Phenome-wide identification of therapeutic genetic targets, leveraging knowledge graphs, graph neural networks, and UK Biobank data.

The ongoing expansion of human genomic datasets propels therapeutic target identification; however, extracting gene-disease associations from gene annotations remains challenging. Here, we introduce Mantis-ML 2.0, a framework integrating AstraZeneca's Biological Insights Knowledge Graph and numerous tabular datasets, to assess gene-disease probabilities throughout the phenome. We use graph neural networks, capturing the graph's holistic structure, and train them on hundreds of balanced datasets via a robust semi-supervised learning framework to provide gene-disease probabilities across the human exome. Mantis-ML 2.0 incorporates natural language processing to automate disease-relevant feature selection for thousands of diseases. The enhanced models demonstrate a 6.9% average classification power boost, achieving a median receiver operating characteristic (ROC) area under curve (AUC) score of 0.90 across 5220 diseases from Human Phenotype Ontology, OpenTargets, and Genomics England. Notably, Mantis-ML 2.0 prioritizes associations from an independent UK Biobank phenome-wide association study (PheWAS), providing a stronger form of triaging and mitigating against underpowered PheWAS associations. Results are exposed through an interactive web resource.

Passive biomonitoring for per- and polyfluoroalkyl substances using invasive clams, C. fluminea.

Per- and polyfluoroalkyl substances (PFAS) are a class of toxic manufactured chemicals in commercial and consumer products. They are resistant to environmental degradation and mobile in soil, air, and water. This study used the introduced bivalve Corbicula fluminea as a passive biomonitor at sampling locations in a primary drinking water source in Virginia, USA. Many potential PFAS sources were identified in the region. Perfluorohexane sulfonate (PFHxS) and 6:2 fluorotelomer sulfonic acid (6:2 FTS) levels were highest downstream of an airport. The highest levels of short-chain carboxylic acids were in locations downstream of a wastewater treatment plant. Measured PFAS concentrations varied by location in C. fluminea, sediment, and surface water samples. Two compounds were detected across all three mediums. Calculated partitioning coefficients confirm bioaccumulation of PFAS in C. fluminea and sorption to sediment. C. fluminea bioaccumulated two PFAS not found in the other mediums. Perfluoroalkyl carboxylic acids and short-chain compounds dominated in clam tissue, which contrasts with findings of accumulation of longer-chain and perfluorosulfonic acids in fish. These findings suggest the potential for using bivalves to complement other organisms to better understand the bioaccumulation of PFAS and their fate and transport in a freshwater ecosystem.

Once daily cediranib and weekly paclitaxel to prevent malignant bowel obstruction in at-risk patients with platinum-resistant ovarian cancer (CEBOC): a single-arm, phase II safety trial.

OBJECTIVE: Cytotoxic chemotherapy for ovarian cancer can be augmented by co-administration of vascular endothelial growth factor inhibitors but these are contraindicated in patients with bowel obstruction due to the risk of gastrointestinal perforation. We evaluated the safety and feasibility of paclitaxel plus cediranib to treat patients with platinum-resistant ovarian cancer at risk of malignant bowel obstruction. METHODS: A phase II trial included eligible patients between March 2018 and February 2021, identified by clinical symptoms and radiographic risk factors for malignant bowel obstruction. Cediranib (20 mg/day) was added to paclitaxel (70 mg/m2/week) within 9 weeks of starting paclitaxel if pretreatment bowel symptoms had improved. The primary endpoint was the number of patients treated for ≥5 days with cediranib that were free of grade 3-5 gastrointestinal perforation or fistula. Secondary endpoints were hospitalization for bowel obstruction, grade ≥3 adverse events, treatment compliance assessed by relative dose intensity, objective response, progression-free survival, and overall survival. RESULTS: Thirty patients were recruited. Of these, 12 received paclitaxel alone and 17 received paclitaxel and cediranib in combination. One patient died before starting treatment. No patient developed a grade 3-5 gastrointestinal perforation or fistula (one sided 95% confidence interval (CI) upper limit 0.16). One patient required hospitalization for bowel obstruction but recovered with conservative management. The most common cediranib-related grade ≥3 adverse events were fatigue (3/17), diarrhorea (2/17), and hypomagnesemia (2/17). Relative dose intensity for paclitaxel was 90% (interquartile range (IQR) 85-100%; n=29) and for cediranib 88% (IQR 76-93%; n=17). The objective response in patients who received paclitaxel and cediranib was 65.0% (one complete and 10 partial responses). Median progression-free survival was 6.9 months (95% CI 4.4-11.5 months; n=17) and overall survival was 19.4 months (95% CI 10.1-20.4 months; n=17). Median follow-up was 12.4 months (8.9-not reached; n=17). CONCLUSIONS: The unexpectedly high withdrawal rate during paclitaxel alone, before introducing cediranib, meant we were unable to definitely conclude that paclitaxel plus cediranib did not cause gastrointestinal perforation or fistula. The regimen was however tolerated. TRIAL REGISTRATION NUMBER: EudraCT 2016-004618-93.

