Defining Global Benchmarks for Laparoscopic Right Posterior Sectionectomy/H67: An International Multicenter Study.

OBJECTIVE: We aimed to establish global benchmark outcomes indicators for L-RPS/H67. BACKGROUND: Minimally invasive liver resections has seen an increase in uptake in recent years. Over time, challenging procedures as laparoscopic right posterior sectionectomies (L-RPS)/H67 are also increasingly adopted. METHODS: This is a post hoc analysis of a multicenter database of 854 patients undergoing minimally invasive RPS (MI-RPS) in 57 international centers in 4 continents between 2015 and 2021. There were 651 pure L-RPS and 160 robotic RPS (R-RPS). Sixteen outcome indicators of low-risk L-RPS cases were selected to establish benchmark cutoffs. The 75th percentile of individual center medians for a given outcome indicator was set as the benchmark cutoff. RESULTS: There were 573 L-RPS/H67 performed in 43 expert centers, of which 254 L-RPS/H67 (44.3%) cases qualified as low risk benchmark cases. The benchmark outcomes established for operation time, open conversion rate, blood loss ≥500 mL, blood transfusion rate, postoperative morbidity, major morbidity, 90-day mortality and textbook outcome after L-RPS were 350.8 minutes, 12.5%, 53.8%, 22.9%, 23.8%, 2.8%, 0% and 4% respectively. CONCLUSIONS: The present study established the first global benchmark values for L-RPS/H6/7. The benchmark provided an up-to-date reference of best achievable outcomes for surgical auditing and benchmarking.

The impact of social isolation on functional disability in older people: A multi-cohort study.

OBJECTIVES: We assessed the relationship between social isolation and functional disability in older people. DESIGN: Comparison of longitudinal cohort studies. SETTING AND PARTICIPANTS: Harmonised longitudinal datasets from the United States, England, European countries, Japan, Korea, China and Hong Kong. METHODS: Social isolation was operationalised as a composite score with five domains, such as marital status, living alone, and social contact with others. Functional disability was defined as whether the cohort participant had any difficulty in activities of daily living (ADL). In each dataset, we used robust Poisson regression models to obtain the relative risks (RRs) and the corresponding 95 % confidence intervals (CI). We combined the RRs to synthesize a pooled estimate using meta-analysis with random-effects models. RESULTS: Overall, the social isolation composite score was not associated with ADL disability (pooled RR = 1.05, 95 % CI [0.97-1.14], n = 40,119). Subgroup analysis suggested social isolation composite score was associated with ADL disability in Asian regions (pooled RR = 1.09, 95 % CI [1.02, 1.16], but not in Western regions (pooled RR = 1.01, 95 % CI [0.96, 1.07]). The relationships between different domains of social isolation and ADL disability were heterogeneous, except that no participation in any social clubs or religious groups was consistently associated with ADL disability (pooled RR = 1.12, 95 % CI [1.04, 1.21]). CONCLUSION: Targeting social isolation may prevent decline in functional abilities in older adults, providing an avenue to active and healthy ageing. Nonetheless, interventions tackling social isolation should tailor to the unique cultural and social underpinnings. A limitation of the study is that reverse causality could not be ruled out definitively.

Underserved groups could be better considered within population-based eye health surveys: A methodological study.

OBJECTIVE: In pursuit of health equity, the World Health Organization has recently called for more extensive monitoring of inequalities in eye health. Population-based eye health surveys can provide this information, but whether underserved groups are considered in the design, implementation, and reporting of surveys is unknown. We conducted a systematic methodological review of surveys published since 2000 to examine how many population-based eye health surveys have considered underserved groups in their design, reporting, or implementation. STUDY DESIGN AND SETTING: We identified all population-based cross-sectional surveys reporting the prevalence of objectively measured vision impairment or blindness. Using the PROGRESS+ framework to identify underserved groups, we assessed whether each study considered underserved groups within 15 items across the rationale, sampling or recruitment methods, or the reporting of participation and prevalence rates. RESULTS: 388 eye health surveys were included in this review. Few studies prospectively considered underserved groups during study planning or implementation, for example within their sample size calculations (n=5, ∼1%) or recruitment strategies (n=70, 18%). The most common way that studies considered underserved groups was in the reporting of prevalence estimates (n=374, 96%). We observed a modest increase in the number of distinct PROGRESS+ factors considered by a publication over the study period. Gender/sex was considered within at least one item by 95% (n=267) of studies. Forty-three percent (n=166) of included studies were conducted primarily on underserved population groups, particularly for sub-national studies of people living in rural areas, and we identified examples of robust population-based studies in socially excluded groups. CONCLUSION: More effort is needed to improve the design, implementation, and reporting of surveys to monitor inequality and promote equity in eye health. Ideally, national-level monitoring of vision impairment and service coverage would be supplemented with smaller-scale studies to understand the disparities experienced by the most underserved groups.

