Enhancing Clinical Predictive Modeling through Model Complexity-Driven Class Proportion Tuning for Class Imbalanced Data: An Empirical Study on Opioid Overdose Prediction.

Class imbalance issues are prevalent in the medical field and significantly impact the performance of clinical predictive models. Traditional techniques to address this challenge aim to rebalance class proportions. They generally assume that the rebalanced proportions are derived from the original data, without considering the intricacies of the model utilized. This study challenges the prevailing assumption and introduces a new method that ties the optimal class proportions to model complexity. This approach allows for individualized tuning of class proportions for each model. Our experiments, centered on the opioid overdose prediction problem, highlight the performance gains achieved by this approach. Furthermore, rigorous regression analysis affirms the merits of the proposed theoretical framework, demonstrating a statistically significant correlation between hyperparameters controlling model complexity and the optimal class proportions.

Socioeconomic impact and sufficiency of government financial support during COVID-19 pandemic: A retrospective study.

This study examines the socioeconomic impact of the COVID-19 pandemic and the sufficiency of government support. Based on an online survey with 920 respondents, the cross-tabulation and binary logistic regression results show: firstly, in terms of loss of income, male respondents are more likely to have a loss of income as compared to female counterparts, and secondly, among different categories of employment status, the self-employed respondents are the most vulnerable group, given that more than 20 percent of them experienced loss of income due to the COVID-19 pandemic. Moreover, respondents working in small-and-medium enterprises (SMEs) and the informal sector are more likely to face loss of income as compared to respondents working in other sectors of employment. Likewise, respondents without tertiary education level are more likely to have a loss of income as compared to respondents with university certification. The baseline results highlight the insufficiency of government financial support programs based on the perspective of Malaysians from different demographic backgrounds. As a policy implication, the findings could guide the State in formulating the right policies for target groups who need more assistance than others in the community.

Genome sequencing enables diagnosis and treatment of SLC5A6 neuropathy.

The sodium-dependent multivitamin transporter encoded by SLC5A6 is responsible for uptake of biotin, pantothenic acid, and α-lipoic acid. Thirteen individuals from eight families are reported with pathogenic biallelic SLC5A6 variants. Phenotype ranges from multisystem metabolic disorder to childhood-onset peripheral motor neuropathy. We report three additional affected individuals with biallelic SLC5A6 variants. In Family A, a male proband (AII:1) presenting in early childhood with gross motor regression, motor axonal neuropathy, recurrent cytopenia and infections, and failure to thrive was diagnosed at 12 years of age via genome sequencing (GS) with a paternal NM_021095.4:c.393+2T>C variant and a maternal c.1285A>G p.(Ser429Gly) variant. An uncle with recurrent cytopenia and peripheral neuropathy was subsequently found to have the same genotype. We also report an unrelated female with peripheral neuropathy homozygous for the c.1285A>G p.(Ser429Gly) recurrent variant identified in seven reported cases, including this study. RT-PCR studies on blood mRNA from AII:1 showed c.393+2T>C caused mis-splicing with all canonically spliced transcripts in AII:1 containing the c.1285A>G variant. SLC5A6 mRNA expression in AII:1 fibroblasts was ~50% of control levels, indicative of nonsense-mediated decay of mis-spliced transcripts. Biotin uptake studies on AII:1 fibroblasts, expressing the p.(Ser429Gly) variant, showed an ~90% reduction in uptake compared to controls. Targeted treatment of AII:1 with biotin, pantothenic acid, and lipoic acid resulted in clinical improvement. Health Economic analyses showed implementation of GS as an early investigation could have saved $ AUD 105,988 and shortened diagnostic odyssey and initiation of treatment by up to 7 years.

Perceptions of risk and coping strategies during the COVID-19 pandemic among women and older adults.

