NT-proBNP point-of-care testing for predicting mortality in end-stage renal disease: A survival analysis.

This study examines the predictive value of elevated N-terminal-pro brain natriuretic peptide (NT-pro BNP) levels for mortality among patients with end-stage renal disease (ESRD). Data from 768 ESRD patients, excluding those with cancer or lost follow-up, were analyzed using Kaplan-Meier curves and Cox proportional hazards models over three years. Results indicated that patients with very high NT-pro BNP levels had shorter average survival times and a significantly higher risk of mortality (hazard ratio 1.43). Advanced age, ICU admission, and comorbidities like cerebrovascular diseases and chronic obstructive pulmonary disease also contributed to increased mortality risks. Thus, elevated NT-pro BNP is an independent risk factor for mortality in ESRD patients.

Susceptibility to Treatment-Resistant Depression Within Families.

Importance: Antidepressant responses and the phenotype of treatment-resistant depression (TRD) are believed to have a genetic basis. Genetic susceptibility between the TRD phenotype and other psychiatric disorders has also been established in previous genetic studies, but population-based cohort studies have not yet provided evidence to support these outcomes. Objective: To estimate the TRD susceptibility and the susceptibility between TRD and other psychiatric disorders within families in a nationwide insurance cohort with extremely high coverage and comprehensive health care data. Design, Setting, and Participants: This cohort study assessed data from the Taiwan national health insurance database across entire population (N = 26 554 001) between January 2003 and December 2017. Data analysis was performed from August 2021 to April 2023. TRD was defined as having experienced at least 3 distinct antidepressant treatments in the current episode, each with adequate dose and duration, based on the prescribing records. Then, we identified the first-degree relatives of individuals with TRD (n = 34 467). A 1:4 comparison group (n = 137 868) of first-degree relatives of individuals without TRD was arranged for the comparison group, matched by birth year, sex, and kinship. Main Outcomes and Measures: Modified Poisson regression analyses were performed and adjusted relative risks (aRRs) and 95% CIs were calculated for the risk of TRD, the risk of other major psychiatric disorders, and different causes of mortality. Results: This study included 172 335 participants (88 330 male and 84 005 female; mean [SD] age at beginning of follow-up, 22.9 [18.1] years). First-degree relatives of individuals with TRD had lower incomes, more physical comorbidities, higher suicide mortality, and increased risk of developing TRD (aRR, 9.16; 95% CI, 7.21-11.63) and higher risk of other psychiatric disorders than matched control individuals, including schizophrenia (aRR, 2.36; 95% CI, 2.10-2.65), bipolar disorder (aRR, 3.74; 95% CI, 3.39-4.13), major depressive disorder (aRR, 3.65; 95% CI, 3.44-3.87), attention-deficit/hyperactivity disorders (aRR, 2.38; 95% CI, 2.20-2.58), autism spectrum disorder (aRR, 2.26; 95% CI, 1.86-2.74), anxiety disorder (aRR, 2.71; 95% CI, 2.59-2.84), and obsessive-compulsive disorder (aRR, 3.14; 95% CI, 2.70-3.66). Sensitivity and subgroup analyses validated the robustness of the findings. Conclusions and Relevance: To our knowledge, this study is the largest and perhaps first nationwide cohort study to demonstrate TRD phenotype transmission across families and coaggregation with other major psychiatric disorders. Patients with a family history of TRD had an increased risk of suicide mortality and tendency toward antidepressant resistance; therefore, more intensive treatments for depressive symptoms might be considered earlier, rather than antidepressant monotherapy.

High myopia at high altitudes.

