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Abstract Background Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. Methods To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. Results We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. Conclusion Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

Objective: This study evaluated the safety and efficacy of elamipretide in dry age-related macular degeneration (AMD) with noncentral geographic atrophy (GA). Design: ReCLAIM-2 was a prospective, phase II, randomized, placebo-controlled, double-masked, multicenter trial (NCT03891875). Subjects: Patients aged ≥55 years with ≥1 eye with dry AMD with GA were enrolled. Methods: Administration of daily subcutaneous elamipretide 40 mg was investigated in subjects for 48 weeks followed by a 4-week follow-up period. Main Outcome Measures: The primary efficacy end points were the mean change from baseline (BL) in low-luminance best-corrected visual acuity (LL BCVA) and the change in square root (Sqrt) converted GA area from BL as measured by OCT. Additional predefined end points included ellipsoid zone (EZ) integrity preservation assessment and categorical changes in LL BCVA. The primary safety end point was the incidence and severity of adverse events. Results: Of the 176 patients randomized, there were 117 and 59 patients in the elamipretide and placebo groups, respectively. Although elamipretide did not meet statistical significance for the primary end points (mean change in LL BCVA and mean change in Sqrt converted GA area), elamipretide produced a 43% reduction in the mean progression from BL in the macular percentage of total EZ attenuation/loss (i.e., complete loss of EZ band; nominal P = 0.0034) and 47% reduction in the mean progression of macular percentage of partial EZ attenuation/degradation (i.e., EZ-retinal pigment endothelium thickness of ≤20 microns; nominal P = 0.0040) versus placebo at week 48. Elamipretide treatment was also associated with significantly more patients experiencing a ≥10 letter gain in LL BCVA versus placebo (14.6% vs. 2.1%; nominal P = 0.0404). Adverse events were reported in 86% of those receiving elamipretide and 71% of the placebo group with the most common events being injection site reactions (e.g., pruritus, injection site pain, bruising, and erythema). Conclusions: While the primary end points were not met in this phase II study, elamipretide treatment was associated with a slowing of progressive EZ degradation/loss, a surrogate for photoreceptor damage. These findings have important clinical relevance since EZ attenuation/photoreceptor loss precedes and predicts the progressive pathological changes associated with vision loss and AMD. The EZ attenuation/loss end point will serve as the regulatory approved primary end point in the elamipretide phase III clinical development program. Financial Disclosure(s): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Category: Arthroscopy; Midfoot/Forefoot Introduction/Purpose: Hallux rigidus is a degenerative disorder of the first metatarsophalangeal (MTP) joint. Patients with this condition experience symptoms including pain, stiffness, and reduced range of motion of the 1st MTP joint. Cheilectomy is a surgical treatment option that removes dorsal periarticular osteophytes to alleviate pain and improve range of motion. Minimally invasive cheilectomy is becoming a more prominent surgical approach due to its clinical benefits including smaller incisions, reduced complications, and faster return to function. This systematic review aims to analyze and present the current literature on patient-reported outcomes (PROs) following MIS cheilectomy for mild to moderate hallux rigidus. Methods: A systematic review of the literature was conducted using articles pulled from PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), and Scopus databases in December 2023 using the search term “cheilectomy.” ​​This systematic review was performed based on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and was registered in Prospero (Blinded ID:XX). Articles were included in the systematic review if they reported on preoperative or postoperative patient-reported outcomes in patients undergoing minimally invasive cheilectomy (MIS) in English. Minimally invasive was defined as an arthroscopic or percutaneous approach. The primary outcome measure was scored patient-reported outcomes. The secondary outcome measures included complications, secondary surgeries, surgical techniques, qualitative patient experiences, and grades of hallux rigidus. Results: Eight studies met the inclusion criteria, and a total of 284 patients were evaluated. 130/284 underwent an MIS percutaneous approach with burr, 70/284 underwent arthroscopy with shaver, and 84/284 had a combination of both techniques. Most patients (79%) had Coughlin-Shurnas grade one or two hallux rigidus (range: 1-3). The mean American Orthopaedic Foot & Ankle Society scores improved from 57.7 (range: 43-71) to 90.1 (range: 87-97). The mean range of motion (dorsiflexion) improved from 28.5 (range: 8-42) to 49.5 (range: 30-73) degrees. Complication rates were low at 18/284 (6%). The most common complication was numbness, affecting 6/284 (2%) patients. Four out of eight articles reported zero complications. 113/125 (90.4%) patients would recommend the procedure. Conclusion: Treatment of hallux rigidus with MIS cheilectomy appears to result in favorable and safe outcomes when performed for patients with early degenerative disease who have failed conservative treatment. Patients reported high satisfaction rates, significant symptomatic improvements, and experienced low complication rates.

