Early introductions and transmission of SARS-CoV-2 variant B.1.1.7 in the United States.

The emergence and spread of SARS-CoV-2 lineage B.1.1.7, first detected in the United Kingdom, has become a global public health concern because of its increased transmissibility. Over 2,500 COVID-19 cases associated with this variant have been detected in the United States (US) since December 2020, but the extent of establishment is relatively unknown. Using travel, genomic, and diagnostic data, we highlight that the primary ports of entry for B.1.1.7 in the US were in New York, California, and Florida. Furthermore, we found evidence for many independent B.1.1.7 establishments starting in early December 2020, followed by interstate spread by the end of the month. Finally, we project that B.1.1.7 will be the dominant lineage in many states by mid- to late March. Thus, genomic surveillance for B.1.1.7 and other variants urgently needs to be enhanced to better inform the public health response.

The quantitative genetics of gene expression in Mimulus guttatus.

Gene expression can be influenced by genetic variants that are closely linked to the expressed gene (cis eQTLs) and variants in other parts of the genome (trans eQTLs). We created a multiparental mapping population by sampling genotypes from a single natural population of Mimulus guttatus and scored gene expression in the leaves of 1,588 plants. We find that nearly every measured gene exhibits cis regulatory variation (91% have FDR < 0.05). cis eQTLs are usually allelic series with three or more functionally distinct alleles. The cis locus explains about two thirds of the standing genetic variance (on average) but varies among genes and tends to be greatest when there is high indel variation in the upstream regulatory region and high nucleotide diversity in the coding sequence. Despite mapping over 10,000 trans eQTL / affected gene pairs, most of the genetic variance generated by trans acting loci remains unexplained. This implies a large reservoir of trans acting genes with subtle or diffuse effects. Mapped trans eQTLs show lower allelic diversity but much higher genetic dominance than cis eQTLs. Several analyses also indicate that trans eQTLs make a substantial contribution to the genetic correlations in expression among different genes. They may thus be essential determinants of "gene expression modules," which has important implications for the evolution of gene expression and how it is studied by geneticists.

Direct targets of MEF2C are enriched for genes associated with schizophrenia and cognitive function and are involved in neuron development and mitochondrial function.

Myocyte Enhancer Factor 2C (MEF2C) is a transcription factor that plays a crucial role in neurogenesis and synapse development. Genetic studies have identified MEF2C as a gene that influences cognition and risk for neuropsychiatric disorders, including autism spectrum disorder (ASD) and schizophrenia (SCZ). Here, we investigated the involvement of MEF2C in these phenotypes using human-derived neural stem cells (NSCs) and glutamatergic induced neurons (iNs), which represented early and late neurodevelopmental stages. For these cellular models, MEF2C function had previously been disrupted, either by direct or indirect mutation, and gene expression assayed using RNA-seq. We integrated these RNA-seq data with MEF2C ChIP-seq data to identify dysregulated direct target genes of MEF2C in the NSCs and iNs models. Several MEF2C direct target gene-sets were enriched for SNP-based heritability for intelligence, educational attainment and SCZ, as well as being enriched for genes containing rare de novo mutations reported in ASD and/or developmental disorders. These gene-sets are enriched in both excitatory and inhibitory neurons in the prenatal and adult brain and are involved in a wide range of biological processes including neuron generation, differentiation and development, as well as mitochondrial function and energy production. We observed a trans expression quantitative trait locus (eQTL) effect of a single SNP at MEF2C (rs6893807, which is associated with IQ) on the expression of a target gene, BNIP3L. BNIP3L is a prioritized risk gene from the largest genome-wide association study of SCZ and has a function in mitophagy in mitochondria. Overall, our analysis reveals that either direct or indirect disruption of MEF2C dysregulates sets of genes that contain multiple alleles associated with SCZ risk and cognitive function and implicates neuron development and mitochondrial function in the etiology of these phenotypes.