Regiodivergent Synthesis of 4- and 5-Sulfenyl Oxazoles from Alkynyl Thioethers.

The regiodivergent synthesis of 4- and 5-sulfenyl oxazoles from 1,4,2-dioxazoles and alkynyl thioethers has been achieved. Gold-catalysed conditions are used to favour the formation of 5-sulfenyl oxazoles via ß-selective attack of the nitrenoid relative to the sulfenyl group. In contrast, 4-sulfenyl oxazoles are formed by α-selective reaction under Brønsted acid conditions from the same substrates. The nature of stabilising gold-sulfur interactions have been investigated by natural bond orbital analysis, showing that the S→Au interactions are significantly stronger in the intermediate that favours the 5-sulfenyl oxazoles. A kinetic survey identifies catalyst inhibition processes. This study into the regiodivergent methods includes the development of telescoped annulation-oxidation protocols for regioselective access to oxazole sulfoxides and sulfones.

Considerations in Gender-Affirming Hormone Therapy in Transgender and Gender Diverse Patients Undergoing Liver Transplantation.

Liver transplantation is lifesaving for patients with end stage liver disease. Similar to the role of transplantation for patients with end stage liver disease, gender affirming hormone therapy (GAHT) can be lifesaving for transgender and gender diverse (TGGD) patients who experience gender dysphoria. However, management of such hormone therapy during the perioperative period is unknown and without clear guidelines. Profound strides can be made in improving care for TGGD patients through gender affirming care and appropriate management of GAHT in liver transplantation. In this article, we call for the transplant community to acknowledge the integral role of GAHT in the care of TGGD liver transplant candidates and recipients. We review the current literature and describe how the transplant community is ethically obligated to address this healthcare gap. We suggest tangible steps that clinicians may take to improve health outcomes for this minoritized patient population.

Replacing sedentary time for physical activity: Does intensity matter for body composition in oldest-old adults?

To assess the independent and combined relationships among objectively measured sedentary time (ST), light intensity PA (LPA), and moderate-to-vigorous intensity PA (MVPA) with muscle mass and fat mass (FM) and how theoretical displacement of these inter-dependent behaviours relates to body composition in oldest-old men. A total of 1046 men participating in the year 14 visit of the prospective Osteoporotic Fractures in Men (MrOS) cohort study with complete data for accelerometry, dual x-ray absorptiometry, and deuterated creatine dilution (D3Cr) muscle mass were included in the analysis (84.0 ± 3.8 yrs.). Single, partition, and isotemporal substitution models were used to assess the interrelationships between PA intensities and ST with body composition measures, while controlling for relevant confounders. Replacing 30-min of ST with 30-min of MVPA was associated with lower FM (ß =-0.17, p < 0.001) and higher D3Cr muscle mass, although this was of borderline significance (ß = 0.07, p = 0.05). Replacing 30-min of ST for LPA was associated with lower FM (ß =-0.15, p < 0.001), but there was no effect on D3Cr muscle mass (p > 0.05). Exchanging ST with any intensity of PA is associated with benefits for FM in oldest-old adult men, although substitution with MVPA may be more beneficial than LPA for maintaining/improving skeletal muscle mass.