Background: Optic nerve sheath diameter (ONSD) increases significantly at high altitudes, and is associated with the presence and severity of acute mountain sickness (AMS). Exposure to hypobaria, hypoxia, and coldness when hiking also impacts intraocular pressure (IOP). To date, little is known about ocular physiological responses in trekkers with myopia at high altitudes. This study aimed to determine changes in the ONSD and IOP between participants with and without high myopia (HM) during hiking and to test whether these changes could predict symptoms of AMS. Methods: Nine participants with HM and 18 without HM participated in a 3-day trek of Xue Mountain. The ONSD, IOP, and questionnaires were examined before and during the trek of Xue Mountain. Results: The ONSD values increased significantly in both HM (p = 0.005) and non-HM trekkers (p = 0.018) at an altitude of 1,700 m. In the HM group, IOP levels were greater than those in the non-HM group (p = 0.034) on the first day of trekking (altitude: 3,150 m). No statistically significant difference was observed between the two groups for the values of ONSD. Fractional changes in ONSD at an altitude of 1,700 m were related to the development of AMS (r pb = 0.448, p = 0.019) and the presence of headache symptoms (r pb = 0.542, p = 0.004). The area under the ROC curve for the diagnostic performance of ONSD fractional changes at an altitude of 1,700 m was 0.859 for predicting the development of AMS and 0.803 for predicting the presence of headache symptoms. Conclusion: Analysis of changes in ONSD at moderate altitude could predict AMS symptoms before an ascent to high altitude. Myopia may impact physiological accommodation at high altitudes, and HM trekkers potentially demonstrate suboptimal regulation of aqueous humor in such environments.

Calcium/calcimimetic via calcium-sensing receptor ameliorates cholera toxin-induced secretory diarrhea in mice.

BACKGROUND: Enterotoxins produce diarrhea through direct epithelial action and indirectly by activating the enteric nervous system. Calcium-sensing receptor (CaSR) inhibits both actions. The latter has been well documented in vitro but not in vivo. The hypothesis to be tested was that activating CaSR inhibits diarrhea in vivo. AIM: To determine whether CaSR agonists ameliorate secretory diarrhea evoked by cholera toxin (CTX) in mice. METHODS: CTX was given orally to C57BL/6 mice to induce diarrhea. Calcium and calcimimetic R568 were used to activate CaSR. To maximize their local intestinal actions, calcium was administered luminally via oral rehydration solution (ORS), whereas R568 was applied serosally using an intraperitoneal route. To verify that their actions resulted from the intestine, effects were also examined on Cre-lox intestine-specific CaSR knockouts. Diarrhea outcome was measured biochemically by monitoring changes in fecal Cl- or clinically by assessing stool consistency and weight loss. RESULTS: CTX induced secretory diarrhea, as evidenced by increases in fecal Cl-, stool consistency, and weight loss following CTX exposure, but did not alter CaSR, neither in content nor in function. Accordingly, calcium and R568 were each able to ameliorate diarrhea when applied to diseased intestines. Intestinal CaSR involvement is suggested by gene knockout experiments where the anti-diarrheal actions of R568 were lost in intestinal epithelial CaSR knockouts (villinCre/Casrflox/flox) and neuronal CaSR knockouts (nestinCre/Casrflox/flox). CONCLUSION: Treatment of acute secretory diarrheas remains a global challenge. Despite advances in diarrhea research, few have been made in the realm of diarrhea therapeutics. ORS therapy has remained the standard of care, although it does not halt the losses of intestinal fluid and ions caused by pathogens. There is no cost-effective therapeutic for diarrhea. This and other studies suggest that adding calcium to ORS or using calcimimetics to activate intestinal CaSR might represent a novel approach for treating secretory diarrheal diseases.

A novel class of inhibitors that disrupts the stability of integrin heterodimers identified by CRISPR-tiling-instructed genetic screens.

The plasma membrane is enriched for receptors and signaling proteins that are accessible from the extracellular space for pharmacological intervention. Here we conducted a series of CRISPR screens using human cell surface proteome and integrin family libraries in multiple cancer models. Our results identified ITGAV (integrin αV) and its heterodimer partner ITGB5 (integrin ß5) as the essential integrin α/ß pair for cancer cell expansion. High-density CRISPR gene tiling further pinpointed the integral pocket within the ß-propeller domain of ITGAV for integrin αVß5 dimerization. Combined with in silico compound docking, we developed a CRISPR-Tiling-Instructed Computer-Aided (CRISPR-TICA) pipeline for drug discovery and identified Cpd_AV2 as a lead inhibitor targeting the ß-propeller central pocket of ITGAV. Cpd_AV2 treatment led to rapid uncoupling of integrin αVß5 and cellular apoptosis, providing a unique class of therapeutic action that eliminates the integrin signaling via heterodimer dissociation. We also foresee the CRISPR-TICA approach to be an accessible method for future drug discovery studies.

