Effects of Release of TSG-6 from Heparin Hydrogels on Supraspinatus Muscle Regeneration.

Muscle degeneration after rotator cuff tendon tear is a significant clinical problem. In these experiments, we developed a poly(ethylene glycol)-based injectable granular hydrogel containing two heparin derivatives (fully sulfated (Hep) and fully desulfated (Hep-)) as well as a matrix metalloproteinase-sensitive peptide to promote sustained release of Tumor Necrosis Factor Stimulated Gene 6 (TSG-6) over 14+ days in vivo in a rat model of rotator cuff muscle injury. The hydrogel formulations demonstrated similar release profiles in vivo , thus facilitating comparisons between delivery from heparin derivatives on level of tissue repair in two different areas of muscle (near the myotendious junction (MTJ) and in the muscle belly (MB)) that have been shown previously to have differing responses to rotator cuff tendon injury. We hypothesized that sustained delivery of TSG-6 would enhance the anti-inflammatory response following rotator cuff injury through macrophage polarization, and that release from a fully sulfated heparin derivative (Hep) would potentiate this effect throughout the muscle. Inflammatory/immune cells, satellite cells, and fibroadipogenic progenitor cells, were analyzed by flow cytometery 3 and 7 days after injury and hydrogel injection, while metrics of muscle healing were examined via immunohistochemistry up to Day 14. Results showed controlled delivery of TSG-6 from Hep caused heightened macrophage response (Day 14 macrophages, 4.00 ± 1.85% single cells, M2a, 3.27 ± 1.95% single cells) and increased markers of early muscle regeneration (embryonic heavy chain staining) by Day 7, particularly in the MTJ region of the muscle, compared to release from desulfated heparin hydrogels. This work provides a novel strategy for localized, controlled delivery of TSG-6 to enhance muscle healing after rotator cuff tear. IMPACT STATEMENT: Rotator cuff tear is a significant problem that can cause muscle degeneration. In this study, a hydrogel particle system was developed for sustained release of an anti-inflammatory protein, Tumor Necrosis Factor Stimulated Gene 6 (TSG-6), to injured muscle. Release of the protein from a fully sulfated heparin hydrogel-based carrier demonstrated greater changes in amount inflammatory cells and more early regenerative effects than a less-sulfated carrier. Thus, this work provides a novel strategy for localized, controlled delivery of an anti-inflammatory protein to enhance muscle healing after rotator cuff tear.

Results and lessons learnt from the WISTERIA phase I trial combining AZD1775 with cisplatin pre- or post-operatively in head and neck cancer.

Background: Pre-clinical studies suggest AZD1775, a WEE1 kinase inhibitor, potentiates the activity of various chemotherapeutic agents. Methods: WISTERIA was a prospective, parallel two-group, open-label, dose-finding, phase I clinical trial. Eligible patients had histologically confirmed oral, laryngeal, or hypopharyngeal squamous cell carcinoma, ECOG performance status 0/1, and aged ≥18-to-≤70 years. Primary outcomes were adverse events and defining recommended dose and schedule of AZD1775 in combination with cisplatin in pre-operative (Group A), or with cisplatin/radiotherapy in post-operative (Group B) patients. Dose determination was guided by a modified time-to-event continual reassessment method (mTITE-CRM). Results: Between 30-Oct-2017 and 15-Jul-2019, nine patients were registered: Three into Group A and six into Group B. WISTERIA was closed early due to poor recruitment. Five dose-limiting toxicities (DLTs) were reported in four Group B patients. Seven serious adverse events were reported in four patients: One in Group A, and three in Group B. Three were related to treatment. No treatment-related deaths were reported. Conclusions: WISTERIA did not complete its primary objectives due to poor recruitment and toxicities reported in Group B. However, use of the novel mTITE-CRM improved flexibility in reducing accrual suspension periods and should be considered for future trials in complex patient populations. Clinical Trial Registration: ISRCTN76291951.

Immunosuppressant therapy averts rejection of allogeneic FKBP1A-disrupted CAR-T cells.