Attenuation of DNA base oxidation in post-surgery colorectal stage III patients at subsequent follow-ups.

DNA damage caused by oxidative reactions plays a crucial role in the pathogenesis of colorectal cancer (CRC). In a previous cross-sectional study, CRC patients diagnosed with regional disease (stage III) exhibited a higher level of DNA base oxidation in peripheral blood mononuclear cells (PBMCs) 2-9 months post-surgery compared to those with localized disease (stage I-II). To further explore this observation over time, the present study aimed to investigate DNA base oxidation in CRC patients with localized versus regional disease 6 and 12 months after the initial measurements. The present study included patients enrolled in the randomized controlled trial Norwegian Dietary Guidelines and Colorectal Cancer Survival (CRC-NORDIET). The standard comet assay, modified with the lesion-specific enzyme formamidopyrimidine DNA glycosylase (Fpg), was applied to measure DNA base oxidation in PBMCs at the 6- and 12-month follow-ups. Of the 255 patients assessed at baseline, 156 were included at the 6-month follow-up, with 89 of these patients included in the 12-month follow-up. In contrast to our observation at baseline, there were no significant differences in the levels of DNA base oxidation between patients diagnosed with localized disease and those with regional involvement at the 6- and 12-month follow-up visits (P = 0.81 and P = 0.09, respectively). Patients with stage III disease exhibited a significant decrease in the levels of DNA base oxidation from baseline to 6 months (P < 0.01) and baseline to 12 months (P = 0.03), but no significant difference from 6 to 12 months (P = 0.80). In conclusion, the initially elevated levels of DNA base oxidation in PBMCs, observed 2-9 months post-surgery in patients diagnosed with regional disease (stage III), subsequently decreased to levels comparable to patients with localized disease (stage I-II) at the 6- and 12-month follow-ups.

Age, metabolisms, and potential origin of dominant anammox bacteria in the global oxygen-deficient zones.

Anammox bacteria inhabiting oxygen-deficient zones (ODZs) are a major functional group mediating fixed nitrogen loss in the global ocean. However, many basic questions regarding the diversity, broad metabolisms, origin, and adaptive mechanisms of ODZ anammox bacteria remain unaddressed. Here we report two novel metagenome-assembled genomes of anammox bacteria affiliated with the Scalindua genus, which represent most, if not all, of the anammox bacteria in the global ODZs. Metagenomic read-recruiting and comparison with historical data show that they are ubiquitously present in all three major ODZs. Beyond the core anammox metabolism, both organisms contain cyanase, and the more dominant one encodes a urease, indicating most ODZ anammox bacteria can utilize cyanate and urea in addition to ammonium. Molecular clock analysis suggests that the evolutionary radiation of these bacteria into ODZs occurred no earlier than 310 million years ago, ~1 billion years after the emergence of the earliest modern-type ODZs. Different strains of the ODZ Scalindua species are also found in benthic sediments, and the first ODZ Scalindua is likely derived from the benthos. Compared to benthic strains of the same clade, ODZ Scalindua uniquely encodes genes for urea utilization but has lost genes related to growth arrest, flagellum synthesis, and chemotaxis, presumably for adaptation to thrive in the global ODZ waters. Our findings expand the known metabolisms and evolutionary history of the bacteria controlling the global nitrogen budget.

Developing biomarker assays to accelerate tuberculosis drug development: defining target product profiles.

