Treatment shortening of drug-sensitive pulmonary tuberculosis using high-dose rifampicin for 3 months after culture conversion (Hi-DoRi-3): a study protocol for an open-label randomized clinical trial

Background : The standard treatment regimen for drug-sensitive tuberculosis (TB), comprising four companion drugs, requires a minimum duration of 6 months, and this lengthy treatment leads to poor adherence and increased toxicity. To improve rates of adherence, reduce adverse events, and lower costs, a simplified and shortened treatment regimen is warranted. Methods : This study is a multicenter, open-label randomized clinical trial of non-inferiority design that compares a new regimen with the conventional regimen for drug-sensitive pulmonary TB. The investigational group will use a regimen of high-dose rifampicin (30 mg/kg/day) with isoniazid and pyrazinamide, and the treatment will be maintained for 12 weeks after the achievement of negative conversion of sputum culture. The control group will be treated for 6 months with a World Health Organization-endorsed regimen consisting of isoniazid, rifampicin (10 mg/kg/day), ethambutol, and pyrazinamide. The primary endpoint is the proportion of unfavorable outcomes at 18 months after randomization. Secondary outcomes include time to unfavorable treatment outcome, time to culture conversion on liquid medium, treatment success rate at the end of treatment, proportion of recurrence at 18 months after randomization, time to recurrence after treatment completion, and adverse events of grade 3 or higher during the treatment. We predict a 10% unfavorable outcome for the control group, and 0% difference from the investigational group. Based on 80% verification power and a 2.5% one-sided significance level for a non-inferiority margin of 6%, 393 participants per group are required. Considering the 15% dropout rate, a total of 926 participants (463 in each group) will be recruited. Discussion : This study will inform on the feasibility of the treatment regimen using high-dose rifampicin with a shortened and individualized treatment duration for pulmonary TB. Trial registration : ClinicalTrials.gov NCT04485156.Registered on July 24, 2020.This work was supported by a grant from the Korea National Institute of Health (2020-ER5201-01), Republic of Korea. High-dose rifampicin tablets and capsules were donated from Yuhan (Seoul, Republic of Korea) for this study. The funder and donor had no role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript

Changes in Personal Networks of Women in Residential and Outpatient Substance Abuse Treatment

Changes in personal network composition, support and structure over 12 months were examined in 377 women from residential (n=119) and intensive outpatient substance abuse treatment (n=258) through face-to-face interviews utilizing computer based data collection. Personal networks of women who entered residential treatment had more substance users, more people with whom they had used alcohol and/or drugs, and fewer people from treatment programs or self-help groups than personal networks of women who entered intensive outpatient treatment. By 12 months post treatment intake, network composition improved for women in residential treatment; however, concrete support was still lower and substance users still more prevalent in their networks. Network composition of women in outpatient treatment remained largely the same over time. Both groups increased cohesiveness within the network over 12 months. Targeting interventions that support positive changes in personal networks may heighten positive long term outcomes for women entering treatment

High-Quality Microprintable and Stretchable Conductors for High- Performance 5G Wireless Communication

With the advent of 5G wireless and Internet of Things technologies, flexible and stretchable printed circuit boards (PCBs) should be designed to address all the specifications necessary to receive signal transmissions, maintaining the signal integrity, and providing electrical connections. Here, we propose a silver nanoparticle (AgNP)/silver nanowire (AgNW) hybrid conductor and high-quality microprinting technology for fabricating flexible and stretchable PCBs in high-performance 5G wireless communication. A simple and low-cost reverse offset printing technique using a commercial adhesive hand-roller was adapted to ensure high-resolution and excellent pattern quality. The AgNP/ AgNW micropatterns were fabricated in various line widths, from 5 mu m to 5 mm. They exhibited excellent pattern qualities, such as fine line spacing, clear edge definition and outstanding pattern uniformity. After annealing via intense pulsed light irradiation, they showed outstanding electrical resistivity (15.7 mu omega cm). Moreover, they could withstand stretching up to a strain of 90% with a small change in resistance. As a demonstration of their practical application, the AgNP/AgNW micropatterns were used to fabricate 5G communication antennas that exhibited excellent wireless signal processing at operating frequencies in the C-band (4-8 GHz). Finally, a wearable sensor fabricated with these AgNP/ AgNW micropatterns could successfully detected fine finger movements in real time with excellent sensitivity. © 2022 American Chemical Society.FALS