A few essential genetic loci distinguish Penstemon species with flowers adapted to pollination by bees or hummingbirds.

In the formation of species, adaptation by natural selection generates distinct combinations of traits that function well together. The maintenance of adaptive trait combinations in the face of gene flow depends on the strength and nature of selection acting on the underlying genetic loci. Floral pollination syndromes exemplify the evolution of trait combinations adaptive for particular pollinators. The North American wildflower genus Penstemon displays remarkable floral syndrome convergence, with at least 20 separate lineages that have evolved from ancestral bee pollination syndrome (wide blue-purple flowers that present a landing platform for bees and small amounts of nectar) to hummingbird pollination syndrome (bright red narrowly tubular flowers offering copious nectar). Related taxa that differ in floral syndrome offer an attractive opportunity to examine the genomic basis of complex trait divergence. In this study, we characterized genomic divergence among 229 individuals from a Penstemon species complex that includes both bee and hummingbird floral syndromes. Field plants are easily classified into species based on phenotypic differences and hybrids displaying intermediate floral syndromes are rare. Despite unambiguous phenotypic differences, genome-wide differentiation between species is minimal. Hummingbird-adapted populations are more genetically similar to nearby bee-adapted populations than to geographically distant hummingbird-adapted populations, in terms of genome-wide dXY. However, a small number of genetic loci are strongly differentiated between species. These approximately 20 "species-diagnostic loci," which appear to have nearly fixed differences between pollination syndromes, are sprinkled throughout the genome in high recombination regions. Several map closely to previously established floral trait quantitative trait loci (QTLs). The striking difference between the diagnostic loci and the genome as whole suggests strong selection to maintain distinct combinations of traits, but with sufficient gene flow to homogenize the genomic background. A surprisingly small number of alleles confer phenotypic differences that form the basis of species identity in this species complex.

Single-Dose Psilocybin for a Treatment-Resistant Episode of Major Depression.

BACKGROUND: Psilocybin is being studied for use in treatment-resistant depression. METHODS: In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). RESULTS: A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. CONCLUSIONS: In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).

Benznidazole treatment leads to DNA damage in Trypanosoma cruzi and the persistence of rare widely dispersed non-replicative amastigotes in mice.

Benznidazole is the front-line drug used to treat infections with Trypanosoma cruzi, the causative agent of Chagas disease. However, for reasons that are unknown, treatment failures are common. When we examined parasites that survived benznidazole treatment in mice using highly sensitive in vivo and ex vivo bioluminescence imaging, we found that recrudescence is not due to persistence of parasites in a specific organ or tissue that preferentially protects them from drug activity. Surviving parasites are widely distributed and located in host cells where the vast majority contained only one or two amastigotes. Therefore, infection relapse does not arise from a small number of intact large nests. Rather, persisters are either survivors of intracellular populations where co-located parasites have been killed, or amastigotes in single/low-level infected cells exist in a state where they are less susceptible to benznidazole. To better assess the nature of parasite persisters, we exposed infected mammalian cell monolayers to a benznidazole regimen that reduces the intracellular amastigote population to <1% of the pre-treatment level. Of host cells that remained infected, as with the situation in vivo, the vast majority contained only one or two surviving intracellular amastigotes. Analysis, based on non-incorporation of the thymidine analogue EdU, revealed these surviving parasites to be in a transient non-replicative state. Furthermore, treatment with benznidazole led to widespread parasite DNA damage. When the small number of parasites which survive in mice after non-curative treatment were assessed using EdU labelling, this revealed that these persisters were also initially non-replicative. A possible explanation could be that triggering of the T. cruzi DNA damage response pathway by the activity of benznidazole metabolites results in exit from the cell cycle as parasites attempt DNA repair, and that metabolic changes associated with non-proliferation act to reduce drug susceptibility. Alternatively, a small percentage of the parasite population may pre-exist in this non-replicative state prior to treatment.

A whole-food, plant-based intensive lifestyle intervention improves glycaemic control and reduces medications in individuals with type 2 diabetes: a randomised controlled trial.