Chimeric antigen receptor (CAR) T cells from allogeneic donors promise "off-the-shelf" availability by overcoming challenges associated with autologous cell manufacturing. However, recipient immunologic rejection of allogeneic CAR-T cells may decrease their in vivo lifespan and limit treatment efficacy. Here, we demonstrate that the immunosuppressants rapamycin and tacrolimus effectively mitigate allorejection of HLA-mismatched CAR-T cells in immunocompetent humanized mice, extending their in vivo persistence to that of syngeneic humanized mouse-derived CAR-T cells. In turn, genetic knockout (KO) of FKBP prolyl isomerase 1A (FKBP1A), which encodes a protein targeted by both drugs, was necessary to confer CD19-specific CAR-T cells (19CAR) robust functional resistance to these immunosuppressants. FKBP1AKO 19CAR-T cells maintained potent in vitro functional profiles and controlled in vivo tumor progression similarly to untreated 19CAR-T cells. Moreover, immunosuppressant treatment averted in vivo allorejection permitting FKBP1AKO 19CAR-T cell-driven B cell aplasia. Thus, we demonstrate that genome engineering enables immunosuppressant treatment to improve the therapeutic potential of universal donor-derived CAR-T cells.

The Anabolic Response to a Ground Beef Patty and Soy-Based Meat Alternative: A Randomized Controlled Trial.

BACKGROUND: Soy-based meat alternatives (SBMA) are becoming increasingly popular, but it is unclear if they have the same anabolic effect on skeletal muscle as animal meat. OBJECTIVE: We aimed to compare the stimulation of skeletal muscle protein synthesis by consumption of one or two 4 oz patties of SBMA with 4 oz (80%protein/20%fat) beef. METHODS: The study design was a randomized controlled trial. Participants were aged 18 to 40 years of age and in good general health with a BMI between 20 and 32 kg/m2. Stable isotope tracer methods were used (L-[ring-2H5] phenylalanine, [U-13C9-15N]- tyrosine and L-[ring-2H4] tyrosine) to quantify the response of muscle protein fractional synthetic rate to consumption of a single beef (4 oz), single SBMA (4 oz), or two 4 oz SBMA patties (8 oz). Whole-body rates of protein synthesis, breakdown and net balance, as well as plasma essential amino acid (EAA) concentrations, were also measured. RESULTS: The increase above basal in muscle protein FSR following consumption of the 4 oz beef patty (0.020 ± 0.016%/hour) was significantly greater than the increase following consumption of 4 oz SBMA (p = 0.021; 0.003 ± 0.010%/hour) but not 8 oz SBMA (p = 0.454; 0.013 ± 0.016%/hour). The maximal EAA concentration was significantly correlated (p = 0.046; r = 0.411) with the change in muscle FSR from the basal to postprandial period. In addition, the change in muscle FSR from the basal to postprandial period was significantly correlated (p = 0.046; r = 0.412) with the corresponding change in whole-body protein synthesis. CONCLUSION: Consumption of a 4 oz beef patty stimulates muscle and whole -body protein synthesis more than a 4 oz SBMA patty and similarly to 8 oz of SBMA. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT05197140.

Echoes of Concern-AI and Moral Agency in Medicine.

This essay describes concerns that use of artificial intelligence (AI) as a replacement rather than a supplement in the provision of medical care may lead to loss of the art of medicine and the collaborative partnership between physician and patient.

A Comparison of Throwing Arm Kinetics and Ball Velocity in High School Pitchers With Overall Fast and Overall Slow Cumulative Joint and Segment Velocities.