Protocol for the creation and characterization of SARS-CoV-2 variant testing panels using remnant clinical samples for diagnostic assay testing.

The emergence of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Alpha variant in 2020 demonstrated the need for reanalysis of diagnostic tests to ensure detection of emerging variants. Here, we present a protocol for creating and characterizing SARS-CoV-2 variant testing panels using remnant clinical samples for diagnostic assay testing. We describe steps for characterizing SARS-CoV-2 remnant clinical samples and preparing them into pools and their use in preparing varying quantities of virus. We then detail procedures for verifying variant detection using the resulting sample panel. For complete details on the use and execution of this protocol, please refer to Rao et al.1,2.

Update on management of pancreatic cancer: a literature review.

BACKGROUND AND OBJECTIVE: Pancreatic cancer is an aggressive malignancy with high mortality. At the time of diagnosis, majority of patients (80-90%) present with either locally advanced unresectable disease or metastatic disease. Even after curative resection, the recurrence rate remains quite high. This article aimed at reviewing the updated management of pancreatic cancer. METHODS: We identified literature by searching Medline and PubMed from January 2010 to June 2023 using the keywords. KEY CONTENT AND FINDINGS: A multidisciplinary approach is essential to optimize the outcomes for both curable and advanced diseases. Management of pancreatic cancer divided into resectable, borderline resectable, locally advanced, and metastatic diseases. Surgery and adjuvant chemotherapy is a standard treatment approach for resectable pancreatic cancer. The recommended adjuvant chemotherapy regimen for patients with good functional status is modified FOLFIRINOX (5-fluorouracil, folinic acid, irinotecan, and oxaliplatin). The recommended adjuvant chemotherapy regimen for patients with suboptimal functional status is gemcitabine plus capecitabine or monotherapy gemcitabine. The optimal treatment strategy for borderline resectable pancreatic cancer is still uncertain. Traditionally, upfront surgery is the choice of treatment. There is increasing evidence showing benefits of neoadjuvant therapy in borderline resectable pancreatic cancer. However, the optimal neoadjuvant treatment regimen was not certain yet. Advancement of chemotherapy has a positive impact for the survival of advanced disease. For patients with good functional status, the recommended first-line systemic chemotherapy for unresectable locally advanced disease or metastatic disease is combination chemotherapy regimens such as FOLFIRINOX, gemcitabine plus nab-paclitaxel. For patients with suboptimal functional status, the recommended first-line systemic chemotherapy for unresectable locally advanced disease or metastatic disease is gemcitabine plus capecitabine or monotherapy gemcitabine. Recently, more researches showed promising results in the use of nanoliposomal irinotecan, targeted agents such as a poly [adenosine diphosphate (ADB)-ribose] polymerase inhibitor, tyrosine receptor kinase (TRK) inhibitors, and immune checkpoint-inhibitors. CONCLUSIONS: Pancreatic cancer is a challenging disease for management. Radical surgery itself is not enough for prolong survival. The improvement of chemotherapy, target agents and immunotherapy with multidisciplinary approach will be the only solution for improvement of survival outcome and quality of life for patients with pancreatic cancer.