AIMS/HYPOTHESIS: We conducted the largest and longest clinical trial comparing a whole-food, plant-based intervention with standard medical care (SMC) in individuals with type 2 diabetes. METHODS: We randomised (parallel-arm; computerised 1:1 randomisation ratio) 169 adults aged 18-75 years with type 2 diabetes in the Marshall Islands to an intensive whole-food, plant-based intervention with moderate exercise (PB+Ex) or SMC for 24 weeks. The PB+Ex intervention included 12 weeks of meals, exercise sessions and group classes. Primary outcomes were glycaemic control (HbA1c, glucose, insulin and HOMA-IR) and glucose-lowering medication use. Secondary outcomes included lipids, blood pressure, heart rate and C-reactive protein. Only lab analysts were blinded. RESULTS: Compared with SMC (n=90 randomised; n=70 analysed), the PB+Ex (n=79 randomised; n=66 analysed) intervention decreased HbA1c by an additional 14 mmol/mol (1.3%) at week 12 (-22 vs -7 mmol/mol [-2.0% vs -0.7%]; p<0.0001) and 8 mmol/mol (0.7%) at week 24 (-16 vs -8 mmol/mol [-1.4% vs -0.7%]; p=0.01). Concomitantly, 63% of medicated PB+Ex participants reduced their glucose-lowering medications (vs 24%; p=0.006), and 23% of PB+Ex participants with a baseline HbA1c <75 mmol/mol (<9%) achieved remission. Additionally, the PB+Ex intervention reduced weight (-2.7 kg; p<0.0001), C-reactive protein (-11 nmol/l; p=0.005) and cardiovascular medication use compared with SMC. At intermediate timepoints, it improved glucose, insulin, HOMA-IR, cholesterol, triglycerides and heart rate, but not at week 24. CONCLUSIONS/INTERPRETATION: A whole-food, plant-based lifestyle intervention was more effective for improving glycaemic control than SMC. It also reduced the need for diabetes and cardiovascular medications and induced diabetes remission in some participants. Therefore, it is an effective, evidence-based lifestyle option for individuals with type 2 diabetes. TRIAL REGISTRATION: ClinicalTrials.gov NCT03862963 FUNDING: This research was funded by the Department of the Army (W81XWH-05-1-0547). CJH received support through a National Institutes of Health Predoctoral T32 Obesity Fellowship (T32 HL105349).

Sequence tolerance of immunoglobulin variable domain framework regions to noncanonical intradomain disulfide linkages.

Most immunoglobulin (Ig) domains bear only a single highly conserved canonical intradomain, inter-ß-sheet disulfide linkage formed between Cys23-Cys104, and incorporation of rare noncanonical disulfide linkages at other locations can enhance Ig domain stability. Here, we exhaustively surveyed the sequence tolerance of Ig variable (V) domain framework regions (FRs) to noncanonical disulfide linkages. Starting from a destabilized VH domain lacking a Cys23-Cys104 disulfide linkage, we generated and screened phage-displayed libraries of engineered VHs, bearing all possible pairwise combinations of Cys residues in neighboring ß-strands of the Ig fold FRs. This approach identified seven novel Cys pairs in VH FRs (Cys4-Cys25, Cys4-Cys118, Cys5-Cys120, Cys6-Cys119, Cys22-Cys88, Cys24-Cys86, and Cys45-Cys100; the international ImMunoGeneTics information system numbering), whose presence rescued domain folding and stability. Introduction of a subset of these noncanonical disulfide linkages (three intra-ß-sheet: Cys4-Cys25, Cys22-Cys88, and Cys24-Cys86, and one inter-ß-sheet: Cys6-Cys119) into a diverse panel of VH, VL, and VHH domains enhanced their thermostability and protease resistance without significantly impacting expression, solubility, or binding to cognate antigens. None of the noncanonical disulfide linkages identified were present in the natural human VH repertoire. These data reveal an unexpected permissiveness of Ig V domains to noncanonical disulfide linkages at diverse locations in FRs, absent in the human repertoire, whose presence is compatible with antigen recognition and improves domain stability. Our work represents the most complete assessment to date of the role of engineered noncanonical disulfide bonding within FRs in Ig V domain structure and function.