BACKGROUND: Individual maximum joint and segment angular velocities have shown positive associations with throwing arm kinetics and ball velocity in baseball pitchers. PURPOSE: To observe how cumulative maximum joint and segment angular velocities, irrespective of sequence, affect ball velocity and throwing arm kinetics in high school pitchers. STUDY DESIGN: Descriptive laboratory study. METHODS: High school (n = 55) pitchers threw 8 to 12 fastball pitches while being evaluated with 3-dimensional motion capture (480 Hz). Maximum joint and segment angular velocities (lead knee extension, pelvis rotation, trunk rotation, shoulder internal rotation, and forearm pronation) were calculated for each pitcher. Pitchers were classified as overall fast, overall slow, or high velocity for each joint or segment velocity subcategory, or as population, with any pitcher eligible to be included in multiple subcategories. Kinematic and kinetic parameters were compared among the various subgroups using t tests with post hoc regressions and multivariable regression models created to predict throwing arm kinetics and ball velocity, respectively. RESULTS: The lead knee extension and pelvis rotation velocity subgroups achieved significantly higher normalized elbow varus torque (P = .016) and elbow flexion torque (P = .018) compared with population, with equivalent ball velocity (P = .118). For every 1-SD increase in maximum pelvis rotation velocity (87 deg/s), the normalized elbow distractive force increased by 4.7% body weight (BW) (B = 0.054; ß = 0.290; P = .013). The overall fast group was older (mean ± standard deviation, 16.9 ± 1.4 vs 15.4 ± 0.9 years; P = .007), had 8.9-mph faster ball velocity (32.7 ± 3.1 vs 28.7 ± 2.3 m/s; P = .002), and had significantly higher shoulder internal rotation torque (63.1 ± 17.4 vs 43.6 ± 12.0 Nm; P = .005), elbow varus torque (61.8 ± 16.4 vs 41.6 ± 11.4 Nm; P = .002), and elbow flexion torque (46.4 ± 12.0 vs 29.5 ± 6.8 Nm; P < .001) compared with the overall slow group. A multiregression model for ball velocity based on maximum joint and segment angular velocities and anthropometrics predicted 53.0% of variance. CONCLUSION: High school pitchers with higher maximum joint and segment velocities, irrespective of sequence, demonstrated older age and faster ball velocity at the cost of increased throwing shoulder and elbow kinetics. CLINICAL RELEVANCE: Pitchers and coaching staff should consider this trade-off between faster ball velocity and increasing throwing arm kinetics, an established risk factor for elbow injury.

Do e-cigarette retail licensure laws reduce youth tobacco use?

E-cigarette licensure laws (ELLs) require retailers to obtain a state license to sell e-cigarettes over the counter. This study is the first to comprehensively explore the effect of ELL adoption on youth tobacco product use. Using data from the State Youth Risk Behavior Survey (YRBS) and a difference-in-differences approach, we find no evidence that ELL adoption reduces youth ENDS use. The precision of our estimates allows us to rule out, with 95 % confidence, ELL-induced declines in prior-month, frequent, and everyday youth ENDS use of more than 0.7, 0.3, and 0.4 percentage points, respectively. The pattern of null findings persists when we examine ELLs that impose higher penalties for retailer non-compliance, higher renewable licensure fees, and criminal in addition to civil penalties. We conclude that ELLs have only limited success in curbing access to ENDS among youths.

The islet tissue plasminogen activator/plasmin system is upregulated with human islet amyloid polypeptide aggregation and protects beta cells from aggregation-induced toxicity.