Background HBM4003 is a novel anti-CTLA-4 heavy chain-only antibody, designed to enhance Treg ablation and antibody-dependent cell-mediated cytotoxicity while ensuring a manageable safety profile. This phase I trial investigated the safety, pharmacokinetics, immunogenicity and preliminary efficacy of HBM4003 plus with anti-PD-1 antibody toripalimab in patients with advanced solid tumors, especially focusing on melanoma.Methods The multicenter, open-label phase I trial was divided into two parts: dose-escalation phase (part 1) and dose-expansion phase (part 2). In part 1, HBM4003 was administered at doses of 0.03, 0.1, 0.3 mg/kg in combination with toripalimab with fixed dosage of 240 mg every 3 weeks. The recommended phase II dose (RP2D) was used in the expansion phase. Primary endpoints were safety and RP2D in part 1 and objective response rate (ORR) in part 2. Biomarkers based on cytokines and multiplex immunofluorescence staining were explored.Results A total of 40 patients received study treatment, including 36 patients treated with RP2D of HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week. 36 participants (90.0%) experienced at least one treatment-related adverse event (TRAE), of which 10 (25.0%) patients experienced grade ≥3 TRAEs and 5 (12.5%) experienced immune-mediated adverse events (irAEs) with maximum severity of grade 3. No grade 4 or 5 irAEs occurred. Efficacy analysis set included 32 melanoma patients treated with RP2D and with available post-baseline imaging data. The ORRs of anti-PD-1/PD-L1 treatment-naïve subgroup and anti-PD-1/PD-L1 treatment-failed subgroup were 33.3% and 5.9%, respectively. In mucosal melanoma, the ORR of the two subgroups were 40.0% and 10.0%, respectively. Baseline high Treg/CD4+ratio in the tumor serves as an independent predictive factor for the efficacy of immunotherapy.Conclusions HBM4003 0.3 mg/kg plus toripalimab 240 mg every 3 week demonstrated manageable safety in solid tumors and no new safety signal. Limited data demonstrated promising antitumor activity, especially in PD-1 treatment-naïve mucosal melanoma.Trial registration number NCT04727164.

In this review, we present a case report of an immunocompetent 58-year-old male who presented with disseminated histoplasmosis (DH) outside of the known endemic regions. Due to his atypical clinical presentation that did not fit the classical clinical picture of DH, the diagnosis was delayed. In addition, we researched DH in the immunocompetent hosts as these cases are not common and leave the patient population vulnerable to delayed diagnosis. The literature supports considering histoplasmosis in the differential diagnosis among patients who present with possible exposures outside of endemic regions and are immunocompetent.

Autophagy is a crucial mechanism for recycling intracellular materials, and under normal metabolic conditions, it is maintained at low levels in cells. However, when nutrients are deficient or under hypoxic conditions, the level of autophagy significantly increases. Particularly in cancer cells, which grow more rapidly than normal cells and tend to grow in a three-dimensional manner, cells inside the cell mass often face limited oxygen supply, leading to inherently higher levels of autophagy. Therefore, the initial development of anticancer drugs targeting autophagy was based on a strategy to suppress these high levels of autophagy. However, anticancer drugs that inhibit autophagy have not shown promising results in clinical trials, as it has been revealed that autophagy does not always play a role that favors cancer cell survival. Hence, this review aims to suggest anticancer strategies based on the changes in the role of autophagy according to survival conditions and tumorigenesis stage.

Abstract Background More than 75 common variant loci account for only a portion of the heritability for Alzheimer’s disease (AD). A more complete understanding of the genetic basis of AD can be deduced by exploring associations with AD-related endophenotypes. Methods We conducted genome-wide scans for cognitive domain performance using harmonized and co-calibrated scores derived by confirmatory factor analyses for executive function, language, and memory. We analyzed 103,796 longitudinal observations from 23,066 members of community-based (FHS, ACT, and ROSMAP) and clinic-based (ADRCs and ADNI) cohorts using generalized linear mixed models including terms for SNP, age, SNP × age interaction, sex, education, and five ancestry principal components. Significance was determined based on a joint test of the SNP’s main effect and interaction with age. Results across datasets were combined using inverse-variance meta-analysis. Genome-wide tests of pleiotropy for each domain pair as the outcome were performed using PLACO software. Results Individual domain and pleiotropy analyses revealed genome-wide significant (GWS) associations with five established loci for AD and AD-related disorders (BIN1, CR1, GRN, MS4A6A, and APOE) and eight novel loci. ULK2 was associated with executive function in the community-based cohorts (rs157405, P = 2.19 × 10–9). GWS associations for language were identified with CDK14 in the clinic-based cohorts (rs705353, P = 1.73 × 10–8) and LINC02712 in the total sample (rs145012974, P = 3.66 × 10–8). GRN (rs5848, P = 4.21 × 10–8) and PURG (rs117523305, P = 1.73 × 10–8) were associated with memory in the total and community-based cohorts, respectively. GWS pleiotropy was observed for language and memory with LOC107984373 (rs73005629, P = 3.12 × 10–8) in the clinic-based cohorts, and with NCALD (rs56162098, P = 1.23 × 10–9) and PTPRD (rs145989094, P = 8.34 × 10–9) in the community-based cohorts. GWS pleiotropy was also found for executive function and memory with OSGIN1 (rs12447050, P = 4.09 × 10–8) and PTPRD (rs145989094, P = 3.85 × 10–8) in the community-based cohorts. Functional studies have previously linked AD to ULK2, NCALD, and PTPRD. Conclusion Our results provide some insight into biological pathways underlying processes leading to domain-specific cognitive impairment and AD, as well as a conduit toward a syndrome-specific precision medicine approach to AD. Increasing the number of participants with harmonized cognitive domain scores will enhance the discovery of additional genetic factors of cognitive decline leading to AD and related dementias.