Cause-specific mortality and comorbid neurodevelopmental disorder in 167,515 patients with bipolar disorder: An entire population longitudinal study.

OBJECTIVE: Studies addressing premature mortality in bipolar disorder (BD) patients are limited by small sample sizes. Herein, we used almost 99 % of the population of Taiwan to address this issue, and its association with comorbid neurodevelopmental disorders and severe BD. METHODS: Between 2003 and 2017, we enrolled 167,515 individuals with BD and controls matched 1:4 for sex and birth year from the National Health Insurance Database linked to the Database of National Death Registry in Taiwan. Time-dependent Cox regression models were used to examine cause-specific mortality (all-cause, natural, and unnatural causes [accidents or suicide]). RESULTS: With adjustments of sex, age, income, urbanization, and physical conditions, suicide was associated with the highest risk of mortality (reported as hazard ratio with 95 % confidence interval: 9.15; 8.53-9.81) among BD patients, followed by unnatural (4.94; 4.72-5.17), accidental (2.15; 1.99-2.32), and natural causes (1.02; 1.00-1.05). Comorbid attention-deficiency hyperactivity disorder did not contribute to the increased risk of cause-specific mortality; however, comorbid autism spectrum disorder (ASD) increased such risks, particularly for natural (3.00; 1.85-4.88) and accidental causes (7.47; 1.80-31.1). Cause-specific mortality revealed a linear trend with the frequency of psychiatric hospitalization (all, p for trend <0.001), and BD patients hospitalized twice or more each year had 34.63-fold increased risk of suicide mortality (26.03-46.07). CONCLUSIONS: BD patients with a higher frequency of psychiatric hospitalization have the highest risk of suicide mortality, and comorbid ASD was associated with an increased risk of natural and accidental causes of mortality.

Skin sympathetic nerve activity in different ablation settings for atrial fibrillation.

BACKGROUND: Modifying the autonomic system after catheter ablation may prevent the recurrence of atrial fibrillation (AF). Evaluation of skin sympathetic nerve activity (SKNA) is a noninvasive method for the assessment of sympathetic activity. However, there are few studies on the effects of different energy settings on SKNA. OBJECTIVE: To investigate the changes in SKNA in different energy settings and their relationship to AF ablation outcomes. METHODS: Seventy-two patients with paroxysmal and persistent AF were enrolled. Forty-three patients received AF ablation with the conventional (ConV) energy setting (low power for long duration), and 29 patients using a high-power, short-duration (HPSD) strategy. The SKNA was acquired from the right arm 1 day before and after the radiofrequency ablation. We analyzed the SKNA and ablation outcomes in the different energy settings. RESULTS: Both groups had a similar baseline average SKNA (aSKNA). We found that the median aSKNA increased significantly from 446.82 µV to 805.93 µV (p = 0.003) in the ConV group but not in the HPSD group. In the ConV group, patients without AF recurrence had higher aSKNA values. However, the 1-year AF recurrence rate remained similar between both groups (35 % vs. 28 %, p = 0.52). CONCLUSION: The post-ablation aSKNA levels increased significantly in the ConV group but did not change significantly in the HPSD group, which may reflect different neuromodulatory effects. However, the one-year AF recurrence rates were similar for both groups. These results demonstrate that the HPSD strategy has durable lesion creation but less lesion depth, which may reduce collateral damage.

A pilot study of non-invasive diagnostic tools to detect Helicobacter pylori infection and peptic ulcer disease.