AIMS/HYPOTHESIS: Apart from its fibrinolytic activity, the tissue plasminogen activator (tPA)/plasmin system has been reported to cleave the peptide amyloid beta, attenuating brain amyloid deposition in Alzheimer's disease. As aggregation of human islet amyloid polypeptide (hIAPP) is toxic to beta cells, we sought to determine whether activation of the fibrinolytic system can also reduce islet amyloid deposition and its cytotoxic effects, which are both observed in type 2 diabetes. METHODS: The expression of Plat (encoding tPA) and plasmin activity were measured in isolated islets from amyloid-prone hIAPP transgenic mice or non-transgenic control islets expressing non-amyloidogenic mouse islet amyloid polypeptide cultured in the absence or presence of the amyloid inhibitor Congo Red. Plat expression was also determined in hIAPP-treated primary islet endothelial cells, bone marrow-derived macrophages (BMDM) and INS-1 cells, in order to determine the islet cell type(s) producing tPA in response to hIAPP aggregation. Cell-free thioflavin-T assays and MS were used to respectively monitor hIAPP aggregation kinetics and investigate plasmin cleavage of hIAPP. Cell viability was assessed in INS-1 beta cells treated with hIAPP with or without plasmin. Finally, to confirm the findings in human samples, PLAT expression was measured in freshly isolated islets from donors with and without type 2 diabetes. RESULTS: In isolated islets from transgenic mice, islet Plat expression and plasmin activity increased significantly with the process of amyloid deposition (p≤0.01, n=5); these effects were not observed in islets from non-transgenic mice and were blocked by Congo Red (p≤0.01, n=4). In response to hIAPP exposure, Plat expression increased in BMDM and INS-1 cells vs vehicle-treated cells (p≤0.05, n=4), but not in islet endothelial cells. Plasmin reduced hIAPP fibril formation in a dose-dependent manner in a cell-free system, and restored hIAPP-induced loss of cell viability in INS-1 beta cells (p≤0.01, n=5). Plasmin cleaved monomeric hIAPP, inducing a rapid decrease in the abundance of full-length hIAPP and the appearance of hIAPP 1-11 and 12-37 fragments. hIAPP 12-37, which contains the critical amyloidogenic region, was not toxic to INS-1 cells. Finally, PLAT expression was significantly increased by 2.4-fold in islets from donors with type 2 diabetes (n=4) vs islets from donors without type 2 diabetes (n=7) (p≤0.05). CONCLUSIONS/INTERPRETATION: The fibrinolytic system is upregulated in islets with hIAPP aggregation. Plasmin rapidly degrades hIAPP, limiting its aggregation into amyloid and thus protecting beta cells from hIAPP-induced toxicity. Thus, increasing islet plasmin activity might be a strategy to limit beta cell loss in type 2 diabetes.

Post-acute COVID-19 outcomes including participant-reported long COVID: amubarvimab/romlusevimab versus placebo in the ACTIV-2 trial.

Background: It is unknown if early COVID-19 monoclonal antibody (mAb) therapy can reduce risk of Long COVID. The mAbs amubarvimab/romlusevimab were previously demonstrated to reduce risk of hospitalization/death by 79%. This study assessed the impact of amubarvimab/romlusevimab on late outcomes, including Long COVID. Methods: Non-hospitalized high-risk adults within 10 days of COVID-19 symptom onset enrolled in a randomized, double-blind, placebo-controlled phase 2/3 trial of amubarvimab/romlusevimab for COVID-19 treatment. Late symptoms, assessed using a participant-completed symptom diary, were a pre-specified exploratory endpoint. The primary outcome for this analysis was the composite of Long COVID by participant self-report (presence of COVID-19 symptoms as recorded in the diary at week 36) or hospitalization or death by week 36. Inverse probability weighting (IPW) was used to address incomplete outcome ascertainment, giving weighted risk ratios (wRR) comparing amubarvimab/romlusevimab to placebo. Findings: Participants received amubarvimab/romlusevimab (n = 390) or placebo (n = 390) between January and July 2021. Median age was 49 years, 52% were female, 18% Black/African American, 49% Hispanic/Latino, and 9% COVID-19-vaccinated at entry. At week 36, 103 (13%) had incomplete outcome ascertainment, and 66 (17%) on amubarvimab/romlusevimab and 92 (24%) on placebo met the primary outcome (wRR = 0.70, 95% confidence interval (CI) 0.53-0.93). The difference was driven by fewer hospitalizations/deaths with amubarvimab/romlusevimab (4%) than placebo (13%). Among 652 participants with available diary responses, 53 (16%) on amubarvimab/romlusevimab and 44 (14%) on placebo reported presence of Long COVID. Interpretation: Amubarvimab/romlusevimab treatment, while highly effective in preventing hospitalizations/deaths, did not reduce risk of Long COVID. Additional interventions are needed to prevent Long COVID. Funding: National Institute of Allergy and Infectious Diseases of the National Institutes of Health. Amubarvimab and romlusevimab supplied by Brii Biosciences.

Mitigating the Risk of Instability After Reverse Shoulder Arthroplasty: A Critical Analysis Review of Patient and Surgical Factors.