Evaluation of objective tools and artificial intelligence in robotic surgery technical skills assessment: a systematic review.

BACKGROUND: There is a need to standardize training in robotic surgery, including objective assessment for accreditation. This systematic review aimed to identify objective tools for technical skills assessment, providing evaluation statuses to guide research and inform implementation into training curricula. METHODS: A systematic literature search was conducted in accordance with the PRISMA guidelines. Ovid Embase/Medline, PubMed and Web of Science were searched. Inclusion criterion: robotic surgery technical skills tools. Exclusion criteria: non-technical, laparoscopy or open skills only. Manual tools and automated performance metrics (APMs) were analysed using Messick's concept of validity and the Oxford Centre of Evidence-Based Medicine (OCEBM) Levels of Evidence and Recommendation (LoR). A bespoke tool analysed artificial intelligence (AI) studies. The Modified Downs-Black checklist was used to assess risk of bias. RESULTS: Two hundred and forty-seven studies were analysed, identifying: 8 global rating scales, 26 procedure-/task-specific tools, 3 main error-based methods, 10 simulators, 28 studies analysing APMs and 53 AI studies. Global Evaluative Assessment of Robotic Skills and the da Vinci Skills Simulator were the most evaluated tools at LoR 1 (OCEBM). Three procedure-specific tools, 3 error-based methods and 1 non-simulator APMs reached LoR 2. AI models estimated outcomes (skill or clinical), demonstrating superior accuracy rates in the laboratory with 60 per cent of methods reporting accuracies over 90 per cent, compared to real surgery ranging from 67 to 100 per cent. CONCLUSIONS: Manual and automated assessment tools for robotic surgery are not well validated and require further evaluation before use in accreditation processes.PROSPERO: registration ID CRD42022304901.

BACKGROUND: Robotic surgery is increasingly used worldwide to treat many different diseases. The robot is controlled by a surgeon, which may give them greater precision and better outcomes for patients. However, surgeons' robotic skills should be assessed properly, to make sure patients are safe, to improve feedback and for exam assessments for certification to indicate competency. This should be done by experts, using assessment tools that have been agreed upon and proven to work. AIM: This review's aim was to find and explain which training and examination tools are best for assessing surgeons' robotic skills and to find out what gaps remain requiring future research. METHOD: This review searched for all available studies looking at assessment tools in robotic surgery and summarized their findings using several different methods. FINDINGS AND CONCLUSION: Two hundred and forty-seven studies were looked at, finding many assessment tools. Further research is needed for operation-specific and automatic assessment tools before they should be used in the clinical setting.

Imaging CAR-NK cells targeted to HER2 ovarian cancer with human sodium-iodide symporter-based positron emission tomography.

Chimeric antigen receptor (CAR) cell therapies utilize CARs to redirect immune cells towards cancer cells expressing specific antigens like human epidermal growth factor receptor 2 (HER2). Despite their potential, CAR T cell therapies exhibit variable response rates and adverse effects in some patients. Non-invasive molecular imaging can aid in predicting patient outcomes by tracking infused cells post-administration. CAR-T cells are typically autologous, increasing manufacturing complexity and costs. An alternative approach involves developing CAR natural killer (CAR-NK) cells as an off-the-shelf allogeneic product. In this study, we engineered HER2-targeted CAR-NK cells co-expressing the positron emission tomography (PET) reporter gene human sodium-iodide symporter (NIS) and assessed their therapeutic efficacy and PET imaging capability in a HER2 ovarian cancer mouse model.NK-92 cells were genetically modified to express a HER2-targeted CAR, the bioluminescence imaging reporter Antares, and NIS. HER2-expressing ovarian cancer cells were engineered to express the bioluminescence reporter Firefly luciferase (Fluc). Co-culture experiments demonstrated significantly enhanced cytotoxicity of CAR-NK cells compared to naive NK cells. In vivo studies involving mice with Fluc-expressing tumors revealed that those treated with CAR-NK cells exhibited reduced tumor burden and prolonged survival compared to controls. Longitudinal bioluminescence imaging demonstrated stable signals from CAR-NK cells over time. PET imaging using the NIS-targeted tracer 18F-tetrafluoroborate ([18F]TFB) showed significantly higher PET signals in mice treated with NIS-expressing CAR-NK cells.Overall, our study showcases the therapeutic potential of HER2-targeted CAR-NK cells in an aggressive ovarian cancer model and underscores the feasibility of using human-derived PET reporter gene imaging to monitor these cells non-invasively in patients.

