bluuebunny/crossref_metadata_2025 huggingface dataset:
Three-Year Overall Survival of Patients With Advanced Non–Small-Cell Lung Cancers With ≥50% PD-L1 Expression Treated With First-Line Pembrolizumab Monotherapy in a Real-World Setting (ESCKEYP GFPC Study)
Authors: Decroisette Chantal , Greillier Laurent , Curcio Hubert , Pérol Maurice , Ricordel Charles , Auliac Jean-Bernard , Falchero Lionel , Veillon Remi , Vieillot Sabine , Guisier Florian , Marcq Marie , Justeau Grégoire , Bigay-Game Laurence , Bernardi Marie , Doubre Hélène , Pinsolle Julian , Amrane Karim , Chouaïd Christos , Descourt Renaud
Published: October 2023

Outside clinical trials, few data are available on the effect of long-term first-line pembrolizumab in patients with advanced non–small-cell lung cancers with ≥50% of tumor cells expressing programmed cell death ligand 1 (PD-L1). This French, multicenter study included consecutive advanced patients with non–small-cell lung cancer given first-line pembrolizumab alone between May 2017 (authorization date for this indication) and November 2019 (authorization date for pembrolizumab–chemotherapy combination). Information was collected from patients’ medical files, with a local evaluation of the response and progression-free survival (PFS). Overall survival (OS) was calculated from pembrolizumab onset using the Kaplan-Meier method. The analysis concerned 845 patients, managed in 33 centers: median age: 65 (range: 59–72) years, 67.8% men, 78.1% Eastern Cooperative Oncology Group performance status 0/1, 38.9%/51.5%/6.6% active, ex or never-smokers, respectively, 10.9%/16.8% taking or recently took corticosteroids/antibiotics, 69.6% nonsquamous histology, 48.9% ≥75% PD-L1–positive, and 20.8% had brain metastases at diagnosis. After a median (95% CI) follow-up of 45 (44.1–45.9) months, respective median (95% CI) PFS and OS lasted 8.2 (6.9–9.2) and 22 (8.5–25.9) months; 3-year PFS and OS rates were 25.4% and 39.4%, respectively. Multivariate analysis retained never-smoker status, adenocarcinoma histology, Eastern Cooperative Oncology Group performance status ≥2, and neutrophil/lymphocyte ratio >4 as being significantly associated with shorter survival, but not brain metastases at diagnosis or <75% PD-L1 tumor-cell expression. These long-term results of pembrolizumab efficacy based on a nationwide “real-world” cohort reproduced those obtained in clinical trials.
Istaroxime: A Novel Therapeutic Agent for Acute Heart Failure
Authors: Newbury Danielle , Frishman William
Published: October 2023

Acute decompensated heart failure (ADHF) is a multifactorial process that is associated with high morbidity and mortality. Treatment with inotropes can rapidly improve hemodynamic status; however, their use has been associated with increased mortality and incidence of arrhythmias. Istaroxime is a first-in-class intravenous agent currently undergoing clinical trials for acute heart failure. It has the unique mechanism of action of both Na+/K+ ATPase inhibition and sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a stimulation. Notably, its action on sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a improves calcium handling, which is known to be abnormal in heart failure. Clinical trials have shown that istaroxime has beneficial hemodynamic effects; in particular, its ability to increase systolic blood pressure without causing significant increases in heart rate or clinically significant arrhythmias differentiates it from inotropes currently utilized for ADHF treatment, such as milrinone. While initial studies are encouraging, additional trials are needed to assess outcomes and to compare their performance to standard inotropes in patients hospitalized with ADHF. This article will review the relevant preclinical and clinical trials for istaroxime, as well as the relevant pharmacology.
Mechanism of Ion Channel Impairment in the Occurrence of Arrhythmia in Patients with Hypertrophic Cardiomyopathy
Authors: Zhang Ke , Wang Shengwei , Li Xiaoyan , Cui Hao , Lai Yongqiang
Published: October 2023

Sudden cardiac death is the most unpredictable and devastating consequence of hypertrophic cardiomyopathy, most often caused by persistent ventricular tachycardia or ventricular fibrillation. Although myocardial hypertrophy, fibrosis, and microvascular disorders are the main mechanisms of persistent reentrant ventricular arrhythmias in patients with advanced hypertrophic cardiomyopathy, the cardiomyocyte mechanism based on ion channel abnormalities may play an important role in the early stages of the disease.
Current opinion: postpartum urinary disorders
Authors: Dong Shirley M. , Hickman Lisa C.
Published: October 2023

Purpose of review

The aim of this study was to describe the common postpartum urinary sequelae including urinary retention and incontinence, and to summarize the management of these conditions.