Drug development for tuberculosis is hindered by the methodological limitations in the definitions of patient outcomes, particularly the slow organism growth and difficulty in obtaining suitable and representative samples throughout the treatment. We developed target product profiles for biomarker assays suitable for early-phase and late-phase clinical drug trials by consulting subject-matter experts on the desirable performance and operational characteristics of such assays for monitoring of tuberculosis treatment in drug trials. Minimal and optimal criteria were defined for scope, intended use, pricing, performance, and operational characteristics of the biomarkers. Early-stage trial assays should accurately quantify the number of viable bacilli, whereas late-stage trial assays should match the number, predict relapse-free cure, and replace culture conversion endpoints. The operational criteria reflect the infrastructure and resources available for drug trials. The effective tools should define the sterilising activity of the drug and lower the probability of treatment failure or relapse in people with tuberculosis. The target product profiles outlined in this Review should guide and de-risk the development of biomarker-based assays suitable for phase 2 and 3 clinical drug trials.

Risk Analysis of Respiratory Syncytial Virus Among Infants in the United States by Birth Month.

BACKGROUND: Respiratory syncytial virus (RSV) is a major cause of morbidity and mortality among U.S. infants. A child's calendar birth month determines their age at first exposure(s) to RSV. We estimated birth month-specific risk of medically attended (MA) RSV lower respiratory tract infection (LRTI) among infants during their first RSV season and first year of life. METHODS: We analyzed infants born in the USA between July 2016 and February 2020 using three insurance claims databases (two commercial, one Medicaid). We classified infants' first MA RSV LRTI episode by highest level of care incurred (outpatient, emergency department, or inpatient), employing specific and sensitive diagnostic coding algorithms to define index RSV diagnoses. In our main analysis we focused on infants' first RSV season. In our secondary analysis we compared the risk of MA RSV LRTI during infants' first RSV season to that of their first year of life. RESULTS: Infants born from May through September generally had the highest risk of first-season MA RSV LRTI-approximately 6%-10% under the specific RSV index diagnosis definition and 16%-26% under the sensitive. Infants born between October and December had the highest risk of RSV-related hospitalization during their first season. The proportion of MA RSV LRTI events classified as inpatient ranged from 9%-54% (specific) and 5%-33% (sensitive) across birth month and comorbidity group. Through the first year of life, the overall risk of MA RSV LRTI is comparable across birth months within each claims database (6%-11% under the specific definition, 17%-30% under the sensitive), with additional cases progressing to care at outpatient or ED settings. CONCLUSIONS: Our data support recent national recommendations for the use of nirsevimab in the USA. For infants born at the tail end of an RSV season who do not receive nirsevimab, a dose administered prior to the onset of their second RSV season could reduce the incidence of outpatient and ED-related events.

Surgical treatment of headshaking by removal of a paracondylar process fragment via modified hyovertebrotomy approach: A detailed anatomical and surgical description in an adult horse.

OBJECTIVE: To describe, in detail, the relevant anatomy and surgical approach to access the paracondylar process (PCP) and report its application in a clinical case of headshaking. ANIMAL: A seven-year-old, mixed breed mare. STUDY DESIGN: Experimental study/case report. METHODS: A seven-year-old mixed breed mare was presented for investigation of acute onset progressing violent headshaking, resulting in the horse falling on multiple occasions. The horse was highly reactive to palpation over the right PCP. Standing computed tomographic (CT) investigation and ultrasonographic examination of the head detected a fracture of the right PCP. Five equine heads of mixed breeds and sizes were dissected to demonstrate the relevant anatomy surrounding the PCP with regard to surgical access. A modified hyovertebrotomy approach was used to remove the fracture fragment under general anesthesia. RESULTS: The anatomy surrounding the PCP was described. The fragment was successfully removed resulting in gradual resolution of clinical signs. The horse recovered well postoperatively and was back into light levels of work with no signs of headshaking present two and a half years following surgery. CONCLUSION: The caudal meningeal artery and vein as well as the glossopharyngeal and hypoglossal nerves are adjacent to the PCP and must be avoided during dissections. The modified hyovertebrotomy approach allows safe surgical access to the PCP. Surgical excision of a PCP fragment can result in complete resolution of clinical signs of headshaking. Computed tomography and ultrasonography are valuable diagnostic tools to identify a fracture of the PCP.

Sex Distributions in Non-ABCA4 Autosomal Macular Dystrophies.