Helicobacter pylori (H. pylori) infection can lead to various digestive system diseases, making accurate diagnosis crucial. However, not all available tests are equally non-invasive and sensitive. This study aimed to compare the efficacy of non-invasive and invasive diagnostic tools for H. pylori infection and assess their correlation with esophagogastroduodenoscopic (EGD) findings. The study utilized the Campylobacter-Like Organism (CLO) test, serum anti-HP IgG blood test, and C-13-urea breath test (UBT) to diagnose H. pylori infection. A total of 100 patients with peptic ulcer symptoms, including 45 males and 55 females, were recruited for the study. Symptomatic patients between the ages of 20-70, eligible for EGD examination, were enrolled. Each diagnostic test and any combination of two positive tests were considered the reference standard and compared against the other diagnostic methods. Additionally, the relationship between these diagnostic tests and EGD findings was evaluated. Among the participants, 74.0% were diagnosed with peptic ulcer disease through EGD. The UBT demonstrated the highest Youden's index, ranging from 58 to 100%, against all the non-invasive tests. The IgG blood test displayed the highest sensitivity at 100%, with a specificity of 60-70%. On the other hand, the CLO test exhibited the highest specificity at 100% and a sensitivity of 50-85%. Furthermore, only the CLO test showed a significant association with esophageal ulcers (p-value = 0.01). The IgG blood test holds promise as a primary screening tool due to its exceptional sensitivity. While the UBT is relatively expensive, its non-invasive nature and high sensitivity and specificity make it a potential standalone diagnostic test for H. pylori infection. Moreover, the noteworthy negative correlation between the CLO test and esophageal ulcers provides evidence of the differing effects of H. pylori infection on antral-predominant and corpus-predominant gastritis.

Risk of All-Cause and Suicide Death in Patients With Schizophrenia: An Entire-Population Longitudinal Study in Taiwan.

Background: Schizophrenia increases mortality from all causes and specific causes. Comprehensive research on modifiable risk factors for early mortality from multiple sources is needed.Methods: Taiwan's National Health Insurance Research Database, which contains claims data from a lifetime insurance program for the whole population, provided extensive medical inpatient and outpatient data categorized by ICD-9-CM and ICD-10 for this nationwide retrospective longitudinal cohort study. The National Mortality Registry provided data on all-cause, natural, suicide, and accidental deaths. 191,553 patients with schizophrenia and 26,362,448 individuals without schizophrenia were monitored from January 1, 2003, to December 31, 2017. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) for mortality risk were calculated using Cox regression models. We compared different mortality risks associated with schizophrenia across age, sex, and Charlson Comorbidity Index (CCI) subgroups.Results: We found that schizophrenia results in a relatively higher increase in suicidal mortality in those aged ≤ 20 years (aHR = 15.55; 95% CI, 13.95-17.34), and that effect decreased with age. The effect of schizophrenia in female individuals (suicide death: female, aHR = 11.82, 95% CI, 11.21-12.46; male, aHR = 8.11, 95% CI, 7.77-8.47; difference, P < .001) and individuals without comorbidity (natural cause of death, CCI = 0 aHR = 5.94, 95% CI, 5.68-6.22; CCI = 1-2 aHR = 3.62, 95% CI, 3.52-3.73; CCI > 2 aHR = 1.61, 95% CI, 1.58-1.64) led to comparatively higher mortality risks. The effect of schizophrenia in individuals with AIDS (suicide death, aHR = 2.73, 95% CI, 1.70-4.39) resulted in a relatively smaller increase in suicide mortality compared to individuals with other comorbidities; however, in patients with connective tissue diseases, a diagnosis of schizophrenia still leads to an alarming increase in natural and unnatural mortality.Conclusions: Schizophrenia in combination with younger age, female sex, comorbid connective tissue disease, or major organ problems necessitates more tailored countermeasures to lessen the higher mortality risk in these patients compared with patients who have these characteristics and conditions but do not have schizophrenia.

Risks and familial coaggregation of death by suicide, accidental death and major psychiatric disorders in first-degree relatives of individuals who died by suicide.

