Phantom Limb Pain Management.

With an estimated 2 million major limb amputees and projections reaching 3.6 million by 2050, the increasing prevalence of limb loss in the United States underscores the importance of addressing complications associated with limb loss. Phantom limb pain (PLP) is a common and often chronic condition affecting 40% to 80% of amputees. The heterogeneous pathology of PLP encompasses cortical, spinal, and peripheral mechanisms that present a challenge to providing effective treatments. The spectrum of available treatments spans pharmacologic interventions, noninvasive modalities like mirror therapy, and surgical techniques. A review of the current body of evidence on the treatment of PLP favors novel methods of surgical management. Nonetheless, a majority of literature pushes for the evaluation of other methods of ameliorating PLP as imperative to offering patient-centered options that address the myriad of etiologies that contribute to this pathology. More extensive research, especially randomized controlled trials, is needed to establish the long-term efficacy of interventions, compare the impact of different treatments, and identify which modalities are most effective in various patient populations.

Body Mass Index Improvement Reduces Total Knee Arthroplasty Complications Among Patients Who Have Extreme, but Not Severe, Obesity.

BACKGROUND: While morbid obesity has been associated with increased complication risk in primary total knee arthroplasty (TKA), limited evidence is available to attribute decreased surgical complication rates with body mass index (BMI) reduction. METHODS: We retrospectively assessed 464 unilateral TKAs performed in morbidly obese patients, including 158 extremely obese (BMI ≥ 45) and 306 severely obese patients (BMI 40 to 44.9). A detailed medical record review identified concurrent modifiable risk factors and successful preoperative BMI reduction, reaching either a contemporary risk target (BMI < 40) or an institutionally accepted threshold (BMI < 45). Postoperative blood glucose levels and 1-year adverse outcomes (periprosthetic joint infection, wound dehiscence, knee manipulation, periprosthetic fracture) were compared to 557 contemporary control subjects with expected slightly lower (moderate obesity, BMI 35 to 39.9) or sufficiently lower complication risk (overweight, BMI 25 to 29.9). RESULTS: Periprosthetic joint infection and postoperative hyperglycemia were identified more frequently among morbidly obese patients in comparison with a moderately obese control group. Extremely obese patients (BMI ≥ 45) whose BMI improved below 45 had no measurable difference in infection risk from the control group (odds ratio [OR] 0.84, 95% confidence interval [CI] 0.04 to 16.88), while those with a nonimproved BMI had a significantly higher risk (OR 7.70, 95% CI 1.89 to 31.41). No significant differences in the risk for infection were observed between severely obese patients (BMI 40 to 44.9) with preoperative BMI improvement (1.5% rate, OR 1.70, 95% CI 0.17 to 16.57) or nonimprovement (1.7% rate, OR 1.87, 95% CI 0.41 to 8.43). CONCLUSIONS: Preoperative medical optimization may decrease postoperative TKA complications. The findings of this study support BMI improvement for extremely obese patients (BMI ≥ 45). The assignment of 40 BMI as a threshold for otherwise healthy patients may exclude patients from potential surgical benefits without realizing risk reduction.

Acceptability of HIV Prevention Approaches Among USA Faith-Based Leaders.

HIV/AIDS disproportionately impacts underserved communities in the USA. This study evaluated the acceptability of partnering with faith communities to improve HIV prevention, screening, and engagement in care with a focus on Hispanic/Latinx (H/L) communities. We engaged faith-based leaders to identify how the cultural competence and foundations of trust within these communities may be leveraged to improve HIV-related healthcare access for underserved groups including H/L individuals. Using a semi-structured qualitative interview approach, we interviewed N = 20 faith-based leaders in Providence County, Rhode Island (RI). Data were analyzed using the framework approach which utilized inductive generation of themes and systematic grouping into predetermined categories. Seven of the 20 interviewees self-identified as H/L faith leaders and discussed needs specific to H/L communities including destigmatization of HIV, increased access to care, and partnerships founded on mutual respect. The other 13 faith leaders did not personally identify as H/L but all served communities with significant H/L populations. We included these individuals given their communities already performed HIV and/or other health outreach and could provide insight into what approaches could be adapted to the needs expressed by H/L leaders. All interviewees were accepting of developing partnerships with outside organizations to engage in HIV prevention, and all identified potential solutions to identified barriers. Results suggested that faith-based outreach should be further investigated as a method of improving HIV prevention in the general and H/L populations.

The Physiologic Basis of Molecular Therapeutics for Peripheral Nerve Injury: A Primer.

Peripheral nerve injuries affect a significant number of patients who experience trauma affecting the hand and upper extremity. Improving unsatisfactory outcomes from repair of these injuries remains a clinical challenge despite advancements in microsurgical repair. Imperfections of the nerve regeneration process, including imprecise reinnervation, distal axon degradation, and muscular atrophy, complicate the repair process. However, the capacity for peripheral nerves to regenerate offers an avenue for therapeutic advancement. Regeneration is a temporally and spatially dynamic process coordinated by Schwann cells and neurons among other cell types. Neurotrophic factors are a primary means of controlling cell growth and differentiation in the repair setting. Sustained axon survival and regrowth and consequently functional outcomes of nerve repair in animal models are improved by the administration of neurotrophic factors, including glial cell-derived neurotrophic factor, nerve growth factor, sterile alpha and TIR motif containing 1, and erythropoietin. Targeted and sustained delivery of neurotrophic factors through gelatin-based nerve conduits, multiluminal conduits, and hydrogels have been shown to enhance the innate roles of these factors to promote expedient and accurate peripheral nerve regeneration in animal models. These delivery methods may help address the practical limitations to clinical use of neurotrophic factors, including systemic side effects and the need for carefully timed, precisely localized release schedules. In addition, tacrolimus has also improved peripheral nerve regrowth in animal models and has recently shown promise in addressing human disease. Ultimately, this realm of adjunct pharmacotherapies provides ample promise to improve patient outcomes and advance the field of peripheral nerve repair.

Oxysterol derivatives Oxy186 and Oxy210 inhibit WNT signaling in non-small cell lung cancer.

BACKGROUND: Developmental signaling pathways such as those of Hedgehog (HH) and WNT play critical roles in cancer stem cell self-renewal, migration, and differentiation. They are often constitutively activated in many human malignancies, including non-small cell lung cancer (NSCLC). Previously, we reported that two oxysterol derivatives, Oxy186 and Oxy210, are potent inhibitors of HH/GLI signaling and NSCLC cancer cell growth. In addition, we also showed that Oxy210 is a potent inhibitor of TGF-ß/SMAD signaling. In this follow-up study, we further explore the mechanism of action by which these oxysterols control NSCLC cell proliferation and tumor growth. RESULTS: Using a GLI-responsive luciferase reporter assay, we show here that HH ligand could not mount a signaling response in the NSCLC cell line A549, even though Oxy186 and Oxy210 still inhibited non-canonical GLI activity and suppressed the proliferation of A549 cells. Further, we uncover an unexpected activity of these two oxysterols in inhibiting the WNT/ß-catenin signaling at the level of LRP5/6 membrane receptors. We also show that in a subcutaneous xenograft tumor model generated from A549 cells, Oxy186, but not Oxy210, exhibits strong inhibition of tumor growth. Subsequent RNA-seq analysis of the xenograft tumor tissue reveal that the WNT/ß-catenin pathway is the target of Oxy186 in vivo. CONCLUSION: The oxysterols Oxy186 and Oxy210 both possess inhibitory activity towards WNT/ß-catenin signaling, and Oxy186 is also a potent inhibitor of NSCLC tumor growth.