Recent findings

Despite the high frequency of urinary disorders in obstetrics, screening and management protocols are rarely utilized by providers. Large variation exists in the literature regarding assessment of postpartum urinary retention, values of postvoid residuals and management of indwelling catheters in the immediate postpartum population. Recent expert guidance outlines a strategy for managing this condition.

Research also highlights that screening for peripartum urinary incontinence is not a routine practice. The diagnosis is made more challenging by the fact that patients commonly understate and over-normalize their symptoms. Emerging studies have found that pelvic floor muscle training is cost-effective, preventive, and may improve symptoms in the postpartum setting.

Increased awareness of urinary disorders in pregnancy and postpartum is imperative for appropriate diagnosis and management. Instituting standardized voiding protocols postpartum will allow providers to avoid undiagnosed postpartum urinary retention and its repercussions. Improved screening and education regarding urinary incontinence in the peripartum is important for early management, such as pelvic floor muscle training, and improved quality of life.
Wise-pattern Split-reduction Incision to Facilitate Mastectomy and Direct-to-Implant Reconstruction for Superficial Breast Cancers
Authors: Schwartz Jean-Claude D.
Published: October 2023

The split reduction allows for oncoplastic breast conserving surgery using a modified Wise-pattern closure in ptotic patients with cancers in close proximity to a skin margin. Although cancers involving skin within the Wise pattern are conveniently resected during closure, cancers in close proximity to skin outside the Wise pattern require a modified closure. This modified Wise-pattern closure preserves skin near the inferior pole of the breast which is normally resected and shifts this resection superiorly over the cancer. This also shifts the final medial or lateral inframammary scar onto the visible breast mound. Although this split-reduction Wise pattern has been well described for resecting advanced cancers in patients who undergo oncoplastic breast conserving surgery, this approach has not been described in patients who require mastectomy. Here, we report on 10 consecutive patients with ptosis and advanced breast cancers that require skin resection outside the standard Wise pattern, where we used the split-reduction incision to facilitate mastectomy and direct-to-implant reconstruction.
Influence of Closed-incision Negative Pressure Wound Therapy on Abdominal Site Complications in Autologous Breast Reconstruction
Authors: Dunson Blake , Kogan Samuel , Grosser Joshua A. , Davidson Amelia , Llull Ramon
Published: October 2023

Background:

Closed-incision negative pressure wound therapy (ciNPWT) has shown promise in reducing surgical wound complications. Among its numerous benefits, it allows for exudate management and tension offloading from wound edges. The purpose of this systematic review and meta-analysis was to assess the efficacy of prophylactic ciNPWT versus conventional dressings on abdominal donor site complications in microsurgical breast reconstruction (MR).

Methods:

A systematic review was conducted according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines in January 2023. PubMed and Embase were searched to identify all relevant studies. Data collected included rates of total wound complications, wound dehiscence, infection, seroma, and length of hospital stay.

Results:

A total of 202 articles were screened, and eight studies (1009 patients) met the inclusion criteria. Use of ciNPWT was associated with a significantly lower rate of wound dehiscence (OR, 0.53; 95% confidence interval, 0.33–0.85; P = 0.0085, I
2 = 0%). There was no significant difference in the rate of total wound complications [odds ratio (OR), 0.63; 95% CI, 0.35–1.14; P = 0.12, I
2 = 69%], donor site infection (OR, 0.91; 95% CI, 0.42–1.50; P = 0.47, I
2 = 13%), seroma (OR, 0.74; 95% CI, 0.22–2.49; P = 0.63, I
2 = 57%), or length of hospital stay (SMD, 0.089; 95% CI, –0.13–0.35; P = 0.37, I
2 = 29%).

