwhile, offers a diversified services portfolio that comprises healthcare informatics, hospital management, laboratory services including COVID-19 PCR testing and medical supplies.

Following completion of this merger, ADQ will become the largest shareholder in Pure Health. The companys other shareholders are Alpha Dhabi Holding, International Holding Company (IHC), AH Capital and Ataa Financial Investments.

WHY IT MATTERS

Offering the largest integrated healthcare ecosystem means that Pure Health will significantly contribute to the UAEs healthcare landscape and deliver on the countrys mission to elevate the health and wellbeing of citizens and residents, ADQ said in a statement. Patients will benefit from access to greater clinical expertise and healthcare services across the spectrum of care.

In March of last year, ADQ transferred ownership of its healthcare support service entities Rafed and Union71 to Pure Health.

ON THE RECORD

Pure Health remains committed to delivering convenient, accessible, and transparent healthcare as we become the largest integrated healthcare services platform in the UAE, said Farhan Malik, CEO and Managing Director of Pure Health. We believe that healthcare is too important to remain the same.

Our north star is to enable greater longevity of humankind, and we will constantly work towards a healthier and longer life for the people of UAE.

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How Abu Dhabi's ADQ is creating the UAE's largest healthcare platform - Mobihealth News

Exclusive: Ronnie Coleman on Recent Weight Gain, Current Strength, and Health Progress – BarBend

Fans of bodybuilding are familiar with the health struggles that have plagued eight-time Mr. Olympia Ronnie Coleman in recent years. Coleman has endured over a dozen surgeries to his neck and back and, as a result, walks with crutches. Through it all, Coleman maintains a positive spirit and remains optimistic thanks in part to two stem cell treatments, which are starting to pay off.

Coleman joined co-host Giles Thomas in a recent episode of the Aint Nothing but a Podcast show. In the video, released on Dec. 29, 2021, Coleman says that hes beginning to feel like his old self again, and his weight gain reflects his health improvements.

Sporting a Ronnie Coleman Signature Series shirt that showed off his noticeable arm improvement, the Texas native his home revealed that hes back up to 285 pounds. And if youre having trouble believing that Coleman weighs close to what he did in his competitive prime, youre not alone.

I weighed myself five times on the scale downstairs, and I thought maybe its because Im downstairs,' Coleman said on the podcast episode. I was freaking out, so I went upstairs, and [that scale] was the same. I was like wow.'

BarBend reached out to the 2016 International Sports Hall of Fame inductee directly to follow up on what he revealed on his podcast. Coleman was happy to share more about his progress, including what he considers the best improvement of all the return of his signature leg size.

Thats the thing Im most proud of, Coleman tells BarBend. My legs had atrophied a whole lot since 2016 when I went in and had my first surgery 2017, same thing, 2018, 2019, 2020, same thing. I was just about to give up on it, you know. Then, suddenly, about four months ago, I started feeling a pump in my legs. And then I noticed the size had come back, and the atrophy was gone. I was geeked!

The man considered the most legendary bodybuilder of all time wasnt just known for being big. His freakish feats of strength including an 800-pound back squat and deadlift only added to the mystique he brought to the stage.

While Coleman isnt going to be moving that kind of weight anytime soon, hes been more active on social media, sharing training clips, such as the one below in which he performed a set of leg extensions on Dec. 12, 2021.

Coleman isnt leg-pressing 2,300 pounds as he did in his prime, but he is throwing more 45s on the machine nowadays than during his recovery.

Im back up to doing five plates, one each side, up from three per side a few months ago, Coleman says.

The eight-time Mr. Olympias improvements arent exclusively in the lower body. Coleman shared that hes getting stronger on numerous lifts in the gym. For example, Coleman is moving weight, performing 20 reps of rear lateral raises. The new size is evident, and his trademark smile was on full display during the set (see below).

My strength has come up a whole lot. Im going to say that its up about 40 percent.

He used the flat dumbbell press as another example, saying that he is now working with 70-pound dumbbells for his sets of 20 reps, which he does for every lift. He is training six days a week, as he did during his reign as the number one bodybuilder on the planet.

Returning leg strength is undoubtedly a strong sign that Colemans physical health is improving. That said, the former police officer mentions that itll still be a while before hes able to ditch the crutches.

My feet are still numb, and my quads are still numb, but theyre not quite as numb. I can start to feel them a little bit, he says. Once Im able to relieve this numbness, I will stand a much better chance of balancing myself.

Coleman says that the stem cell specialist told him that nerve regeneration takes about two years. As Coleman explains on the podcast, the specialists claim was verified when the numbness in his neck went away after two years, almost to the day. Coleman is confident that the same will happen with his lower extremities.

I thought about what the doctor said, and he was right. Thats what Im looking at now. It will be about two years before I get my full mobility and balance back. Then I can work on walking unassisted.

With his most recent stem cell treatment having taken place on Dec. 27, 2021, Coleman is optimistic that hell keep on progressing. This positive news caps off a good year overall for the 57-year-old icon.

In September, he was honored with the Arnold Classic Lifetime Achievement award by fellow Mr. Olympia Arnold Schwarzenegger. As great as that honor was, hes even more excited to get back out to events and meet fans now that he is in better shape and spirits I cant wait!

Featured Image: @ronniecoleman8 on Instagram

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Exclusive: Ronnie Coleman on Recent Weight Gain, Current Strength, and Health Progress - BarBend