Category: Ankle Arthritis; Ankle Introduction/Purpose: There is a paucity of aggregate literature reporting on long-term patient-reported outcomes (PROs) and implant failure after total ankle arthroplasty (TAA). The purpose of this study is to report an aggregate of literature on minimum 10-year patient-reported outcomes after total ankle arthroplasty. Methods: A systematic review on minimum 10-year PROs of TAA was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) guidelines. Pubmed, Scopus, and Cochrane Trials were queried on December 28th, 2022, with the following keywords: (ankle) AND (replacement or arthroplasty) AND (long-term or 10-year). Primary research articles were included if they reported minimum 10-year PROs for patients undergoing primary TAA and written in English. Forest plots with heterogeneity were created for PROs reported preoperatively and postoperatively in three or more studies. Long-term was defined as minimum 10-year follow-up. Survivorship was defined by implant failure which was determined uniquely by each study. Results: Six studies met the inclusion criteria with all 6 studies being level IV. A total of 277 ankles with average age range of 54-60.9 years were included in the study with follow up ranging from 10 to 24 years. The primary indication for total ankle replacement was osteoarthritis. Two of the six studies reported significant improvement in PROs following surgery. The remaining 4 studies also demonstrated improvement in PRO however no p values were reported. A forest plot was generated for the AOFAS score and I2 of 67% was calculated. Survivorship at a minimum of 10 year follow up ranged from 66-94.4%. Average time to implant failure ranged from 54.7-166 months. Conclusion: Patients undergoing primary TAA demonstrated improved outcomes at minimum 10-year follow-up. However, they demonstrated variable rates of survivorship ranging from 66-94.4% with average time to implant failure ranging from 54.7 – 166 months.

ABSTRACTPatients with Special Health Care Needs (SHCN) encounter many barriers in achieving optimal health. This includes primary care, mental health, and oral health. Social workers are adept at addressing these barriers and are trained to provide additional assistance such as emotional counseling, clinical case management, community resource navigation, patient education, and anticipatory guidance. While their assistance is well documented in medical care and hospital settings, collaboration between dentistry and social work is less common. The initiation and integration of a social worker program in dentistry that focused on patients with SHCNs was examined. It was found that social work integration allowed for improved identification of unmet psychosocial needs and decreased barriers to care. As a result, initial appointment attendance rates increased post-integration. Social work in a dental setting has demonstrated the ability to improve bio-psychosocial wellbeing in patients and families, helping address unmet social and psychological needs and reducing barriers to oral health care.

Abstract Histopathologic assessment is indispensable for diagnosing colorectal cancer (CRC). However, manual evaluation of the diseased tissues under the microscope cannot reliably inform patient prognosis or genomic variations crucial for treatment selections. To address these challenges, we develop the Multi-omics Multi-cohort Assessment (MOMA) platform, an explainable machine learning approach, to systematically identify and interpret the relationship between patients’ histologic patterns, multi-omics, and clinical profiles in three large patient cohorts (n = 1888). MOMA successfully predicts the overall survival, disease-free survival (log-rank test P-value

Objectives: To determine whether first-year college students cluster in networks based on subjective perceptions of loneliness. Participants: 492 first-year Notre Dame students completed surveys across two semesters and provided communication data used to reconstruct their social networks. Methods: Subjective perceptions of loneliness are measured using the Social and Emotional Loneliness Scale for Adults (SELSA). Correlations between an individual's loneliness and the average loneliness of their alters are compared to associations in random networks created using a rewiring algorithm to determine statistical significance. Results: During their first semester, students are more likely than chance to form ties with other students with similar levels of family and romantic loneliness. In their second semester, students cluster on romantic loneliness but not on family or social loneliness. Conclusions: Students are more likely than chance to form ties with people with similar self-perceived levels of loneliness, but only for certain types of loneliness and during certain periods.