Purpose: We sought to explore whether sex imbalances are discernible in several autosomally inherited macular dystrophies. Methods: We searched the electronic patient records of our large inherited retinal disease cohort, quantifying numbers of males and females with the more common (non-ABCA4) inherited macular dystrophies (associated with BEST1, EFEMP1, PROM1, PRPH2, RP1L1, and TIMP3). BEST1 cases were subdivided into typical autosomal dominant and recessive disease. For PRPH2, only patients with variants at codons 172 or 142 were included. Recessive PROM1 and recessive RP1L1 cases were excluded because these variants give a more widespread or peripheral degeneration. The proportion of females was calculated for each condition; two-tailed binomial testing was performed. Where a significant imbalance was found, previously published cohorts were also explored. Results: Of 325 patients included, numbers for BEST1, EFEMP1, PROM1, PRPH2, RP1L1, and TIMP3 were 152, 35, 30, 50, 14, and 44, respectively. For autosomal dominant Best disease (n = 115), there were fewer females (38%; 95% confidence interval [CI], 29-48%; P = 0.015). For EFEMP1-associated disease (n = 35), there were significantly more females (77%; 95% CI, 60%-90%; P = 0.0019). No significant imbalances were seen for the other genes. When pooling our cohort with previous large dominant Best disease cohorts, the proportion of females was 37% (95% CI, 31%-43%; P = 1.2 × 10-5). Pooling previously published EFEMP1-cases with ours yielded an overall female proportion of 62% (95% CI, 54%-69%; P = 0.0023). Conclusions: This exploratory study found significant sex imbalances in two autosomal macular dystrophies, suggesting that sex could be a modifier. Our findings invite replication in further cohorts and the investigation of potential mechanisms.

COVID-19 Vaccines: Moderna And Pfizer-BioNTech Use Varied By Urban, Rural Counties.

We investigated county-level variation in mRNA COVID-19 vaccine use among Medicare beneficiaries throughout the United States. There was greater use of Pfizer-BioNTech vaccines than Moderna vaccines in urban areas for first and booster doses.

Extracorporeal photopheresis (ECP) in the treatment of chronic lung allograft dysfunction (CLAD): a prospective, multicentre, open-label, randomised controlled trial studying the addition of ECP to standard care in the treatment of bilateral lung transplant patients with CLAD (E-CLAD UK).

BACKGROUND: Long-term survival after lung transplantation is limited compared with other organ transplants. The main cause is development of progressive immune-mediated damage to the lung allograft. This damage, which can develop via multiple immune pathways, is captured under the umbrella term chronic lung allograft dysfunction (CLAD). Despite the availability of powerful immunosuppressive drugs, there are presently no treatments proven to reverse or reliably halt the loss of lung function caused by CLAD. The aim of the E-CLAD UK trial is to determine whether the addition of immunomodulatory therapy, in the form of extracorporeal photopheresis (ECP), to standard care is more efficacious at stabilising lung function in CLAD compared with standard care alone. METHODS AND ANALYSIS: E-CLAD UK is a Phase II clinical trial of an investigational medicinal product (Methoxsalen) delivered to a buffy coat prepared via an enclosed ECP circuit. Target recruitment is 90 bilateral lung transplant patients identified as having CLAD and being treated at one of the five UK adult lung transplant centres. Participants will be randomised 1:1 to intervention plus standard of care, or standard of care alone. Intervention will comprise nine ECP cycles spread over 20 weeks, each course involving two treatments of ECP on consecutive days. All participants will be followed up for a period of 24 weeks.The primary outcome is lung function stabilisation derived from change in forced expiratory volume in one second and forced vital capacity at 12 and 24 weeks compared with baseline at study entry. Other parameters include change in exercise capacity, health-related quality of life and safety. A mechanistic study will seek to identify molecular or cellular markers linked to treatment response and qualitative interviews will explore patient experiences of CLAD and the ECP treatment.A patient and public advisory group is integral to the trial from design to implementation, developing material to support the consent process and interview materials. ETHICS AND DISSEMINATION: The East Midlands-Derby Research Ethics Committee has provided ethical approval (REC 22/EM/0218). Dissemination will be via publications, patient-friendly summaries and presentation at scientific meetings. TRIAL REGISTRATION NUMBER: EudraCT number 2022-002659-20; ISRCTN 10615985.