Genetic and inflammatory effects on childhood trauma and cognitive functioning in patients with schizophrenia and healthy participants.

Recent studies have reported a negative association between exposure to childhood trauma, including physical neglect, and cognitive functioning in patients with schizophrenia. Childhood trauma has been found to influence immune functioning, which may contribute to the risk of schizophrenia and cognitive symptoms of the disorder. In this study, we aimed to test the hypothesis that physical neglect is associated with cognitive ability, and that this association is mediated by a combined latent measure of inflammatory response, and moderated by higher genetic risk for schizophrenia. The study included 279 Irish participants, comprising 102 patients and 177 healthy participants. Structural equation modelling was used to perform mediation and moderation analyses. Inflammatory response was measured via basal plasma levels of IL-6, TNF-α, and CRP, and cognitive performance was assessed across three domains: full-scale IQ, logical memory, and the emotion recognition task. Genetic variation for schizophrenia was estimated using a genome-wide polygenic score based on genome-wide association study summary statistics. The results showed that inflammatory response mediated the association between physical neglect and all measures of cognitive functioning, and explained considerably more variance than any of the inflammatory markers alone. Furthermore, genetic risk for schizophrenia was observed to moderate the direct pathway between physical neglect and measures of non-social cognitive functioning in both patient and healthy participants. However, genetic risk did not moderate the mediated pathway associated with inflammatory response. Therefore, we conclude that the mediating role of inflammatory response and the moderating role of higher genetic risk may independently influence the association between adverse early life experiences and cognitive function in patients and healthy participants.

Disentangling Acid-Base Chemistry through Blue Shifting Hydrogen Bond Contributions.

The blue shifting of vibrational frequencies in hydrogen bonded molecules, as observed in aqueous environments, has been attributed to local partial charge transfer from solvation. Here, we extrapolate the blue shift model to the stronger ionic interactions between hydrogen bond acceptors associated with protonation through augmented pH levels and competitive interactions with counter ion pairing. The chemical model we utilize in this work is the aqueous pyridine-pyridinium equilibrium to characterize the blue shifts observed in the pyridinium chloride ionic system. The observed agreement between observed experimental and calculated spectral shifts shows that the blue shifting model can be extrapolated to stronger interactions and accurately describe the nature of the hydrogen bond.

The role of urology and radiology in prostate biopsy: current trends and future perspectives.