The world's health, economic, and social systems have been adversely impacted by the COVID-19 pandemic. With lockdown measures being a common response strategy in most countries, many individuals were faced with financial and mental health challenges. The current study explored the effect of the COVID-19 pandemic on the psychological well-being, perception of risk factors and coping strategies of two vulnerable groups in Malaysia, namely women and older adults from low-income households (USD592). A purposive sample of 30 women and 30 older adults was interviewed via telephone during Malaysia's Movement Control Order (MCO) regarding the challenges they faced throughout the pandemic. Thematic analysis was subsequently conducted to identify key themes. The themes identified from the thematic analysis indicated a degree of overlap between both groups. For women, seven themes emerged: 1) Psychological challenges due to COVID-19 pandemic, 2) Family violence, 3) Finance and employment related stress and anxiety, 4) Women's inequality and prejudice, 5) Coping strategies, 6) Professional support, and 7) Women's empowerment. Similarly, there were six themes for the older adults: 1) Adverse emotional experiences from COVID-19, 2) Threats to health security, 3) Loss of social connections, 4) Government aid to improve older adults' psychological well-being, 5) Psychological support from family members and pets, and 6) Self-reliance, religion, and spirituality. The findings provide valuable information on the specific burdens faced by these groups, and support psychological interventions and mitigations that would be appropriate to improve well-being during the recovery phase.

Ancient origin of the rod bipolar cell pathway in the vertebrate retina.

Vertebrates rely on rod photoreceptors for vision in low-light conditions. The specialized downstream circuit for rod signalling, called the primary rod pathway, is well characterized in mammals, but circuitry for rod signalling in non-mammals is largely unknown. Here we demonstrate that the mammalian primary rod pathway is conserved in zebrafish, which diverged from extant mammals ~400 million years ago. Using single-cell RNA sequencing, we identified two bipolar cell types in zebrafish that are related to mammalian rod bipolar cell (RBCs), the only bipolar type that directly carries rod signals from the outer to the inner retina in the primary rod pathway. By combining electrophysiology, histology and ultrastructural reconstruction of the zebrafish RBCs, we found that, similar to mammalian RBCs, both zebrafish RBC types connect with all rods in their dendritic territory and provide output largely onto amacrine cells. The wiring pattern of the amacrine cells postsynaptic to one RBC type is strikingly similar to that of mammalian RBCs and their amacrine partners, suggesting that the cell types and circuit design of the primary rod pathway emerged before the divergence of teleost fish and mammals. The second RBC type, which forms separate pathways, was either lost in mammals or emerged in fish.

Early onset pancreatic cancer-exploring contemporary treatment and outcomes using real-world data.

BACKGROUND: Pancreatic cancer incidence is increasing in younger populations. Differences between early onset pancreatic cancer (EOPC) and later onset pancreatic cancer (LOPC), and how these should inform management warrant exploration in the contemporary setting. METHODS: A prospectively collected multi-site dataset on consecutive pancreatic adenocarcinoma patients was interrogated. Patient, tumour, treatment, and outcome data were extracted for EOPC (≤50 years old) vs LOPC (>50 years old). RESULTS: Of 1683 patients diagnosed between 2016 and 2022, 112 (6.7%) were EOPC. EOPC more frequently had the tail of pancreas tumours, earlier stage disease, surgical resection, and trended towards increased receipt of chemotherapy in the curative setting compared to LOPC. EOPC more frequently received 1st line chemotherapy, 2nd line chemotherapy, and chemoradiotherapy than LOPC in the palliative setting. Recurrence-free survival was improved for the tail of pancreas EOPC vs LOPC in the resected setting; overall survival was superior for EOPC compared to LOPC across the resected, locally advanced unresectable and metastatic settings. CONCLUSIONS: EOPC remains a small proportion of pancreatic cancer diagnoses. The more favourable outcomes in EOPC suggest these younger patients are overall deriving benefits from increased treatment in the curative setting and increased therapy in the palliative setting.

A presynaptic source drives differing levels of surround suppression in two mouse retinal ganglion cell types.

In early sensory systems, cell-type diversity generally increases from the periphery into the brain, resulting in a greater heterogeneity of responses to the same stimuli. Surround suppression is a canonical visual computation that begins within the retina and is found at varying levels across retinal ganglion cell types. Our results show that heterogeneity in the level of surround suppression occurs subcellularly at bipolar cell synapses. Using single-cell electrophysiology and serial block-face scanning electron microscopy, we show that two retinal ganglion cell types exhibit very different levels of surround suppression even though they receive input from the same bipolar cell types. This divergence of the bipolar cell signal occurs through synapse-specific regulation by amacrine cells at the scale of tens of microns. These findings indicate that each synapse of a single bipolar cell can carry a unique visual signal, expanding the number of possible functional channels at the earliest stages of visual processing.