Conclusions:

Although exudate management by ciNPWT fails to reduce surgical site infection, seroma formation, and overall length of stay, ciNPWT tension offloading properties seem to be associated with lower rates of wound dehiscence when compared with conventional dressings in abdominal-based autologous breast reconstruction.
Revolutionizing clinical trials: the role of ai in accelerating medical breakthroughs
Authors: Chopra Hitesh , Annu  , Shin Dong Kil , Munjal Kavita , Priyanka  , Dhama Kuldeep , Emran Talha Bin
Published: October 2023

Clinical trials are the essential assessment for safe, reliable, and effective drug development. Data-related limitations, extensive manual efforts, remote patient monitoring, and the complexity of traditional clinical trials on patients drive the application of Artificial Intelligence (AI) in medical and healthcare organisations. For expeditious and streamlined clinical trials, a personalised AI solution is the best utilisation. AI provides broad utility options through structured, standardised, and digitally driven elements in medical research. The clinical trials are a time-consuming process with patient recruitment, enrollment, frequent monitoring, and medical adherence and retention. With an AI-powered tool, the automated data can be generated and managed for the trial lifecycle with all the records of the medical history of the patient as patient-centric AI. AI can intelligently interpret the data, feed downstream systems, and automatically fill out the required analysis report. This article explains how AI has revolutionised innovative ways of collecting data, biosimulation, and early disease diagnosis for clinical trials and overcomes the challenges more precisely through cost and time reduction, improved efficiency, and improved drug development research with less need for rework. The future implications of AI to accelerate clinical trials are important in medical research because of its fast output and overall utility.
Oncological Surveillance After Radical Cystectomy: a Narrative Review of the Enhanced Recovery After Surgery Cystectomy Committee
Authors: Kaufmann Ernest , Black Peter C. , Catto James W.F. , Djaladat Hooman , Ghodoussipour Saum , Hamilton-Reeves Jill M. , Jensen Bente Thoft , Kassouf Wassim , Lauridsen Susanne Vahr , Lerner Seth P. , Llorente Carlos , Loftus Katherine , Lucca Ilaria , Martini Alberto , Preston Mark A. , Psutka Sarah P. , Sfakianos John P. , Shah Jay , Wettstein Marian Severin , Williams Stephen B. , Daneshmand Siamak , Fankhauser Christian D. ,   on behalf of the Enhanced Recovery After Surgery (ERAS) Cystectomy Committee
Published: October 2023

Purpose:

Follow-up after cystectomy aims to detect relapse, but there are discrepancies in recommendations among guidelines. Routine follow-up for asymptomatic recurrences in urothelial cancer is primarily based on nonvalidated risk factors from retrospective cohort studies in single institutions. This review provides an overview of follow-up investigations, schedules, and potential risk factors of recurrence.

Materials and methods:

We conducted a narrative literature search on PubMed and reviewed guidelines (European Society for Medical Oncology, European Association of Urology, National Comprehensive Cancer Network, American Urology Association, and National Institute for Health and Care Excellence) and institutional protocols for cystectomy patients.

Results:

Our analysis included 29 studies with 23,218 patients. Most relapses occurred within 2 years, either locally or as distant recurrences in the chest, liver, bones, or brain. Factors increasing relapse risk included higher tumor stage, nodal involvement, histological subtypes, and lymphovascular invasion. Surveillance protocols varied in frequency and type of investigation. Limited recommendations were available for patients with ypT0, pT0, or non–muscle-invasive bladder cancer.

Conclusions:

Further research is needed to evaluate the impact of postcystectomy follow-up protocols on oncological outcomes and establish optimal surveillance procedures.
Protein and amino acids in obesity: friends or foes?
Authors: Boirie Yves , Pinel Alexandre , Guillet Christelle
Published: October 2023

Purpose of review

Nutritional interventions using protein and amino acids in obesity are popular therapeutical strategies to limit obesity development. However, the effects of dietary protein intake and amino acid metabolic alterations involved in obesity pathophysiology have not been completely unravelled. Significant recent studies have brought to light new findings in these areas, which are the primary focus of this review.