PURPOSE: Prostate biopsy is central to the accurate histological diagnosis of prostate cancer. In current practice, the biopsy procedure can be performed using a transrectal or transperineal route with different technologies available for targeting of lesions within the prostate. Historically, the biopsy procedure was performed solely by urologists, but with the advent of image-guided techniques, the involvement of radiologists in prostate biopsy has become more common. Herein, we discuss the pros, cons and future considerations regarding their ongoing role. METHODS: A narrative review regarding the current evidence was completed. PubMed and Cochrane central register of controlled trials were search until January 2024. All study types were of consideration if published after 2000 and an English language translation was available. RESULTS: There are no published studies that directly compare outcomes of prostate biopsy when performed by a urologist or radiologist. In all published studies regarding the learning curve for prostate biopsy, the procedure was performed by urologists. These studies suggest that the learning curve for prostate biopsy is between 10 and 50 cases to reach proficiency in terms of prostate cancer detection and complications. It is recognised that many urologists are poorly able to accurately interpret multi parametric (mp)-MRI of the prostate. Collaboration between the specialities is of importance with urology offering the advantage of being involved in prior and future care of the patient while radiology has the advantage of being able to expertly interpret preprocedure MRI. CONCLUSION: There is no evidence to suggest that prostate biopsy should be solely performed by a specific specialty. The most important factor remains knowledge of the relevant anatomy and sufficient volume of cases to develop and maintain skills.

Peri-operative and long-term outcomes of kidney transplantation in patients with cystic fibrosis.

INTRODUCTION: There is a lack of data regarding the peri-operative and long-term outcomes of kidney transplantation in cystic fibrosis (CF) patients. Herein, we report the peri-operative and long-term outcomes of kidney transplantation in CF patients. MATERIALS AND METHODS: All CF patients who received a kidney transplant at the national kidney transplant center between 1993 and 2022 were identified. Recipients of the contralateral donor kidney were selected as a control group. Primary outcomes included 1-, 5-, and 10- year death-censored graft survival and overall survival. Secondary outcomes included peri-operative morbidity, acute graft rejection, delayed graft function (DGF), and length of stay (LOS). RESULTS: Fourteen patients received a kidney transplant over the study period. Median age at transplantation was 35 (IQR 31, 40) years. The 1-, 5-, and 10-year death-censored graft survival was 92, 74, and 74% in the CF group compared to 100, 92, and 92% in the control group (p = .44). The 1-, 5-, and 10-year overall survival in the CF group was 85, 66, and 57% compared to 100, 92, and 82% in the control group (p = .036). There was no significant difference in peri-operative outcomes including LOS (10 vs. 11 days, p = .84), ICU admission (1 vs. 0 patients, p > .99), acute rejection episodes (2 vs. 1 patients, p > .99), and DGF (1 vs. 2 patients, p = .60). CONCLUSION: CF patients have good long-term graft survival, however, overall survival was worse compared to a matched cohort. These data provide important information for transplant surgeons when considering suitable donor allografts in this unique patient population.

Meeting-makers make meaning: alcoholics anonymous participation and personal meaningfulness.

AIMS: The central aim of this study was to determine whether intentional, voluntary alcoholics anonymous (AA) participation showed any independent association with affect, over and above that which has been observed in association with other recovery-related behaviors, such as abstinence, among individuals with a history of alcohol use disorder. Additionally, we sought to determine the nature of the affective changes associated with specific dimensions of AA participation (i.e. meeting  attendance, fellowship  involvement, 12-step  work). METHODS: Thirty abstinent alcohol use disorder individuals were recruited and evaluated. Multivariate linear regressions were used to examine associations between dimensions of AA participation, measured using the Multidimensional Mutual-Help Assessment Scale and standardized measures of affective experiences, including the Profile of Mood States, Subjective Happiness Scale, and the Twelve Promises Scale. RESULTS AND CONCLUSIONS: Increase in AA participation was associated with higher positive affective experiences. These associations were observed independently with AA meeting  attendance and fellowship  involvement, but not 12-step work. This study's findings suggest that greater AA meeting  attendance and fellowship  involvement are correlated with enhancements in the meta-emotional experience of personal meaningfulness. This study extends evidence on AA-related changes by considering affective improvements as a primary clinical outcome, thereby laying the foundation for subsequent, more comprehensive research into the relationship between dimensions of AA participation and recovery-related affective changes.

Predicting evolutionary change at the DNA level in a natural Mimulus population.