The structural landscape of Microprocessor Mediated pri-let-7 miRNAs processing.

miRNA biogenesis is initiated upon cleavage of a primary miRNA (pri-miRNA) hairpin by Microprocessor (MP), composed of the Drosha RNase III enzyme and its partner DGCR8. Multiple pri-miRNA sequence motifs affect MP recognition, fidelity, and efficiency. Here, we performed cryo-EM and biochemical studies of several let-7 family pri-miRNAs in complex with human MP. We show that MP has structural plasticity to accommodate different pri-miRNAs. These also revealed key structural features of the 5' UG sequence motif, more comprehensively represented as the "fUN" motif. Our analysis explains how the bulged nucleotide in class-II pri-let-7 members alters Drosha cleavage, generating a noncanonical precursor with 1-nt 3' overhang. Finally, the MP-SRSF3-pri-let-7f1 structure reveals how SRSF3 interacts with the CNNC motif and Drosha's PAZ-like domain, to promote proper Drosha loading onto the basal hairpin junction. Overall, our work illuminates the mechanisms for flexible recognition, accurate cleavage, and regulated processing of different pri-miRNAs by MP.

The rapidly evolving X-linked MIR-506 family fine-tunes spermatogenesis to enhance sperm competition.

Despite rapid evolution across eutherian mammals, the X-linked MIR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (SLITRK2 and FMR1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked MIR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernible defects, but simultaneous ablation of five clusters containing 19 members of the MIR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility, and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked MIR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the MIR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.

Social determinants of intrinsic capacity: A systematic review of observational studies.

BACKGROUND: The World Health Organization defined healthy ageing as the maintenance of functional ability with ageing. Intrinsic capacity is a measurement of healthy ageing, and can be shaped by social determinants. However, an overall understanding of how multiple social determinants contribute to intrinsic capacity remains unclear. We aim to summarize observational studies investigating the relationships between social determinants and intrinsic capacity among community-dwelling adults. METHODS: A systematic search was conducted through Medline, Embase, PsycInfo, Web of Science, and CINAHL until August 14, 2023. RESULTS: After reviewing 813 articles, we included 21 studies from nine countries in Asia, Europe, and America. Seventeen studies used a cross-sectional design and the others were longitudinal studies. Social determinants related to intrinsic capacity can be classified into five domains, containing socioeconomic status (16, 76.2% of studies), lifestyles (14, 66.7%), psychosocial factors (9, 42.9%), material circumstances (4, 19.0%), and healthcare systems (1, 4.8%). Strong evidence supported that better intrinsic capacity was associated with higher education, higher wealth, more physical activities, no smoking, more social engagement, and being married or partnered. The relationships of intrinsic capacity with dietary patterns and alcohol drinking were contradictory across studies. Research on the associations of working status, housing environments, and healthcare accessibility with intrinsic capacity was insufficient to draw conclusions. CONCLUSION: These findings highlight roles of socioeconomic status, lifestyles, and psychosocial factors in improving intrinsic capacity thus promoting healthy ageing. Future research is needed to investigate causal relationships between social determinants and intrinsic capacity, especially material circumstances and healthcare systems.

The Rapidly Evolving X-linked miR-506 Family Finetunes Spermatogenesis to Enhance Sperm Competition.

Despite rapid evolution across eutherian mammals, the X-linked miR-506 family miRNAs are located in a region flanked by two highly conserved protein-coding genes (Slitrk2 and Fmr1) on the X chromosome. Intriguingly, these miRNAs are predominantly expressed in the testis, suggesting a potential role in spermatogenesis and male fertility. Here, we report that the X-linked miR-506 family miRNAs were derived from the MER91C DNA transposons. Selective inactivation of individual miRNAs or clusters caused no discernable defects, but simultaneous ablation of five clusters containing nineteen members of the miR-506 family led to reduced male fertility in mice. Despite normal sperm counts, motility and morphology, the KO sperm were less competitive than wild-type sperm when subjected to a polyandrous mating scheme. Transcriptomic and bioinformatic analyses revealed that these X-linked miR-506 family miRNAs, in addition to targeting a set of conserved genes, have more targets that are critical for spermatogenesis and embryonic development during evolution. Our data suggest that the miR-506 family miRNAs function to enhance sperm competitiveness and reproductive fitness of the male by finetuning gene expression during spermatogenesis.

Autologous Breast Reconstruction Success Rates in Hypercoagulable Patients.