Clinical, Ophthalmic and Genetic Characterization of RPGRIP1-Associated Leber Congenital Amaurosis/Early Onset Severe Retinal Dystrophy.

PURPOSE: To present the clinical characteristics, retinal features, natural history, and genetics of RPGRIP1-Associated Early Onset Severe Retinal Dystrophy (EOSRD)/Leber Congenital Amaurosis (LCA). DESIGN: Retrospective case series. METHODS: Review of clinical notes, multi-modal retinal imaging, and molecular diagnosis of 18 patients (17 families) with EOSRD/LCA and disease-causing variants in RPGRIP1. RESULTS: The mean age of visual symptoms onset was 0.87 ± 1 year (birth-3 years) and the mean age at baseline visit was 11.4 ± 10.2 years (1-39 years). At the baseline visit, 44% of patients were legally blind (range= 2-39 years) and there was no significant association found between age and best corrected visual acuity (BCVA) in cross sectional analysis. Retinal evaluation showed an abolished electroretinogram or a cone-rod dystrophy pattern, none or minimal pigment deposits, a hyperautofluorescent ring at the posterior pole, and a largely preserved central macular architecture, with retained outer nuclear layer and ellipsoid zone island into adulthood. Eleven variants (48%) were previously unreported, and 13 families (76%) had a double null genotype (DN). Twelve patients (67%) had follow up assessments over a 15.7 ± 9.5 year period. The rate of BCVA decline was 0.02 LogMAR (1 letter)/year. CONCLUSIONS: RPGRIP1-EOSRD/LCA often presents at birth or early infancy, with nystagmus, decreased VA, hyperopia, and photophobia. Patients with a DN genotype may develop symptoms earlier and have worse vision. Multimodal imaging may show a hyperautofluorescent posterior pole ring, and relatively preserved central macular architecture, suggesting that the condition is a promising candidate for gene supplementation.

Emotion expression salience and racially biased weapon identification: A diffusion modeling approach.

Racial stereotypes are commonly activated by informational cues that are detectable in people's faces. Here, we used a sequential priming task to examine whether and how the salience of emotion (angry/scowling vs. happy/smiling expressions) or apparent race (Black vs. White) information in male face primes shapes racially biased weapon identification (gun vs. tool) decisions. In two experiments (Ntotal = 546) using two different manipulations of facial information salience, racial bias in weapon identification was weaker when the salience of emotion expression versus race was heightened. Using diffusion decision modeling, we tested competing accounts of the cognitive mechanism by which the salience of facial information moderates this behavioral effect. Consistent support emerged for an initial bias account, whereby the decision process began closer to the "gun" response upon seeing faces of Black versus White men, and this racially biased shift in the starting position was weaker when emotion versus race information was salient. We discuss these results vis-à-vis prior empirical and theoretical work on how facial information salience moderates racial bias in decision-making.

Considerations for first field trials of low-threshold gene drive for malaria vector control.