Evolution by natural selection occurs when the frequencies of genetic variants change because individuals differ in Darwinian fitness components such as survival or reproductive success. Differential fitness has been demonstrated in field studies of many organisms, but it remains unclear how well we can quantitatively predict allele frequency changes from fitness measurements. Here, we characterize natural selection on millions of Single Nucleotide Polymorphisms (SNPs) across the genome of the annual plant Mimulus guttatus. We use fitness estimates to calibrate population genetic models that effectively predict allele frequency changes into the next generation. Hundreds of SNPs experienced "male selection" in 2013 with one allele at each SNP elevated in frequency among successful male gametes relative to the entire population of adults. In the following generation, allele frequencies at these SNPs consistently shifted in the predicted direction. A second year of study revealed that SNPs had effects on both viability and reproductive success with pervasive trade-offs between fitness components. SNPs favored by male selection were, on average, detrimental to survival. These trade-offs (antagonistic pleiotropy and temporal fluctuations in fitness) may be essential to the long-term maintenance of alleles. Despite the challenges of measuring selection in the wild, the strong correlation between predicted and observed allele frequency changes suggests that population genetic models have a much greater role to play in forward-time prediction of evolutionary change.

Editorial Commentary: Surgical Videos on YouTube Are Not Peer Reviewed and Have Low Educational Value.

The rise of online platforms like YouTube for health information has prompted scrutiny over the quality of medical/surgical-related video content. Recent research on YouTube videos regarding anterior cruciate ligament reconstruction (ACLR) with quadriceps tendon autograft shows low educational quality and reliability using established assessment tools. Physicians primarily published content, with longer videos, and physician-generated videos, generally correlating with higher quality. However, YouTube's inadequacy as a reliable source for ACLR information underscores the need for alternative educational resources. Orthopaedic health care professionals must play a pivotal role in guiding patients toward credible sources and take aim at improving online content quality. Understanding patient preferences for online resources is essential for enhancing patient education, the patient-provider relationship, and decision-making in orthopaedic care.

Primary Arthroscopic Repair for Massive Rotator Cuff Tears Results in Good Shoulder Function, Low Pain, and Satisfactory Outcomes at 2-Year Minimum Follow-Up.

PURPOSE: To evaluate outcomes of patients who underwent primary arthroscopic repair for massive rotator cuff tears (MRCTs). METHODS: Patients with MRCTs (full-thickness tear of 2 or more tendons or full-thickness tear ≥5 cm) who underwent arthroscopic repair with a minimum follow-up of 2 years were retrospectively reviewed (n = 51). All patients had preoperative magnetic resonance imaging used to characterize pattern of tear, degree of fatty degeneration (Goutallier classification), and degree of rotator cuff arthropathy (Hamada classification). Outcomes were determined by American Shoulder and Elbow Surgeons (ASES) scores and Penn Shoulder Scores (PSS). RESULTS: A total of 51 patients with a minimum 2.3-year follow-up (mean, 5.4 years; range, 2.3-9.7 years) were included in this study. Mean ASES score was 46.1 ± 7.8 (95% CI, 43.9-48.3) for pain and 39.4 ± 12.1 (95% CI, 36.0-42.8) for function. Total ASES score averaged 85.5 ± 18.4 (95% CI, 80.4-90.7). PSS had a mean pain score of 26.8 ± 4.4 (95% CI, 25.4-28.1), a mean satisfaction score of 7.9 ± 2.9 (95% CI, 7.0-8.2), and a mean function score of 48.5 ± 13.5 (95% CI, 44.7-52.3). Total PSS averaged 83.2 ± 19.6 (95% CI, 77.7-87.7). No correlation was found between Goutallier grade and ASES/PSS scores or between Hamada grade and ASES/PSS scores. Three patients underwent reoperation after primary arthroscopic repair of an MRCT (5.9%). CONCLUSIONS: Patients with MRCTs who undergo primary arthroscopic repair have postoperative outcome scores indicative of good shoulder function, low pain, and high satisfaction. The rate of reoperation for individuals who underwent primary arthroscopic repair with MRCTs was low at 6%. LEVEL OF EVIDENCE: Level IV, retrospective case series.