BACKGROUND: Evidence suggests a familial coaggregation of major psychiatric disorders, including schizophrenia, bipolar disorder, major depression (MDD), autism spectrum disorder (ASD) and attention-deficit hyperactivity disorder (ADHD). Those disorders are further related to suicide and accidental death. However, whether death by suicide may coaggregate with accidental death and major psychiatric disorders within families remains unclear. AIMS: To clarify the familial coaggregation of deaths by suicide with accidental death and five major psychiatric disorders. METHOD: Using a database linked to the entire Taiwanese population, 68 214 first-degree relatives of individuals who died by suicide between 2003 and 2017 and 272 856 age- and gender-matched controls were assessed for the risks of death by suicide, accidental death and major psychiatric disorders. RESULTS: A Poisson regression model showed that the first-degree relatives of individuals who died by suicide were more likely to die by suicide (relative risk RR = 4.61, 95% CI 4.02-5.29) or accident (RR = 1.62, 95% CI 1.43-1.84) or to be diagnosed with schizophrenia (RR = 1.53, 95% CI 1.40-1.66), bipolar disorder (RR = 1.99, 95% CI 1.83-2.16), MDD (RR = 1.98, 95% CI 1.89-2.08) or ADHD (RR = 1.34, 95% CI 1.24-1.44). CONCLUSIONS: Our findings identified a familial coaggregation of death by suicide with accidental death, schizophrenia, major affective disorders and ADHD. Further studies would be required to elucidate the pathological mechanisms underlying this coaggregation.

Discriminant ability of the shock index, modified shock index, and reverse shock index multiplied by the Glasgow coma scale on mortality in adult trauma patients: a PATOS retrospective cohort study.

BACKGROUND: The shock index (SI) predicts short-term mortality in trauma patients. Other shock indices have been developed to improve discriminant accuracy. The authors examined the discriminant ability of the SI, modified SI (MSI), and reverse SI multiplied by the Glasgow Coma Scale (rSIG) on short-term mortality and functional outcomes. METHODS: The authors evaluated a cohort of adult trauma patients transported to emergency departments. The first vital signs were used to calculate the SI, MSI, and rSIG. The areas under the receiver operating characteristic curves and test results were used to compare the discriminant performance of the indices on short-term mortality and poor functional outcomes. A subgroup analysis of geriatric patients with traumatic brain injury, penetrating injury, and nonpenetrating injury was performed. RESULTS: A total of 105 641 patients (49±20 years, 62% male) met the inclusion criteria. The rSIG had the highest areas under the receiver operating characteristic curve for short-term mortality (0.800, CI: 0.791-0.809) and poor functional outcome (0.596, CI: 0.590-0.602). The cutoff for rSIG was 18 for short-term mortality and poor functional outcomes with sensitivities of 0.668 and 0.371 and specificities of 0.805 and 0.813, respectively. The positive predictive values were 9.57% and 22.31%, and the negative predictive values were 98.74% and 89.97%. rSIG also had better discriminant ability in geriatrics, traumatic brain injury, and nonpenetrating injury. CONCLUSION: The rSIG with a cutoff of 18 was accurate for short-term mortality in Asian adult trauma patients. Moreover, rSIG discriminates poor functional outcomes better than the commonly used SI and MSI.

All-cause mortality and suicide mortality in autistic individuals: An entire population longitudinal study in Taiwan.

LAY ABSTRACT: Our study was the first population-based study in an Asian country to investigate the mortality rates among autistic individuals. Among the entire Taiwanese population (N = 29,253,529), between 2003 and 2017, 45,398 autistic individuals were identified and 1:4 age-/sex-matched to 181,592 non-autistic individuals. We found that autistic individuals had increased risks of all-cause mortality, natural-cause mortality, and suicide mortality compared with non-autistic individuals. Furthermore, autistic males were more likely to die by suicide, and autistic females were more likely to die of accident compared with the non-autistic individuals.

Epigenetic Control of Translation Checkpoint and Tumor Progression via RUVBL1-EEF1A1 Axis.