¼ Instability and dislocation after reverse shoulder arthroplasty may occur in up to 31% of patients.¼ Clinical risk factors for instability include younger age, male sex, increased body mass index, preoperative diagnosis of proximal humerus fracture or rotator cuff pathology, history of instability of the native shoulder or after surgery, and a medical history of Parkinson's disease.¼ Patients with rheumatoid arthritis and decreased proximity to the coracoid may also be at greater risk.¼ In patients at a high risk of instability, surgeons should consider a more lateralized prosthesis (particularly in patients with an incompetent rotator cuff), repairing the subscapularis (particularly when using a medialized prosthesis), and upsizing the glenosphere (>40 mm in male and 38-40 mm in female patients).¼ While potentially useful, less evidence exists for the use of a constrained liner (particularly with a lateralized glenosphere and/or in low-demand patients) and rotating the polyethylene liner posteriorly to avoid impingement.

Perinatal Outcomes Following Intravenous Iron for Treatment of Iron Deficiency With and Without Anemia.

OBJECTIVE: To determine maternal and neonatal outcomes in individuals with iron deficiency receiving antepartum intravenous (IV) iron supplementation, stratified by the degree of anemia. STUDY DESIGN: Retrospective cohort study of iron-deficient pregnant patients who received at least one IV infusion of iron (iron sucrose, low molecular weight iron dextran [LMWID], or ferric carboxymaltose) during their pregnancy from January 1, 2011 through June 16, 2022. Our primary outcomes included both neonatal composite morbidity and maternal composite morbidity in the context of maternal anemia. RESULTS: Patients who received LMWID had fewer infusion visits, received higher total doses of iron and had a more substantial correction of hemoglobin compared to those who received iron sucrose (p < 0.01). Maternal anemia at the time of admission was not associated with neonatal composite morbidity. However, there was a significant association between anemia status and maternal composite outcome (p = 0.05). Anemia at time of delivery was associated with the likelihood of requiring a blood transfusion (p = 0.01). CONCLUSION: This study reinforces previous findings emphasizing the adverse effects of iron deficiency on maternal health and the role of IV iron in reducing these risks.

A familial Alzheimer's disease associated mutation in presenilin-1 mediates amyloid-beta independent cell specific neurodegeneration.

Mutations in the presenilin (PS) genes are a predominant cause of familial Alzheimer's disease (fAD). An ortholog of PS in the genetic model organism Caenorhabditis elegans (C. elegans) is sel-12. Mutations in the presenilin genes are commonly thought to lead to fAD by upregulating the expression of amyloid beta (Aß), however this hypothesis has been challenged by recent evidence. As C. elegans lack amyloid beta (Aß), the goal of this work was to examine Aß-independent effects of mutations in sel-12 and PS1/PS2 on behaviour and sensory neuron morphology across the lifespan in a C. elegans model. Olfactory chemotaxis experiments were conducted on sel-12(ok2078) loss-of-function mutant worms. Adult sel-12 mutant worms showed significantly lower levels of chemotaxis to odorants compared to wild-type worms throughout their lifespan, and this deficit increased with age. The chemotaxis phenotype in sel-12 mutant worms is rescued by transgenic over-expression of human wild-type PS1, but not the classic fAD-associated variant PS1C410Y, when expression was driven by either the endogenous sel-12 promoter (Psel-12), a pan-neuronal promoter (Primb-1), or by a promoter whose primary expression was in the sensory neurons responsible for the chemotaxis behavior (Psra-6, Podr-10). The behavioural phenotype was also rescued by over-expressing an atypical fAD-linked mutation in PS1 (PS1ΔS169) that has been reported to leave the Notch pathway intact. An examination of the morphology of polymodal nociceptive (ASH) neurons responsible for the chemotaxis behavior also showed increased neurodegeneration over time in sel-12 mutant worms that could be rescued by the same transgenes that rescued the behaviour, demonstrating a parallel with the observed behavioral deficits. Thus, we report an Aß-independent neurodegeneration in C. elegans that was rescued by cell specific over-expression of wild-type human presenilin.