Machine Learning–Based Hospital Discharge Prediction for Patients With Cardiovascular Diseases: Development and Usability Study

BackgroundEffective resource management in hospitals can improve the quality of medical services by reducing labor-intensive burdens on staff, decreasing inpatient waiting time, and securing the optimal treatment time. The use of hospital processes requires effective bed management; a stay in the hospital that is longer than the optimal treatment time hinders bed management. Therefore, predicting a patient’s hospitalization period may support the making of judicious decisions regarding bed management. ObjectiveFirst, this study aims to develop a machine learning (ML)–based predictive model for predicting the discharge probability of inpatients with cardiovascular diseases (CVDs). Second, we aim to assess the outcome of the predictive model and explain the primary risk factors of inpatients for patient-specific care. Finally, we aim to evaluate whether our ML-based predictive model helps manage bed scheduling efficiently and detects long-term inpatients in advance to improve the use of hospital processes and enhance the quality of medical services. MethodsWe set up the cohort criteria and extracted the data from CardioNet, a manually curated database that specializes in CVDs. We processed the data to create a suitable data set by reindexing the date-index, integrating the present features with past features from the previous 3 years, and imputing missing values. Subsequently, we trained the ML-based predictive models and evaluated them to find an elaborate model. Finally, we predicted the discharge probability within 3 days and explained the outcomes of the model by identifying, quantifying, and visualizing its features. ResultsWe experimented with 5 ML-based models using 5 cross-validations. Extreme gradient boosting, which was selected as the final model, accomplished an average area under the receiver operating characteristic curve score that was 0.865 higher than that of the other models (ie, logistic regression, random forest, support vector machine, and multilayer perceptron). Furthermore, we performed feature reduction, represented the feature importance, and assessed prediction outcomes. One of the outcomes, the individual explainer, provides a discharge score during hospitalization and a daily feature influence score to the medical team and patients. Finally, we visualized simulated bed management to use the outcomes. ConclusionsIn this study, we propose an individual explainer based on an ML-based predictive model, which provides the discharge probability and relative contributions of individual features. Our model can assist medical teams and patients in identifying individual and common risk factors in CVDs and can support hospital administrators in improving the management of hospital beds and other resources

Are polypharmacy side effects predicted by public data still valid in real-world data?

Background and Objective: Although interest in predicting drug-drug interactions is growing, many predictions are not verified by real-world data. This study aimed to confirm whether predicted polypharmacy side effects using public data also occur in data from actual patients. Methods: We utilized a deep learning-based polypharmacy side effects prediction model to identify cefpodoxime-chlorpheniramine-lung edema combination with a high prediction score and a significant patient population. The retrospective study analyzed patients over 18 years old who were admitted to the Asan medical center between January 2000 and December 2020 and took cefpodoxime or chlorpheniramine orally. The three groups, cefpodoxime-treated, chlorpheniramine-treated, and cefpodoxime &amp; chlorpheniramine-treated were compared using inverse probability of treatment weighting (IPTW) to balance them. Differences between the three groups were analyzed using the Kaplan-Meier method and Cox proportional hazards model. Results: The study population comprised 54,043 patients with a history of taking cefpodoxime, 203,897 patients with a history of taking chlorpheniramine, and 1,628 patients with a history of taking cefpodoxime and chlorpheniramine simultaneously. After adjustment, the 1-year cumulative incidence of lung edema in the patient group that took cefpodoxime and chlorpheniramine simultaneously was significantly higher than in the patient groups that took cefpodoxime or chlorpheniramine only (p=0.001). Patients taking cefpodoxime and chlorpheniramine together had an increased risk of lung edema compared to those taking cefpodoxime alone [hazard ratio (HR) 2.10, 95% CI 1.26–3.52, p<0.005] and those taking chlorpheniramine alone, which also increased the risk of lung edema (HR 1.64, 95% CI 0.99-2.69, p=0.05). Conclusions: Validation of polypharmacy side effect predictions with real-world data can aid patient and clinician decision-making before conducting randomized controlled trials. Simultaneous use of cefpodoxime and chlorpheniramine was associated with a higher long-term risk of lung edema compared to the use of cefpodoxime or chlorpheniramine alone