Epigenetic dysregulation is reported in multiple cancers including Ewing sarcoma (EwS). However, the epigenetic networks underlying the maintenance of oncogenic signaling and therapeutic response remain unclear. Using a series of epigenetics- and complex-focused CRISPR screens, RUVBL1, the ATPase component of NuA4 histone acetyltransferase complex, is identified to be essential for EwS tumor progression. Suppression of RUVBL1 leads to attenuated tumor growth, loss of histone H4 acetylation, and ablated MYC signaling. Mechanistically, RUVBL1 controls MYC chromatin binding and modulates the MYC-driven EEF1A1 expression and thus protein synthesis. High-density CRISPR gene body scan pinpoints the critical MYC interacting residue in RUVBL1. Finally, this study reveals the synergism between RUVBL1 suppression and pharmacological inhibition of MYC in EwS xenografts and patient-derived samples. These results indicate that the dynamic interplay between chromatin remodelers, oncogenic transcription factors, and protein translation machinery can provide novel opportunities for combination cancer therapy.

A pilot study of digital bedside cards in the emergency room of a medical centre in Taiwan.

The emergency room (ER) digital bedside card is a simple and important invention. It can be directly connected to the hospital information system to display important patient information in real time, reduce the workload of ER staff, improve their satisfaction, and provide useful information for patients and their families. We conducted a prospective study of ER staff using questionnaires and conducted Wilcoxon signed-rank test to compare before and after ER digital bedside card implementation in the Tamsui MacKay Memorial Hospital. Sixty participants of the ER staff joined the study before and after digital card implementation. After the ER digital bedside card was set up, the number of round trips from the nursing station to the ER bedside and the number of common questions asked by patients and their family members were significantly reduced. The cards reduced the response time for frequently asked questions by patients and their family members and significantly improved the satisfaction of ER staff. Our study showed that ER digital bedside cards reduced the workload of ER staff, provided patients and their families with useful information, and greatly improved ER staff satisfaction. This marks an important milestone in the future development of smart ER.

Effect of low-frequency repetitive transcranial magnetic stimulation as adjunctive treatment for insomnia patients under hypnotics: A randomized, double-blind, sham-controlled study.

BACKGROUND: Pharmacotherapy of insomnia is prescribed often but may be complicated by drug dependence. Cognitive-behavioral therapy for insomnia is effective, but requires time to take effect. Repetitive transcranial magnetic stimulation (rTMS) is effective for depression but of uncertain benefit for insomnia. We studied low-frequency rTMS of the left dorsal medial prefrontal cortex (DMPFC) as an adjunctive therapy of insomnia. METHODS: We recruited 60 patients with insomnia, of whom 49 completed the study. We applied 1 Hz rTMS to the DMPFC in the experimental group (n = 36) and sham coil for the placebo group (n = 13). Outcome measures included objective polysomnography (PSG) and subjective Pittsburgh Sleep Quality Index (PSQI). All participants were requested to continue prescribed pharmacotherapy. RESULTS: After 10 sessions of low-frequency DMPFC-rTMS, the experimental group demonstrated a reduction of duration of wake after sleep onset (WASO) from 75.4 (±53.3) to 51.2 (±75.1) min ( p = 0.011). Sleep efficiency (SE) increased from 74.6% (±15.6) to 80.8% (±13.8) ( p = 0.004). The sham group experienced improved SE from 79.4% (±30.7) to 88.9% (±5.6) ( p = 0.039). After controlling for baseline PSG parameters and hypnotic dosage, the sham group exhibited better effects of sleep onset latency and SE than the rTMS group but no difference on PSQI. CONCLUSION: Although the effects of rTMS and sham coil on insomnia were similar (which implied significant placebo effect), low-frequency DMPFC-rTMS might offer a safe, non-invasive, and useful adjunctive therapy of insomnia by reducing WASO. The DMPFC may represent a new target for future rTMS insomnia studies.

Evaluation of Early Warning Scores on In-Hospital Mortality in COVID-19 Patients: A Tertiary Hospital Study from Taiwan.