Association of Tumor Mutational Burden and Microsatellite Instability With Response and Outcomes in Patients With Urothelial Carcinoma Treated With Immune Checkpoint Inhibitor.

BACKGROUND: Microsatellite Instability (MSI) and Tumor Mutational Burden (TMB) are associated with immune checkpoint inhibitor (ICI) efficacy. We examined the association between TMB and MSI status with survival in patients with urothelial carcinoma (UC) treated with ICI. METHODS: Patients from 15 institutions were treated with ICI monotherapy. Primary endpoint was overall survival and secondary endpoints included observed response rate (ORR), and progression-free (PFS) calculated from ICI initiation. TMB was analyzed as dichotomous (≥10 vs. <10 mut/Mb) and continuous variable. RESULTS: We identified 411 patients: 203 were treated with ICI 1L/upfront; 104 with 2 + L. For the 1L/upfront: median [m] OS was numerically longer in patients with TMB ≥10 versus TMB <10: mOS 35 versus 26 months (HR = 0.6) and with MSI-H and MSI-S (mOS NR vs. 22 months), though neither association was statistically significant. A statistically significant association was found between TMB (continuous variable) and OS (HR = 0.96, P = .01). For 2 + L: mOS was numerically longer in patients with TMB ≥10 versus TMB <10: (20 vs. 12 months; HR = 0.9); mOS was 12 and 17 months for patients with MSI-H and MSI-S, respectively. Eighty-nine patients received maintenance avelumab (mAV): mOS was longer in patients with TMB ≥10 versus TMB <10: 61 versus 17 months; (HR = 0.2, P = .02) and with MSI-H and MSI-S (NR vs. 24 months). CONCLUSIONS: Although not reaching statistical significance in several subsets, patients with high TMB and MSI-H had numerically longer OS with ICI, especially with mAV. Further validation is needed.

Open Isolated Distal Rectus Tendon Repair.

Isolated distal rectus femoris avulsions from the common quadriceps tendon are rare and may be missed due to the integrity of the remaining extensor mechanism. In healthy, active patients, surgical repair is recommended due to the potential for persistent pain, cramping, and weakness. In the case of isolated distal rectus femoris avulsions, however, there are important surgical considerations and differences when compared with the treatment of complete quadriceps tendon ruptures. This Technical Note describes an open repair of an isolated distal rectus femoris rupture with reinsertion into the common quadriceps tendon.

Distribution and habitat suitability of the endangered lion-tailed macaque Macaca silenus and other primate species in the Kodagu region of the Western Ghats, India.

Because of the universal decline in biodiversity, it is important to map and assess the populations of the endangered species, especially those endemic to small regions, in their remaining wild habitats. With the main focus on the distribution and habitat suitability of the endangered lion-tailed macaque, Macaca silenus, we carried out a survey on primates in the Kodagu region of the Western Ghats, an area not properly explored earlier. The survey trails covered a length of 523 km. We encountered 185 groups of primates including 112, 12, 43 and 18 groups of bonnet macaques, M. radiata, lion-tailed macaques, black-footed gray langurs, Semnopithecus hypoleucos and Nilgiri langurs, S. johnii, respectively. The Brahmagiri Hills harbored the northernmost group of Nilgiri langurs and the southernmost group of black-footed gray langurs. Habitat suitability analysis revealed that the distribution of bonnet macaques and black-footed gray langurs was associated with a large number of environmental factors whereas only a few factors each influenced the distribution of other primate species. When considering the whole landscape spanning over 1295 km2, black-footed gray langurs (961 km2), bonnet macaques (910 km2) and lion-tailed macaques (779 km2) had more suitable habitats than Nilgiri langurs (258 km2). The reserved forests between two Wildlife Sanctuaries covered an area of 311 km2 where 282 km2, 228 km2, 272 km2, and 140 km2 areas were found to be suitable for lion-tailed macaques, bonnet macaques, black-footed gray langurs and Nilgiri langurs, respectively. We recommend these reserved forests to be included in the protected area network. The study brings out the Kodagu region to be a potential conservation area not only for the lion-tailed macaques but also for other primate species.