Recent findings

We describe the effects of protein intake on weight regain prevention, the influence on gut microbiota, the response to low-protein highly processed foods, and the contrasting impacts of a high-protein diet on adults and children. We also explore newly discovered correlations between amino acids, liver fat accumulation, and the dysregulation of the liver–pancreas axis due to alterations in amino acid levels in the context of obesity. Lastly, we consider branched-chain amino acids, along with glycine and tryptophan, as significant biomarkers during periods of positive or negative energy balance.

Interventions using dietary protein in obesity may be useful, especially during energy restriction but also in sarcopenic obesity. Furthermore, metabolic profiles that encompass alterations in certain amino acids can provide valuable insights into the metabolic condition of patients with obesity, particularly in relation to insulin resistance and the risk of developing type 2 diabetes.
Updates in endoscopic management of ampullary and duodenal adenomas
Authors: Chadalavada Pravallika , Shah Tilak Upendra
Published: October 2023

Purpose of review

Adenomas are the most common benign lesions of the gastrointestinal tract. The current review aims to summarize recent literature regarding risk factors, natural history, diagnostic and staging technique, and management strategies for ampullary and nonampullary duodenal adenomas.

Recent findings

Recent studies identified several possible risks factors for duodenal adenomas (e.g., cholecystectomy, proton pump inhibitor use), although these associations require corroboration. Chromoendoscopy and endocystoscopy may offer accuracy comparable to biopsies in expert hands. Recent publications underscore the reduction in morbidity with endoscopic resection for lesions without signs of malignancy with submucosal invasion. Submucosal injection did not improve safety of endoscopic ampullectomy.

Surveillance may be a reasonable strategy for sub-centimeter ampullary adenomas occurring in familial adenomatous polyposis, as they carry a relatively low risk of malignancy. Endoscopic resection is the preferred strategy over surgery in patients without lesions suggestive of invasive malignancy. For nonampullary duodenal adenomas, several endoscopic resection techniques are available, each with their unique advantages and trade-offs. In patients who are not operative candidates but have intraductal extension, endoscopic ablation is an emerging option.
The First 6 Months as a Novice Director of Nursing Education
Authors: Weiss Rebecca
Published: October 2023

A novice director of nursing education and professional practice started her first formal leadership role in a new hospital and a new organization. This article will discuss tactics used within the first 6 months in the role that helped the director integrate into the hospital and leadership teams, improve team structure and processes, and improve employee engagement scores.
A Survey of PICU Clinician Practices and Perceptions regarding Respiratory Cultures in the Evaluation of Ventilator-Associated Infections in the BrighT STAR Collaborative
Authors: Sick-Samuels Anna C. , Koontz Danielle W. , Xie Anping , Kelly Daniel , Woods-Hill Charlotte Z. , Aneja Anushree , Xiao Shaoming , Colantuoni Elizabeth A. , Marsteller Jill , Milstone Aaron M. ,   the BrighT STAR Authorship Group
Published: October 2023

OBJECTIVES:

To characterize respiratory culture practices for mechanically ventilated patients, and to identify drivers of culture use and potential barriers to changing practices across PICUs.

DESIGN:

Cross-sectional survey conducted May 2021–January 2022.

SETTING:

Sixteen academic pediatric hospitals across the United States participating in the BrighT STAR Collaborative.

Subjects:

Pediatric critical care medicine physicians, advanced practice providers, respiratory therapists, and nurses.

INTERVENTIONS:

None.

MEASUREMENTS AND MAIN RESULTS:

We summarized the proportion of positive responses for each question within a hospital and calculated the median proportion and IQR across hospitals. We correlated responses with culture rates and compared responses by role. Sixteen invited institutions participated (100%). Five hundred sixty-eight of 1,301 (44%) e-mailed individuals completed the survey (median hospital response rate 60%). Saline lavage was common, but no PICUs had a standardized approach. There was the highest variability in perceived likelihood (median, IQR) to obtain cultures for isolated fever (49%, 38–61%), isolated laboratory changes (49%, 38–57%), fever and laboratory changes without respiratory symptoms (68%, 54–79%), isolated change in secretion characteristics (67%, 54–78%), and isolated increased secretions (55%, 40–65%). Respiratory cultures were likely to be obtained as a “pan culture” (75%, 70–86%). There was a significant correlation between higher culture rates and likelihood to obtain cultures for isolated fever, persistent fever, isolated hypotension, fever, and laboratory changes without respiratory symptoms, and “pan cultures.” Respondents across hospitals would find clinical decision support (CDS) helpful (79%) and thought that CDS would help align ICU and/or consulting teams (82%). Anticipated barriers to change included reluctance to change (70%), opinion of consultants (64%), and concern for missing a diagnosis of ventilator-associated infections (62%).