Sustainable reductions in African malaria transmission require innovative tools for mosquito control. One proposal involves the use of low-threshold gene drive in Anopheles vector species, where a 'causal pathway' would be initiated by (i) the release of a gene drive system in target mosquito vector species, leading to (ii) its transmission to subsequent generations, (iii) its increase in frequency and spread in target mosquito populations, (iv) its simultaneous propagation of a linked genetic trait aimed at reducing vectorial capacity for Plasmodium, and (v) reduced vectorial capacity for parasites in target mosquito populations as the gene drive system reaches fixation in target mosquito populations, causing (vi) decreased malaria incidence and prevalence. Here the scope, objectives, trial design elements, and approaches to monitoring for initial field releases of such gene dive systems are considered, informed by the successful implementation of field trials of biological control agents, as well as other vector control tools, including insecticides, Wolbachia, larvicides, and attractive-toxic sugar bait systems. Specific research questions to be addressed in initial gene drive field trials are identified, and adaptive trial design is explored as a potentially constructive and flexible approach to facilitate testing of the causal pathway. A fundamental question for decision-makers for the first field trials will be whether there should be a selective focus on earlier points of the pathway, such as genetic efficacy via measurement of the increase in frequency and spread of the gene drive system in target populations, or on wider interrogation of the entire pathway including entomological and epidemiological efficacy. How and when epidemiological efficacy will eventually be assessed will be an essential consideration before decisions on any field trial protocols are finalized and implemented, regardless of whether initial field trials focus exclusively on the measurement of genetic efficacy, or on broader aspects of the causal pathway. Statistical and modelling tools are currently under active development and will inform such decisions on initial trial design, locations, and endpoints. Collectively, the considerations here advance the realization of developer ambitions for the first field trials of low-threshold gene drive for malaria vector control within the next 5 years.

Lumbopelvic Stability during a Single Leg Step Down Predicts Elbow Varus Torque during Baseball Pitching.

CONTEXT: During a baseball pitch, energy is transferred from the lower extremities through the lumbopelvic junction to the upper extremity. Reduced lumbopelvic stability has been associated with elbow injuries, but the mechanisms are unclear. OBJECTIVE: Characterize the predictive ability of lumbopelvic stability on elbow varus torque during a baseball pitch. DESIGN: Cross-Sectional. SETTING: Facilities at NCAA Division 1 universities. PATIENTS OR OTHER PARTICIPANTS: NCAA Division 1 baseball players (N=44; 19.6+1.3yrs). MAIN OUTCOME MEASURES: Pitchers completed a warm-up and then threw ten fastballs from a mound to a catcher. During the pitches, elbow varus torque was recorded using an inertial measurement unit and ball velocity was recorded with a radar gun. Participants also completed a single leg step down (SLSD) task with and without a cognitive Stroop, while triplanar pelvic and trunk kinematics were recorded by inertial measurement units. Statistical analysis consisted of a cluster analysis, principal component analysis (PCA), and a multivariate logistic regression model. RESULTS: Cluster analysis revealed 2 clusters: Low Torque-High Velocity and High-Torque-Low Velocity. The PCA analysis revealed 4 patterns of variability (principal components) during the SLSD: 1-sagittal plane, 2-transverse plane, 3-frontal plane trail limb, and 4-frontal plane lead limb. Logistic regression indicated increased transverse plane trunk and pelvis motion predicted higher odds of belonging to the High Torque-Low Velocity cluster; trunk [OR=2.9 (95%CI:1.1,8.0), p=0.036] and pelvis [OR=2.6 (95%CI:1.1,6.0), p=0.031]. CONCLUSIONS: Lumbopelvic movement assessed during the SLSD can identify deficits that relate to high elbow torque-low ball velocity during the baseball pitch. Specifically, higher pelvis and trunk transverse plane motion was associated with pitchers in the High Torque-Low Velocity cluster. Our assessment of trunk and pelvis motion during a SLSD provides a method for coaches and clinicians to identify a potential risk factor related to increased elbow varus torque and decreased ball velocity.

Differential effects of FcRn antagonists on the subcellular trafficking of FcRn and albumin.

The homeostasis of IgG is maintained by the neonatal Fc receptor, FcRn. Consequently, antagonism of FcRn to reduce endogenous IgG levels is an emerging strategy for treating antibody-mediated autoimmune disorders using either FcRn-specific antibodies or an engineered Fc fragment. For certain FcRn-specific antibodies, this approach has resulted in reductions in the levels of serum albumin, the other major ligand transported by FcRn. Cellular and molecular analyses of a panel of FcRn antagonists have been carried out to elucidate the mechanisms leading to their differential effects on albumin homeostasis. These analyses have identified 2 processes underlying decreases in albumin levels during FcRn blockade: increased degradation of FcRn and competition between antagonist and albumin for FcRn binding. These findings have potential implications for the design of drugs to modulate FcRn function.