Adjuvant Chemotherapy for Older Patients With Stage III Colorectal Cancer: A Real-World Analysis of Treatment Recommendations, Treatment Administered and Impact on Cancer Recurrence.

BACKGROUND: A substantial proportion of patients with stage III colorectal cancer (CRC) are older than 70 years. Optimal adjuvant chemotherapy (AC) for older patients (OP) continues to be debated, with subgroup analyses of randomized trials not demonstrating a survival benefit from the addition of oxaliplatin to a fluoropyrimidine backbone. PATIENTS AND METHODS: We analyzed the multisite Australian ACCORD registry, which prospectively collects patient, tumor and treatment data along with long term clinical follow-up. We compared OP (≥70) with stage III CRC to younger patients ([YP] <70), including the proportion recommended AC and any reasons for not prescribing AC. AC administration, regimen choice, completion rates, and survival outcomes were also examined. RESULTS: One thousand five hundred twelve patients enrolled in the ACCORD registry from 2005 to 2018 were included. Median follow-up was 57.0 months. Compared to the 827 YP, the 685 OP were less likely to be offered AC (71.5% vs. 96.5%, P < .0001) and when offered, were more likely to decline treatment (15.1% vs. 2.8%, P < .0001). Ultimately, 60.0% of OP and 93.7% of YP received AC (P < .0001). OP were less likely to receive oxaliplatin (27.5% vs. 84.7%, P < .0001) and to complete AC (75.9% vs. 85.7%, P < .0001). The probability of remaining recurrence-free was significantly higher in OP who received AC compared to those not treated (HR 0.73, P = .04) but not significantly improved with the addition of oxaliplatin (HR 0.75, P = .18). CONCLUSION: OP were less likely than YP to receive AC. Receipt of AC reduced recurrences in OP, supporting its use, although no significant benefit was observed from the addition of oxaliplatin.

Sleep-related painful erections: a survey-based analysis of patient-reported experiences with diagnosis and management.

Sleep-related painful erection (SRPE) is a condition characterized by painful nocturnal erections and frequent nighttime awakenings; however, the pathophysiology is not well understood and existing literature consists mainly of case reports. We aimed to investigate the causes, treatments, and impact on quality of life among individuals affected by SRPE. An e-questionnaire comprising of 30 items was administered to a group of men with SRPE identified through social media in October of 2021. The survey collected information on demographics, clinical and social history, symptomatology, interventions and quality of life. 44 patients with SRPE completed surveys (70.9% response rate), with a mean age ± SD of 43.3 ± 12.8 years. Most respondents had no relevant medical history related to erectile function disorders. 43.2% of subjects reported sleep apnea, and 27.1% reported a mental health disorder or psychiatric medication use. Baclofen was the most common medication, but only 25% of patients found it beneficial. Sleep repositioning, oxygen device use and pelvic floor therapy were interventions that provided the most relief. Most patients did not require emergency department visits (93.2%); only a small number needed penile aspiration (n = 2). As reported by most respondents, SRPE significantly impacted patients' quality of life.

Effectiveness of video-based health promotion: A systematic review and meta-analysis.

BACKGROUND: Although health promotion scholars and practitioners frequently employ video-based promotion, its effectiveness remains uncertain due to mixed findings. Nuanced details regarding content and design also remain under-explored. METHODS: We conducted a comprehensive search across nine databases to identify relevant empirical research articles. RESULTS: Our systematic review included a total of 54 studies, with 38 studies eligible for meta-analysis. Findings highlight the promising potential of video messaging strategies in promoting health behaviors. CONCLUSIONS: Future research should focus on designing video content that targets detection behaviors within an appropriate length, guided by robust theoretical frameworks to maximize the efficacy of video promotion. More substantial evidence is needed to assess whether video promotion can achieve similar persuasive effectiveness across diverse cultural, political, and economic circumstances. Factors related to the audience (e.g., distinct psychological and personality influences) and message characteristics (e.g., length, credibility) should be further explored to better elucidate the relationship between video-based health promotion and health outcomes. PRACTICE IMPLICATIONS: Health practitioners and organizations should incorporate video-based messages in interventions as supplement or alternative means to educate audiences of positive prevention methods, establish accurate attitude and intentions toward prevention behaviors, and increase their vigilance toward risky behaviors.