Coronavirus disease 2019 (COVID-19) remains a global pandemic. Early warning scores (EWS) are used to identify potential clinical deterioration, and this study evaluated the ability of the Rapid Emergency Medicine score (REMS), National Early Warning Score (NEWS), and Modified EWS (MEWS) to predict in-hospital mortality in COVID-19 patients. This study retrospectively analyzed data from COVID-19 patients who presented to the emergency department and were hospitalized between 1 May and 31 July 2021. The area under curve (AUC) was calculated to compare predictive performance of the three EWS. Data from 306 COVID-19 patients (61 ± 15 years, 53% male) were included for analysis. REMS had the highest AUC for in-hospital mortality (AUC: 0.773, 95% CI: 0.69-0.85), followed by NEWS (AUC: 0.730, 95% CI: 0.64-0.82) and MEWS (AUC: 0.695, 95% CI: 0.60-0.79). The optimal cut-off value for REMS was 6.5 (sensitivity: 71.4%; specificity: 76.3%), with positive and negative predictive values of 27.9% and 95.4%, respectively. Computing REMS for COVID-19 patients who present to the emergency department can help identify those at risk of in-hospital mortality and facilitate early intervention, which can lead to better patient outcomes.

Family coaggregation of type 1 diabetes mellitus, major depressive disorder, attention-deficiency hyperactivity disorder and autism spectrum disorder in affected families: a nationwide study.

AIMS: This study aimed to examine the risk of T1D, major depressive disorder (MDD), attention-deficiency hyperactivity disorder (ADHD), and autism spectrum disorder (ASD), in first-degree relatives (FDRs) of patients with T1D. METHODS: We enrolled 24,555 FDRs of individuals with T1D and 1:4 matched controls (N = 98,220) based on age and sex using data from the Taiwan National Health Insurance Research Database between 2001 and 2011. Poisson regression analyses were performed to estimate the risks of MDD, attention-deficiency hyperactivity disorder (ADHD), and autism spectrum disorder among the FDRs. Finally, we assessed the impact of DKA in the familial coaggregation. RESULTS: After adjusting for demographic characteristics, FDRs of individuals with T1D had higher risk of T1D (reported as relative risk with 95% confidence interval: 46.07, 33.36-63.63) and MDD (1.17, 1.04-1.32) than controls. Stratified by sex, female FDRs had increased risk of MDD (1.30, 1.13-1.51), while male FDRs had increased risk of ADHD (1.21, 1.01-1.44). Stratified by kinship, parents of individuals with T1D had increased risk of MDD (1.24, 1.06-1.44); offspring of individuals with T1D had increased risk of ADHD (1.41, 1.11-1.79). Importantly, FDRs of individuals with T1D and DKA had higher risk of MDD (1.35, 1.11-1.64) and ADHD (1.40, 1.07-1.82) than controls; however, such risks were not observed in FDRs of individuals with T1D but without DKA. CONCLUSIONS: The individual risks of T1D, MDD, and ADHD were increased in families that included patients with T1D, and DKA might play a role in such coaggregation with MDD and ADHD. Future studies are warranted to investigate the underlying mechanisms.

Antidepressant effects of prolonged intermittent theta-burst stimulation monotherapy at the bilateral dorsomedial prefrontal cortex for medication and standard transcranial magnetic stimulation-resistant major depression: a three arm, randomized, double blind, sham-controlled pilot study.