BACKGROUND: Hypercoagulable disorders may adversely affect microsurgical outcomes, including increased flap failure and complication rates. Outcomes specific to autologous breast reconstruction are not well described. METHODS: A retrospective review was performed of autologous breast reconstructions between 2009 and 2020. Patients with either a thrombophilic disorder (TD) diagnosis or a previous thrombotic event (TE) were identified. The analysis compared perioperative complications and flap success rates. RESULTS: In this series, 23 patients with a TD underwent 39 flaps, and 78 patients who had experienced a TE underwent 126 flaps, compared with 815 control patients, who underwent 1300 flaps. In logistic regression models, a TD diagnosis was an independent predictor of early total flap loss [OR, 8.42 (95% CI, 1.59 to 44.47); P = 0.01], late partial flap loss [OR, 3.9 (95% CI, 1.0 to 15.22); P = 0.05], and delayed healing [OR, 2.26 (95% CI, 1.02 to 5.04); P = 0.04]. TE history trended toward an association only with late partial flap loss ( P = 0.057). Flap salvage rates (25%) and flap success rates (92.3%) were statistically lower in patients with a TD but normal in patients who had experienced a TE. CONCLUSIONS: Microsurgical breast reconstruction is a reasonable option for patients with hypercoagulation disorders. No increased risk of flap complications was associated with a previous TE; however, TDs carried increased risk. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

A tailed mirtron promotes longevity in Drosophila.

Thousands of atypical microRNAs (miRNAs) have been described in the genomes of animals; however, it is unclear if many of these non-canonical miRNAs can measurably influence phenotypes. Mirtrons are the largest class of non-canonical miRNAs that are produced from hairpins excised by splicing, which after debranching become substrates for Dicer and load into RISC. Most mirtrons require additional processing after splicing to remove 'tail' residues interposed between one of the host intron splice sites and base of the hairpin precursor structure. Despite most mirtrons requiring tail removal no function has been elucidated for a tailed species, indeed for all mirtrons identified function has only been assigned to a single species. Here we study miR-1017, a mirtron with a 3' tail, which is well expressed and conserved in Drosophila species. We found that miR-1017 can extend lifespan when ectopically expressed in the neurons, which seems partly due to this miRNA targeting its host transcript, acetylcholine receptor Dα2. Unexpectedly we found that not only did miR-1017 function in trans but also in cis by affecting splicing of Dα2. This suggests a mechanism for mirtron evolution where initial roles of structural elements in splicing lead to secondary acquisition of trans-regulatory function.

Impact of liver cirrhosis, severity of cirrhosis and portal hypertension on the difficulty of laparoscopic and robotic minor liver resections for primary liver malignancies in the anterolateral segments.

INTRODUCTION: We performed this study in order to investigate the impact of liver cirrhosis (LC) on the difficulty of minimally invasive liver resection (MILR), focusing on minor resections in anterolateral (AL) segments for primary liver malignancies. METHODS: This was an international multicenter retrospective study of 3675 patients who underwent MILR across 60 centers from 2004 to 2021. RESULTS: 1312 (35.7%) patients had no cirrhosis, 2118 (57.9%) had Child A cirrhosis and 245 (6.7%) had Child B cirrhosis. After propensity score matching (PSM), patients in Child A cirrhosis group had higher rates of open conversion (p = 0.024), blood loss >500 mls (p = 0.001), blood transfusion (p < 0.001), postoperative morbidity (p = 0.004), and in-hospital mortality (p = 0.041). After coarsened exact matching (CEM), Child A cirrhotic patients had higher open conversion rate (p = 0.05), greater median blood loss (p = 0.014) and increased postoperative morbidity (p = 0.001). Compared to Child A cirrhosis, Child B cirrhosis group had longer postoperative stay (p = 0.001) and greater major morbidity (p = 0.012) after PSM, and higher blood transfusion rates (p = 0.002), longer postoperative stay (p < 0.001), and greater major morbidity (p = 0.006) after CEM. After PSM, patients with portal hypertension experienced higher rates of blood loss >500 mls (p = 0.003) and intraoperative blood transfusion (p = 0.025). CONCLUSION: The presence and severity of LC affect and compound the difficulty of MILR for minor resections in the AL segments. These factors should be considered for inclusion into future difficulty scoring systems for MILR.

Impact of Liver Cirrhosis, Severity of Cirrhosis, and Portal Hypertension on the Difficulty and Outcomes of Laparoscopic and Robotic Major Liver Resections for Primary Liver Malignancies.