The effect of tuberosity healing on functional outcomes after reverse shoulder arthroplasty for proximal humerus fractures: a systematic review and meta-analysis.

PURPOSE: This systematic review and meta-analysis compared clinical outcome measures in patients undergoing reverse shoulder arthroplasty (RSA) for proximal humerus fracture (PHF) with healed versus non-healed greater tuberosity (GT). METHODS: We performed a systematic review using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines querying PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane for studies that stratified results by the GT healing status. Studies that did not attempt to repair the GT were excluded. We extracted and compared clinical outcomes including postoperative forward flexion (FF), external rotation (ER), internal rotation (IR), Constant score, and complications and revision rates. RESULTS: Of the included patients, 295 (78.5%) demonstrated GT healing while 81 did not (21.5%). The healed GT cohort exhibited increased postoperative FF (P < .001), ER (P < .001), IR (P = .006), and Constant score (P = .006) compared to the non-healed GT cohort. The overall dislocation rate was 0.8% with no study differentiating GT status of dislocation cases. CONCLUSION: Healing of the GT after RSA for PHF yields improved postoperative range of motion and strength, whereas patient-reported pain and function were largely not affected by GT healing indicating merit to RSA for PHF regardless of the likelihood of the GT healing.

A novel pan-proteome array for high-throughput profiling of the humoral response to Treponema pallidum.

Given the resurgence of syphilis, research endeavors to improve current assays for serological diagnosis and management of this disease are a priority. A proteome-scale platform for high-throughput profiling of the humoral response to Treponema pallidum (T. pallidum) proteins during infection could identify antigens suitable to ameliorate the performance and capabilities of treponemal tests for syphilis. Additionally, because infection-induced immunity is partially protective, profiling the response to T. pallidum outer membrane proteins (OMPs) could help select vaccine candidates. Therefore, we developed a pan-proteome array (PPA) based on the Nichols and SS14 strain complete proteomes and used it to define the immunoglobulin M (IgM) and IgG humoral response to T. pallidum proteins in sera collected longitudinally from long-term infected rabbits and from rabbits that were infected, treated, and re-infected. We identified antigens that could facilitate early diagnosis and immunity to a core set of OMP that could explain protection upon reinfection.

A multi-omics atlas of sex-specific differences in obstructive hypertrophic cardiomyopathy.

BACKGROUND: Hypertrophic cardiomyopathy (HCM) is a common genetic heart disease. Women with HCM tend to have a later onset but more severe disease course. However, the underlying pathobiological mechanisms for these differences remain unknown. METHODS: Myectomy samples from 97 patients (53 males/44 females) with symptomatic obstructive HCM and 23 control cardiac tissues were included in this study. RNA-sequencing was performed on all samples. Mass spectrometry-based proteomics and phosphoproteomics was performed on a representative subset of samples. RESULTS: The transcriptome, proteome, and phosphoproteome was similar between sexes and did not separate on PCA plotting. Overall, there were 482 differentially expressed genes (DEGs) between control females and control males while there were only 53 DEGs between HCM females and HCM males. There were 1983 DEGs between HCM females and control females compared to 1064 DEGs between HCM males and control males. Additionally, there was increased transcriptional downregulation of hypertrophy pathways in HCM females and in HCM males. HCM females had 119 differentially expressed proteins compared to control females while HCM males only had 27 compared to control males. Finally, the phosphoproteome showed females had 341 differentially phosphorylated proteins (DPPs) compared to controls while males only had 184. Interestingly, there was hypophosphorylation and inactivation of hypertrophy pathways in females but hyperphosphorylation and activation in males. CONCLUSION: There are subtle, but biologically relevant differences in the multi-omics profile of HCM. This study provides the most comprehensive atlas of sex-specific differences in the transcriptome, proteome, and phosphoproteome present at the time of surgical myectomy for obstructive HCM.

Is Medical Assistance in Dying Part of Palliative Care?

This Viewpoint considers whether medical assistance in dying should be included as a tenet of palliative care medicine.