Unified framework for patient-derived, tumor-organoid-based predictive testing of standard-of-care therapies in metastatic colorectal cancer.

Predictive drug testing of patient-derived tumor organoids (PDTOs) holds promise for personalizing treatment of metastatic colorectal cancer (mCRC), but prospective data are limited to chemotherapy regimens with conflicting results. We describe a unified framework for PDTO-based predictive testing across standard-of-care chemotherapy and biologic and targeted therapy options. In an Australian community cohort, PDTO predictions based on treatment-naive patients (n = 56) and response rates from first-line mCRC clinical trials achieve 83% accuracy for forecasting responses in patients receiving palliative treatments (18 patients, 29 treatments). Similar assay accuracy is achieved in a prospective study of third-line or later mCRC treatment, AGITG FORECAST-1 (n = 30 patients). "Resistant" predictions are associated with inferior progression-free survival; misclassification rates are similar by regimen. Liver metastases are the optimal site for sampling, with testing achievable within 7 weeks for 68.8% cases. Our findings indicate that PDTO drug panel testing can provide predictive information for multifarious standard-of-care therapies for mCRC.

Ancient origin of the rod bipolar cell pathway in the vertebrate retina.

Vertebrates rely on rod photoreceptors for vision in low-light conditions. Mammals have a specialized downstream circuit for rod signaling called the primary rod pathway, which comprises specific cell types and wiring patterns that are thought to be unique to this lineage. Thus, it has been long assumed that the primary rod pathway evolved in mammals. Here, we challenge this view by demonstrating that the mammalian primary rod pathway is conserved in zebrafish, which diverged from extant mammals ~400 million years ago. Using single-cell RNA-sequencing, we identified two bipolar cell (BC) types in zebrafish that are related to mammalian rod BCs (RBCs) of the primary rod pathway. By combining electrophysiology, histology, and ultrastructural reconstruction of the zebrafish RBCs, we found that, like mammalian RBCs, both zebrafish RBC types connect with all rods in their dendritic territory, and provide output largely onto amacrine cells. The wiring pattern of the amacrine cells post-synaptic to one RBC type is strikingly similar to that of mammalian RBCs, suggesting that the cell types and circuit design of the primary rod pathway have emerged before the divergence of teleost fish and amniotes. The second RBC type, which forms separate pathways, is either lost in mammals or emerged in fish.

Translational roadmap for regenerative therapies of eye disease.

The translation of regenerative therapies to neuronal eye diseases requires a roadmap specific to the nature of the target diseases, patient population, methodologies for assessing outcome, and other factors. This commentary focuses on critical issues for translating regenerative eye therapies relevant to retinal neurons to human clinical trials.

Ancient origin of the rod bipolar cell pathway in the vertebrate retina.

Vertebrates rely on rod photoreceptors for vision in low-light conditions1. Mammals have a specialized downstream circuit for rod signaling called the primary rod pathway, which comprises specific cell types and wiring patterns that are thought to be unique to this lineage2-6. Thus, it has been long assumed that the primary rod pathway evolved in mammals3,5-7. Here, we challenge this view by demonstrating that the mammalian primary rod pathway is conserved in zebrafish, which diverged from extant mammals ~400 million years ago. Using single-cell RNA-sequencing, we identified two bipolar cell (BC) types in zebrafish that are related to mammalian rod BCs (RBCs) of the primary rod pathway. By combining electrophysiology, histology, and ultrastructural reconstruction of the zebrafish RBCs, we found that, like mammalian RBCs8, both zebrafish RBC types connect with all rods and red-cones in their dendritic territory, and provide output largely onto amacrine cells. The wiring pattern of the amacrine cells post-synaptic to one RBC type is strikingly similar to that of mammalian RBCs. This suggests that the cell types and circuit design of the primary rod pathway may have emerged before the divergence of teleost fish and amniotes (mammals, bird, reptiles). The second RBC type in zebrafish, which forms separate pathways from the first RBC type, is either lost in mammals or emerged in fish to serve yet unknown roles.