Here, Diot et al. use the nematode Caenorhabditis elegans as a model to identify off-target toxicity mechanisms for tamoxifen, and find that these include fatty acid metabolism and cell death, which can be modulated by different bacterial species.

Abstract Introduction A major challenge to enabling precision health at a global scale is the bias between those who enroll in state sponsored genomic research and those suffering from chronic disease. More than 30 million people have been genotyped by direct-to-consumer (DTC) companies such as 23andMe, Ancestry DNA, and MyHeritage, providing a potential mechanism for democratizing access to medical interventions and thus catalyzing improvements in patient outcomes as the cost of data acquisition drops. However, much of these data are sequestered in the initial provider network, without the ability for the scientific community to either access or validate. Here, we present a novel geno-pheno platform that integrates heterogeneous data sources and applies learnings to common chronic disease conditions including Type 2 diabetes (T2D) and hypertension. Methods We collected genotyped data from a novel DTC platform where participants upload their genotype data files and were invited to answer general health questionnaires regarding cardiometabolic traits over a period of 6 months. Quality control, imputation, and genome-wide association studies were performed on this dataset, and polygenic risk scores were built in a case–control setting using the BASIL algorithm. Results We collected data on N = 4,550 (389 cases / 4,161 controls) who reported being affected or previously affected for T2D and N = 4,528 (1,027 cases / 3,501 controls) for hypertension. We identified 164 out of 272 variants showing identical effect direction to previously reported genome-significant findings in Europeans. Performance metric of the PRS models was AUC = 0.68, which is comparable to previously published PRS models obtained with larger datasets including clinical biomarkers. Discussion DTC platforms have the potential of inverting research models of genome sequencing and phenotypic data acquisition. Quality control (QC) mechanisms proved to successfully enable traditional GWAS and PRS analyses. The direct participation of individuals has shown the potential to generate rich datasets enabling the creation of PRS cardiometabolic models. More importantly, federated learning of PRS from reuse of DTC data provides a mechanism for scaling precision health care delivery beyond the small number of countries who can afford to finance these efforts directly. Conclusions The genetics of T2D and hypertension have been studied extensively in controlled datasets, and various polygenic risk scores (PRS) have been developed. We developed predictive tools for both phenotypes trained with heterogeneous genotypic and phenotypic data generated outside of the clinical environment and show that our methods can recapitulate prior findings with fidelity. From these observations, we conclude that it is possible to leverage DTC genetic repositories to identify individuals at risk of debilitating diseases based on their unique genetic landscape so that informed, timely clinical interventions can be incorporated.

Abstract Background Lysophosphatidic acid receptor 3 (LPAR3) is coupled to Gα i/o and Gα 11/q signaling. Previously, we reported that LPAR3 is highly methylated in carcinogen-induced transformed cells. Here, we demonstrate that LPAR3 exhibits malignant transforming activities, despite being downregulated in transformed cells. Methods The LPAR3 knockout (KO) in NIH 3 T3 and Bhas 42 cells was established using the CRISPR/Cas9 system. Both RT-PCR and DNA sequencing were performed to confirm the KO of LPAR3. The cellular effects of LPAR3 KO were further examined by WST-1 assay, immunoblotting analysis, transwell migration assay, colony formation assay, wound scratch assday, in vitro cell transformation assay, and autophagy assay. Results In v-H-ras-transformed cells (Ras-NIH 3 T3) with LPAR3 downregulation, ectopic expression of LPAR3 significantly enhanced the migration. In particular, LPAR3 knockout (KO) in Bhas 42 (v-Ha-ras transfected Balb/c 3 T3) and NIH 3 T3 cells caused a decrease in cell survival, transformed foci, and colony formation. LPAR3 KO led to the robust accumulation of LC3-II and autophagosomes and inhibition of autophagic flux by disrupting autophagosome fusion with lysosome. Conversely, autolysosome maturation proceeded normally in Ras-NIH 3 T3 cells upon LPAR3 downregulation. Basal phosphorylation of MEK and ERK markedly increased in Ras-NIH 3 T3 cells, whereas being significantly lower in LPAR3 KO cells, suggesting that increased MEK signaling is involved in autophagosome–lysosome fusion in Ras-NIH 3 T3 cells. Conclusions Paradoxical downregulation of LPAR3 exerts cooperative tumor-promoting activity with MEK activation through autophagy induction in Ras-transformed cells. Our findings have implications for the development of cancer chemotherapeutic approaches.