BACKGROUND: Minimally invasive liver resections (MILR) offer potential benefits such as reduced blood loss and morbidity compared with open liver resections. Several studies have suggested that the impact of cirrhosis differs according to the extent and complexity of resection. Our aim was to investigate the impact of cirrhosis on the difficulty and outcomes of MILR, focusing on major hepatectomies. METHODS: A total of 2534 patients undergoing minimally invasive major hepatectomies (MIMH) for primary malignancies across 58 centers worldwide were retrospectively reviewed. Propensity score (PSM) and coarsened exact matching (CEM) were used to compare patients with and without cirrhosis. RESULTS: A total of 1353 patients (53%) had no cirrhosis, 1065 (42%) had Child-Pugh A and 116 (4%) had Child-Pugh B cirrhosis. Matched comparison between non-cirrhotics vs Child-Pugh A cirrhosis demonstrated comparable blood loss. However, after PSM, postoperative morbidity and length of hospitalization was significantly greater in Child-Pugh A cirrhosis, but these were not statistically significant with CEM. Comparison between Child-Pugh A and Child-Pugh B cirrhosis demonstrated the latter had significantly higher transfusion rates and longer hospitalization after PSM, but not after CEM. Comparison of patients with cirrhosis of all grades with and without portal hypertension demonstrated no significant difference in all major perioperative outcomes after PSM and CEM. CONCLUSIONS: The presence and severity of cirrhosis affected the difficulty and impacted the outcomes of MIMH, resulting in higher blood transfusion rates, increased postoperative morbidity, and longer hospitalization in patients with more advanced cirrhosis. As such, future difficulty scoring systems for MIMH should incorporate liver cirrhosis and its severity as variables.

The role of older adult-focused social vulnerability on the relationship between temperature and emergency department attendance in a subtropical Asian city.

PURPOSE: Older adults exhibit a wide range of capabilities and vulnerabilities that affect their capacity to respond to heat. This study analysed the associations between hot temperatures and Accident & Emergency (A&E) attendance taking into account older adult-focused social vulnerability. METHODS: Daily A&E attendance data of Young-old (65-74) and Old-old (75+) was obtained for Hong Kong 2010-2019 hot seasons and stratified into three Social Vulnerability Index (SVI) groups (Low, Moderate, High). Mean temperature (lag 0-2) was analysed on A&E attendance at each SVI using Generalized Additive Models and Distributed Lag Non-linear Models. RESULTS: High temperatures were associated with increased same-day (lag 0) relative risk (RR) of A&E attendance for Young-old and Old-old in High SVI districts, with RR being 1.024 (95 % CI: 1.011, 1.037) and 1.036 (95 % CI: 1.018, 1.053), respectively. The Old-old living in Moderate and Low SVI districts also demonstrated increased RR of 1.037 (95 % CI: 1.028, 1.047) and 1.022 (95 % CI: 1.009, 1.036), respectively. Fewer emergency visits were found on the subsequent day (lag 1) of hot temperatures. CONCLUSIONS: Older adults, both young-old and old-old, living in districts with higher social vulnerability tended to have increased risk of A&E attendance associated with same-day high temperature. With climate change and rapidly aging population, cities should prepare to meet needs of more vulnerable older adults in extreme heat.

A nonneural miRNA cluster mediates hearing via repression of two neural targets.

We show here that mir-279/996 are absolutely essential for development and function of Johnston's organ (JO), the primary proprioceptive and auditory organ in Drosophila Their deletion results in highly aberrant cell fate determination, including loss of scolopale cells and ectopic neurons, and mutants are electrophysiologically deaf. In vivo activity sensors and mosaic analyses indicate that these seed-related miRNAs function autonomously to suppress neural fate in nonneuronal cells. Finally, genetic interactions pinpoint two neural targets (elav and insensible) that underlie miRNA mutant JO phenotypes. This work uncovers how critical post-transcriptional regulation of specific miRNA targets governs cell specification and function of the auditory system.

Standardization and Comparison of Emergency Use Authorized COVID-19 Assays and Testing Laboratories.