Visualizing the Influence of Social Networks on Recovery: A Mixed-Methods Social Identity Mapping Study with Recovering Adolescents.

Background: Social recovery capital (SRC) refers to resources and supports gained through relationships and is vital to adolescent addiction recovery. Much is known about how substance use relates to social networks, but little is known about how other dimensions of social networks influence recovery (e.g., network size/exposure, degree of conflict). Methods: This mixed-methods study sampled 28 adolescents who received treatment for alcohol and other drug (AOD) use disorder (14-19 yrs.: 71% male; M = 17.32 yrs., SD = 1.33; White 82%): 20 were recovery high school (RHS) students. Adolescents completed a social identity map for addiction recovery (SIM-AR), survey, and interview. Qualitative data were content analyzed and the data from the SIM-AR were quantified. Results: On average, participants reported belonging to five distinct groups within their network (Range, 2-9; SD = 1.63; M = 27.89 people, SD = 20.09). Of their social network connections, 51% drank alcohol and 46% used other substances, on average. Larger networks involved more conflict (r = 0.57). Participants were more likely to spend more time with groups that had greater proportions of non-substance-using members. These linkages were stronger for RHS than for non-RHS students. Qualitative analyses revealed that youth reported their recovery-oriented groups as supportive, but some reported that their substance-using friends also supported their recovery. Discussion: SIM-AR was a useful measurement tool, and, through qualitative interviews, we identified unique aspects of youths' social networks important for further examination. Research with recovering youth should examine SRC-related elements within their networks including relationship quality, belonging, and conflict, alongside the substance use behaviors of network members.

Similar return to sport between double cortical button and docking techniques for ulnar collateral ligament reconstruction in baseball players.

BACKGROUND AND HYPOTHESIS: A double cortical button technique for ulnar collateral ligament reconstruction (UCLR) has advantages including significant control over graft tensioning, less concern about graft length, and minimized risk of bone tunnel fracture compared with traditional UCLR techniques. This double cortical button technique was recently found to be noninferior in mechanical performance to the traditional docking technique regarding joint strength, joint stiffness, and graft strain. However, clinical outcomes have not been compared between these UCLR techniques. Therefore, the purpose of this study was to determine whether baseball players who underwent UCLR with a double cortical button (double button) technique have similar return-to-sport (RTS) outcomes to baseball players who underwent UCLR with the traditional docking (docking) technique. MATERIALS AND METHODS: Baseball players who underwent primary UCLR from 2011 to 2020 across 2 institutions were identified. Included patients were contacted to complete a follow-up survey evaluating reoperations, RTS, and functional outcome scores. Functional outcome surveys include the Kerlan-Jobe Orthopaedic Clinic score, the Conway-Jobe score, the Andrews-Timmerman elbow score, and the Single Assessment Numeric Evaluation score. RESULTS: Overall, 78 male baseball players (age: 18.9 ± 2.4 years) with an average follow-up of 3.1 ± 2.4 years were evaluated, with 73 of the players being baseball pitchers. Players in the double button group more frequently received palmaris longus autografts (78% vs. 30%) and less frequently received gracilis autografts (22% vs. 58%) compared with players in the docking group (P = .001); however, all other demographic factors were similar between the groups. All players in the double button group were able to RTS in 11.1 ± 2.6 months, whereas 96% of players in the docking group were able to RTS in 13.5 ± 3.4 months (P > .05). All postoperative outcomes and patient-reported outcomes were statistically similar between the groups and remained similar after isolating pitchers only and after separating partial-thickness from full-thickness UCL tears (all P > .05). CONCLUSION: RTS and other postoperative outcomes may be similar between baseball players who underwent UCLR with the double button technique and the docking technique. Although future research may be necessary to strengthen clinical recommendations, these findings provide the first clinical outcomes in light of a recent cadaveric study finding similar elbow strength, joint stiffness, and graft strain compared with the docking technique.