Management of Oncogene Driven Locally Advanced Unresectable Non-small Cell Lung Cancer.

INTRODUCTION: The current standard of care of locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiation, followed by consolidation durvalumab. However, there is evidence that the efficacy of chemoradiation and also immunotherapy in many oncogene-positive LA-NSCLC are attenuated, and dependent on the subgroup. AREAS COVERED: We will firstly review the outcomes of standard-of-care therapy in oncogene-driven LA-NSCLC. We looked at various oncogene driven subgroups and the tumor microenvironment that may explain differential response. Finally, we review the role of targeted therapy in the treatment of LA-NSCLC. EXPERT OPINION: Each oncogene-positive subgroup should be treated as its own entity, and continued efforts should be undertaken to incorporate targeted therapy, which is likely to yield superior survival outcomes if trial design can be optimized and toxicities can be managed.

Comparison of Clinical Outcomes, Pathologic Characteristics, and Immune-Related Features of Postradiation vs Sporadic Oral Cavity Squamous Cell Carcinoma.

Importance: Postradiation oral cavity squamous cell carcinoma (OCSCC) is a common secondary malignant neoplasm affecting survivors of head and neck cancer who underwent radiotherapy. The clinical, pathologic, and immune-related features of postradiation OCSCC are poorly characterized, and treatment options are limited because of surgical difficulty and high morbidity associated with reirradiation. Objective: To determine whether postradiation OCSCC has distinctive clinical, pathologic, and immune-related features compared with demographic-matched sporadic OCSCC. Design, Setting, and Participants: This retrospective matched cohort study was conducted at a single tertiary oncology center in Hong Kong. Participants included consecutive patients with OCSCC diagnosed between 2000 and 2020. Patients with postradiation OCSCC were matched with patients with sporadic OCSCC using age, year of diagnosis, sex, and anatomic subsites. Data analysis was performed from July to December 2022. Exposure: Head and neck irradiation involving the oral cavity before the diagnosis of OCSCC. Main Outcomes and Measures: The primary outcomes were relapse pattern, survival, and causes of death. Pathologic features; immunohistochemical staining for programmed death-ligand 1, PD-1, MSH6, PMS2, FOXP3, and Ki67; and mRNA expression of 31 immune-related genes were also analyzed. Results: A total of 173 patients, 60 with postradiation OCSCC (median [IQR] age, 63.8 [53.0-71.7] years; 43 men [71.7%]) and 113 with sporadic OCSCC (median [IQR] age, 64.4 [52.8-70.6] years; 83 men [73.5%]), were included. Patients with postradiation OCSCC had a higher proportion of N0 disease than those with sporadic OCSCC (50 patients [83.3%] vs 56 patients [49.6%]). With a median (IQR) follow-up of 10.2 (1.2-20.5) years, the 10-year relapse-free survival rates were lower in patients with postradiation OCSCC than sporadic OCSCC (29.6% [95% CI, 17.1%-43.2%] vs 52.4% [95% CI, 41.8%-62.0%]; P = .04), and the same was true for overall survival (30.5% [95% CI, 17.6%-44.4%] vs 52.3% [95% CI, 41.4%-62.1%]; P = .03). All relapses in patients with postradiation OCSCC were locoregional, whereas 35.2% of relapses (12 of 34 patients) in patients with sporadic OCSCC were distant. Despite similar 10-year disease-specific survival rates between the 2 groups (68.8% [95% CI, 55.8%-81.0%] vs 67.1% [95% CI, 57.5%-76.5%]; P = .91), patients with postradiation OCSCC had excess mortality due to pneumonia and cerebrovascular events. Postradiation OCSCC exhibited more adverse pathologic features (perineural invasion, worse pattern of invasion, and tumor budding), higher PD-1 expression, and higher gene expression of CD4 and TGF-ß compared with sporadic OCSCC. Conclusions and Relevance: This retrospective matched cohort study found distinctive pathologic characteristics and relapse patterns of postradiation OCSCC compared with sporadic OCSCC, which may be attributable to the lack of adjuvant radiotherapy, aggressive biologic phenotype, and different host immune response. Further exploration of the role of immune checkpoint therapy may be justified.