Motivation: The motivation for this work was the need to establish a predefined cutoff based on genome copies per ml (GE/ml) rather than Ct, which can vary depending on the laboratory and assay used. A GE/ml-based threshold was necessary to define what constituted 'low positives" for samples that were included in data sets submitted to the FDA for emergency use approval for SARS-CoV-2 antigen tests. Summary: SARS-CoV-2, the causal agent of the global COVID-19 pandemic, made its appearance at the end of 2019 and is still circulating in the population. The pandemic led to an urgent need for fast, reliable, and widely available testing. After December 2020, the emergence of new variants of SARS-CoV-2 led to additional challenges since new and existing tests had to detect variants to the same extent as the original Wuhan strain. When an antigen-based test is submitted to the Food and Drug Administration (FDA) for Emergency Use Authorization (EUA) consideration it is benchmarked against PCR comparator assays, which yield cycle threshold (CT) data as an indirect indicator of viral load - the lower the CT, the higher the viral load of the sample and the higher the CT, the lower the viral load. The FDA mandates that 10-20% of clinical samples used to evaluate the antigen test have to be low positive. Low positive, as defined by the FDA, are clinical samples in which the CT of the SARS-CoV-2 target gene is within 3 CT of the mean CT value of the approved comparator test's Limit of Detection (LOD). While all comparator tests are PCR-based, the results from different PCR assays used are not uniform. Results vary depending on assay platform, target gene, LOD and laboratory methodology. The emergence and dominance of the Omicron variant further challenged this approach as the fraction of low positive clinical samples dramatically increased as compared to earlier SARS-CoV-2 variants. This led to 20-40% of clinical samples having high CT values and therefore assays vying for an EUA were failing to achieve the 80% Percent Positive Agreement (PPA) threshold required. Here we describe the methods and statistical analyses used to establish a predefined cutoff, based on genome copies per ml (GE/ml) to classify samples as low positive (less than the cutoff GE/ml) or high positive (greater than the cutoff GE/mL). CT 30 for the E gene target using Cobas® SARS-CoV-2-FluA/B platform performed at TriCore Reference Laboratories, and this low positive cutoff value was used for two EUA authorizations. Using droplet digital PCR and methods described here, a value 49,447.72 was determined as the GE/ml equivalent for the low positive cutoff. The CT cutoff corresponding to 49447.72 GE/ml was determined across other platforms and laboratories. The methodology and statistical analysis described here can now be used for standardization of all comparators used for FDA submissions with a goal towards establishing uniform criteria for EUA authorization.

Secular trends of life expectancy and disability-free life expectancy at age 65 and associated gender and area-level socioeconomic inequalities in Hong Kong: a serial cross-sectional study between 2007 and 2020.

Background: Despite Hong Kong's world leading longevity, little is known about its associated disability burden and social patterning. Hence, this study assessed the gender-specific secular trends and area-level inequalities in life expectancy (LE) and disability-free life expectancy (DFLE) at age 65 in Hong Kong. Methods: Population structure, death records, and disability data in 2007, 2013, and 2020 were retrieved from the Census and Statistics Department to estimate LE and DFLE using the Sullivan Method. District-based sociodemographic indicators were used to compare LE and DFLE across 18 districts of Hong Kong in 2013. Findings: Between 2007 and 2020, LE at age 65 increased by 3.7 years (from 18.3 to 22.0) in men and by 2.1 years (from 22.7 to 24.8) in women. By contrast, DFLE increased more slowly, by 1.8 years (from 14.6 to 16.3) in men and by only 0.1 year (from 16.4 to 16.5) in women, leading to a substantial increase in proportion of life spent with disability. Results from multiple linear regression using district-based data in 2013 showed a similar extent of associations of education with LE and DFLE (mean year difference: 0.81 [95% CI: 0.14, 1.48] and 0.68 [0.10, 1.27], respectively, per 10% increase in average education level), while female gender was more strongly associated with LE (4.44 [3.56, 5.31]) than with DFLE (2.00 [1.18, 2.82]). Interpretation: Expansion of disability burden and male-female health-survival paradox hold true in Hong Kong. Unlike Western countries with a stronger socioeconomic patterning of DFLE, the extent of area-level socioeconomic inequalities in LE and DFLE appears to be more comparable in Hong Kong. Funding: Health and Medical Research Fund (Ref. no.: 19202031) by the Health Bureau of Hong Kong.

Regulation of alternative splicing and polyadenylation in neurons.