The dorsomedial prefrontal cortex (DMPFC) plays a pivotal role in depression and anxiosomatic symptom modulation. However, DMPFC stimulation using a double-cone coil has demonstrated inconsistent results for antidepressant efficacy. No study thus far has investigated the antidepressant and anti-anxiosomatic effects of prolonged intermittent theta-burst stimulation (piTBS) bilaterally over DMPFC. Furthermore, head-to-head comparisons of antidepressant effects between standard iTBS and piTBS warrant investigation. This double-blind, randomized, sham-controlled trial recruited 34 patients with highly treatment-resistant depression (TRD) unresponsive to antidepressants and standard repetitive transcranial magnetic stimulation (rTMS)/piTBS. These patients were randomly assigned to one of three monotherapy groups (standard iTBS, piTBS, or sham), with treatment administered bilaterally over the DMPFC twice per day for 3 weeks. The primary outcome was the overall changes of 17-item Hamilton Depression Rating Scale (HDRS-17) over 3-weeks intervention. The changes in Depression and Somatic Symptoms Scale (DSSS) as the secondary outcome and the anxiosomatic cluster symptoms as rated by HDRS-17 as the post-hoc outcome were measured. Multivariable generalized estimating equation analysis was performed. Although no differences in overall HDRS-17 changes between three groups were found, the antidepressant efficacy based on DSSS was higher in piTBS than in iTBS and sham at week 3 (group effect,p = 0.003, post-hoc: piTBS > iTBS, p = 0.002; piTBS > sham, p = 0.038). In post-hoc analyses, piTBS had more alleviation in anxiosomatic symptoms than iTBS (group effect, p = 0.002; post-hoc, p = 0.001). This first randomized sham-controlled study directly compared piTBS and iTBS targeting the DMPFC using a figure-of-8 coil and found piTBS may fail to demonstrate a significant antidepressant effect on overall depressive symptoms, but piTBS seems superior in alleviating anxiosomatic symptoms, even in depressed patients with high treatment resistance. This Trial registration (Registration number: NCT04037592). URL: https://clinicaltrials.gov/ct2/show/NCT04037592 .

ACTR5 controls CDKN2A and tumor progression in an INO80-independent manner.

Epigenetic dysregulation of cell cycle is a hallmark of tumorigenesis in multiple cancers, including hepatocellular carcinoma (HCC). Nonetheless, the epigenetic mechanisms underlying the aberrant cell cycle signaling and therapeutic response remain unclear. Here, we used an epigenetics-focused CRISPR interference screen and identified ACTR5 (actin-related protein 5), a component of the INO80 chromatin remodeling complex, to be essential for HCC tumor progression. Suppression of ACTR5 activated CDKN2A expression, ablated CDK/E2F-driven cell cycle signaling, and attenuated HCC tumor growth. Furthermore, high-density CRISPR gene tiling scans revealed a distinct HCC-specific usage of ACTR5 and its interacting partner IES6 compared to the other INO80 complex members, suggesting an INO80-independent mechanism of ACTR5/IES6 in supporting the HCC proliferation. Last, our study revealed the synergism between ACTR5/IES6-targeting and pharmacological inhibition of CDK in treating HCC. These results indicate that the dynamic interplay between epigenetic regulators, tumor suppressors, and cell cycle machinery could provide novel opportunities for combinational HCC therapy.

Imbalanced prediction of emergency department admission using natural language processing and deep neural network.

The emergency department (ED) plays a very significant role in the hospital. Owing to the rising number of ED visits, medical service points, and ED market, overcrowding of EDs has become serious worldwide. Overcrowding has long been recognized as a vital issue that increases the risk to patients and negative emotions of medical personnel and impacts hospital cost management. For the past years, many researchers have been applying artificial intelligence to reduce crowding situations in the ED. Nevertheless, the datasets in ED hospital admission are naturally inherent with the high-class imbalance in the real world. Previous studies have not considered the imbalance of the datasets, particularly addressing the imbalance. This study purposes to develop a natural language processing model of a deep neural network with an attention mechanism to solve the imbalanced problem in ED admission. The proposed framework is used for predicting hospital admission so that the hospitals can arrange beds early and solve the problem of congestion in the ED. Furthermore, the study compares a variety of methods and obtains the best composition that has the best performance for forecasting hospitalization in ED. The study used the data from a specific hospital in Taiwan as an empirical study. The experimental result demonstrates that almost all imbalanced methods can improve the model's performance. In addition, the natural language processing model of Bi-directional Long Short-Term Memory with attention mechanism has the best results in all-natural language processing methods.