Can the size of chest wall recurrence after mastectomy in breast cancer patients predict the presence of systemic metastasis?

Background: One of the manifestations of recurrence after mastectomy is the presentation of chest wall lesion. However, it is unclear if the size of the chest wall recurrence (CWR) is related to the presence of simultaneous systemic metastasis in these patients. We aimed to determine if the size of the CWR could affect the outcome in these patients. Methods: Stage I-III breast cancer patients who underwent mastectomy and developed invasive ipsilateral CWR were included. Patients with bilateral mastectomy were excluded. Demographic, radiologic and pathological data were analysed between patients with CWR and simultaneous systemic metastasis versus those with isolated CWR. Results: Of the 1,619 patients treated with mastectomy, 214 (13.2%) patients developed recurrences. 57/214 (26.6%) patients had invasive ipsilateral CWR. 48 patients were analysed after exclusion of patients with missing data. Mean age at diagnosis of first cancer and at recurrence were 55.2 years (32-84 years) and 58.5 years (34-85 years) respectively. 26/48 (54.2%) had CWR with simultaneous systemic metastasis. Mean CWR size was 30.7 mm (6-121 mm) and 21.4 mm (5.3-90 mm) for the patients with simultaneous systemic metastasis and those without respectively (P=0.441). Grade (P=0.0008) and nodal status (P=0.0009) at primary diagnosis, grade (P=0.0011) and progesterone receptor (PR) status (P=0.0487) at recurrence were statistically significant for systemic metastasis in patients with CWR. Conclusions: Biologic factors such as grade of primary and recurrent cancer, PR status of recurrent cancer and nodal status at primary diagnosis, instead of CWR size, were associated with simultaneous systemic metastasis in patients with CWR.

Does COVID-19 Infection Increase the Risk of Diabetes? Current Evidence.

PURPOSE OF REVIEW: Multiple studies report an increased incidence of diabetes following SARS-CoV-2 infection. Given the potential increased global burden of diabetes, understanding the effect of SARS-CoV-2 in the epidemiology of diabetes is important. Our aim was to review the evidence pertaining to the risk of incident diabetes after COVID-19 infection. RECENT FINDINGS: Incident diabetes risk increased by approximately 60% compared to patients without SARS-CoV-2 infection. Risk also increased compared to non-COVID-19 respiratory infections, suggesting SARS-CoV-2-mediated mechanisms rather than general morbidity after respiratory illness. Evidence is mixed regarding the association between SARS-CoV-2 infection and T1D. SARS-CoV-2 infection is associated with an elevated risk of T2D, but it is unclear whether the incident diabetes is persistent over time or differs in severity over time. SARS-CoV-2 infection is associated with an increased risk of incident diabetes. Future studies should evaluate vaccination, viral variant, and patient- and treatment-related factors that influence risk.

Right-leaning egalitarians are just as susceptible to social justice-induced product patronage! Evidence from the US and Malaysia.

We investigated the impact of egalitarianism on consumers' inclination to support fair-trade products and examined whether this effect was observed among individuals with different political affiliations. In four experiments featuring a fictional chocolate brand presented in either a social-justice (fair trade) or quality-focused (control) manner, we examined the product purchase intentions of both left- and right-leaning consumers in the United States and Malaysia (Studies 1a, N = 200; 1b, N = 269; & 2, N = 410). Results revealed that participants expressed a greater willingness to support the product when it was framed as contributing to a social justice cause, but this effect was limited to left- and right-leaning consumers who strongly endorsed egalitarian principles. Study 3 (N = 354) employed a mediated-moderation approach and confirmed that an elevated sensitivity to injustice was the underlying mechanism driving increased intentions to support the product among egalitarians exposed to social justice framing. These results demonstrate that right-leaning consumers can be influenced by social justice framing when their commitment to equity is strong.