Cell-type-specific gene expression is a fundamental feature of multicellular organisms and is achieved by combinations of regulatory strategies. Although cell-restricted transcription is perhaps the most widely studied mechanism, co-transcriptional and post-transcriptional processes are also central to the spatiotemporal control of gene functions. One general category of expression control involves the generation of multiple transcript isoforms from an individual gene, whose balance and cell specificity are frequently tightly regulated via diverse strategies. The nervous system makes particularly extensive use of cell-specific isoforms, specializing the neural function of genes that are expressed more broadly. Here, we review regulatory strategies and RNA-binding proteins that direct neural-specific isoform processing. These include various classes of alternative splicing and alternative polyadenylation events, both of which broadly diversify the neural transcriptome. Importantly, global alterations of splicing and alternative polyadenylation are characteristic of many neural pathologies, and recent genetic studies demonstrate how misregulation of individual neural isoforms can directly cause mutant phenotypes.

Parameters of clustered suboptimal miRNA biogenesis.

The nuclear cleavage of a suboptimal primary miRNA hairpin by the Drosha/DGCR8 complex ("Microprocessor") can be enhanced by an optimal miRNA neighbor, a phenomenon termed cluster assistance. Several features and biological impacts of this new layer of miRNA regulation are not fully known. Here, we elucidate the parameters of cluster assistance of a suboptimal miRNA and also reveal competitive interactions amongst optimal miRNAs within a cluster. We exploit cluster assistance as a functional assay for suboptimal processing and use this to invalidate putative suboptimal substrates, as well as identify a "solo" suboptimal miRNA. Finally, we report complexity in how specific mutations might affect the biogenesis of clustered miRNAs in disease contexts. This includes how an operon context can buffer the effect of a deleterious processing variant, but reciprocally how a point mutation can have a nonautonomous effect to impair the biogenesis of a clustered, suboptimal, neighbor. These data expand our knowledge regarding regulated miRNA biogenesis in humans and represent a functional assay for empirical definition of suboptimal Microprocessor substrates.

An Updated Systematic Review and Meta-Analysis of Tissue Oximetry Versus Conventional Methods for Postoperative Monitoring of Autologous Breast Reconstruction.

BACKGROUND: Tissue oximetry monitoring has shown superior outcomes to conventional monitoring methods for autologous breast reconstruction in retrospective studies with consecutive cohorts. A recent study used consecutive cohorts with tissue oximetry as the earlier cohort and found that tissue oximetry was nonsuperior. We hypothesize that improvement in microsurgical outcomes with institutional experience confounds the superiority of tissue oximetry demonstrated in prior studies. This study aimed to perform a systematic review and meta-analysis of the outcomes of tissue oximetry monitoring compared with conventional monitoring. METHODS: Relevant studies were found using PubMed, Embase, and Web of Science searches for keywords such as near-infrared spectroscopy or tissue oximetry and microsurgery. Studies included compared tissue oximetry and conventional monitoring in autologous breast reconstruction patients. Studies were excluded if they did not contain a comparison group. Random-effective models were used to analyze early returns to the operating room, the total number of partial or complete flap loss, and late fat necrosis. RESULTS: Six hundred sixty-nine studies were identified; 3 retrospective cohort studies met the inclusion criteria. A total of 1644 flaps were in the tissue oximetry cohort, and 1387 flaps were in the control cohort. One study contained tissue oximetry as the former cohort; 2 had tissue oximetry as the latter. Neither technique was superior for any measured outcomes. The estimated mean differences between tissue oximetry and conventional monitoring method were early returns, -0.06 (95% confidence interval [CI], -0.52 to 0.410; P = 0.82); partial flap loss, -0.04 (95% CI, -0.86 to 0.79; P = 0.93); complete flap loss, -1.29 (95% CI, -3.45 to 0.87; P = 0.24); and late fat necrosis -0.02 (95% CI, -0.42 to, 0.39; P = 0.94). CONCLUSIONS: In a systematic review and meta-analysis of mixed timeline retrospective cohort studies, tissue oximetry does not provide superior patient outcomes and shifts our current understanding of postoperative breast reconstruction monitoring. Prospective studies and randomized trials comparing monitoring methods need to be included in the existing literature.