Role of Sodium Bicarbonate Cotransporters in Intracellular pH Regulation and Their Regulatory Mechanisms in Human Submandibular Glands

<div><p>Sodium bicarbonate cotransporters (NBCs) are involved in the pH regulation of salivary glands. However, the roles and regulatory mechanisms among different NBC isotypes have not been rigorously evaluated. We investigated the roles of two different types of NBCs, electroneutral (NBCn1) and electrogenic NBC (NBCe1), with respect to pH regulation and regulatory mechanisms using human submandibular glands (hSMGs) and HSG cells. Intracellular pH (pH_i) was measured and the pH_i recovery rate from cell acidification induced by an NH₄Cl pulse was recorded. Subcellular localization and protein phosphorylation were determined using immunohistochemistry and co-immunoprecipitation techniques. We determined that NBCn1 is expressed on the basolateral side of acinar cells and the apical side of duct cells, while NBCe1 is exclusively expressed on the apical membrane of duct cells. The pH_i recovery rate in hSMG acinar cells, which only express NBCn1, was not affected by pre-incubation with 5 μM PP2, an Src tyrosine kinase inhibitor. However, in HSG cells, which express both NBCe1 and NBCn1, the pH_i recovery rate was inhibited by PP2. The apparent difference in regulatory mechanisms for NBCn1 and NBCe1 was evaluated by artificial overexpression of NBCn1 or NBCe1 in HSG cells, which revealed that the pH_i recovery rate was only inhibited by PP2 in cells overexpressing NBCe1. Furthermore, only NBCe1 was significantly phosphorylated and translocated by NH₄Cl, which was inhibited by PP2. Our results suggest that both NBCn1 and NBCe1 play a role in pH_i regulation in hSMG acinar cells, and also that Src kinase does not regulate the activity of NBCn1.</p></div

NBCe1 and NBCn1 are expressed in human submandibular gland (hSMG) and HSG cells.

<p>(A) NBCe1 and NBCn1 mRNA transcripts in hSMG and HSG cells. Aquaporin 5 (AQP5) was used as a marker for acinar cells. (B and C) hSMG tissue sections were stained with NBCe1, NBCn1, and AQP5 antibodies. (Bar = 50 μm). AQP5 was used as a marker for acinar cells. White and yellow arrows indicate acinar cells and duct cells, respectively. NBCe1-B is expressed in human submandibular gland (hSMG) duct cells, whereas NBCn1 is expressed in acinar (white arrow) and duct cells (yellow arrow). (D and E) HSG cells were stained with antibodies for NBCe1 and NBCn1. (Bar = 20 μm).</p

PP2 inhibits tyrosine phosphorylation and translocation of NBCe1-B, but NBCn1, in HSG cells.

<p>(A and B) Cell lysates were subjected to immunoprecipitation with NBCe1 and NBCn1 antibodies and evaluated by Western blotting with a phosphotyrosine antibody. The cells were pre-incubated in 20 mM of NH₄Cl for 2 mins, in 5 μM of PP2 for 20 mins, and in 50 μM of CCh for 5 mins. The input control comprised 5% of the lysates. (C and D) Phosphorylated NBCe1 and NBCn1 were quantified based on protein band intensities. The data are shown as the mean ± S.E. (error bars) (n = 4; *, P < 0.05). (E) Locations of NBCe1 and NBCn1 in response of ammonium pulse in the presence or absence of PP2 were confirmed using immunocytochemistry. (Bar = 20 μm).</p

Transfected NBCe1-B is affected by PP2.

<p>(A and B) Flag-NBCe1-B and NBCn1 were transfected into HSG cells and overexpression was confirmed by immunofluorescence assay. (C and D) pH_i recovery rates were recorded in HSG cells overexpressing NBCe1-B or NBCn1. Horizontal bars indicate all applications. (E and F) Graphical summary of pH_i recovery rates. The data are presented as the mean ± S.E. (error bars) (*, P < 0.05; ***, P < 0.001).</p