CONCLUSIONS:

Respiratory culture collection and ordering practices were inconsistent, revealing opportunities for diagnostic stewardship. CDS would be generally well received; however, anticipated conceptual and psychologic barriers to change must be considered.
A Comprehensive Overview of the Efficacy and Safety of Gadopiclenol: A New Contrast Agent for MRI of the CNS and Body
Authors: Hao Jing , Pitrou Camille , Bourrinet Philippe
Published: October 2023

This review describes the pharmacokinetics, efficacy, and safety of gadopiclenol, a new macrocyclic gadolinium-based contrast agent (GBCA) recently approved by the Food and Drug Administration at the dose of 0.05 mmol/kg. Gadopiclenol is a high relaxivity contrast agent that shares similar pharmacokinetic characteristics with other macrocyclic GBCAs, including a predominant renal excretion. In pediatric patients aged 2–17 years, the pharmacokinetic parameters (assessed through a population pharmacokinetics model) were comparable to those observed in adults, indicating no need for age-based dose adjustment. For contrast-enhanced magnetic resonance imaging (MRI) of the central nervous system (CNS) and body indications, gadopiclenol at 0.05 mmol/kg was shown to be noninferior to gadobutrol at 0.1 mmol/kg in terms of 3 lesion visualization parameters (ie, lesion border delineation, internal morphology, and contrast enhancement). Moreover, for contrast-enhanced MRI of the CNS, compared with gadobenate dimeglumine at 0.1 mmol/kg, gadopiclenol exhibited superior contrast-to-noise ratio at 0.1 mmol/kg and comparable contrast-to-noise ratio at 0.05 mmol/kg. A pooled safety analysis of 1047 participants showed a favorable safety profile for gadopiclenol. Comparative studies showed that the incidence and nature of adverse drug reactions with gadopiclenol were comparable to those observed with other GBCAs. Importantly, no significant safety concerns were identified in pediatric and elderly patients, as well as in patients with renal impairment. Overall, these findings support the clinical utility and safety of gadopiclenol for MRI in adult and pediatric patients aged 2 years and older in CNS and body indications.
TXA does not affect levels of TBI-related biomarkers in blunt TBI with ICH: A secondary analysis of the prehospital TXA for TBI trial
Authors: Hoefer Lea E. , Benjamin Andrew J. , Polcari Ann M. , Schreiber Martin A. , Zakrison Tanya L. , Rowell Susan E.
Published: October 2023

BACKGROUND

Brain specific biomarkers such as glial fibrillary acidic protein (GFAP), ubiquitin C-terminal hydrolase L1 (UCH-L1), and microtubule-associated protein-2 (MAP-2) have been identified as tools for diagnosis in traumatic brain injury (TBI). Tranexamic acid (TXA) has been shown to decrease mortality in patients with intracranial hemorrhage (ICH). The effect of TXA on these biomarkers is unknown. We investigated whether TXA affects levels of GFAP, UCH-L1, and MAP-2, and whether biomarker levels are associated with mortality in patients receiving TXA.

METHODS

Patients enrolled in the prehospital TXA for TBI trial had GFAP, UCHL-1 and MAP-2 levels drawn at 0 hour and 24 hours postinjury (n = 422). Patients with ICH from blunt trauma with a GCS <13 and SBP >90 were randomized to placebo, 2 g TXA bolus, or 1 g bolus +1 g/8 hours TXA infusion. Associations of TXA and 24-hour biomarker change were assessed with multivariate linear regression. Association of biomarkers with 28-day mortality was assessed with multivariate logistic regression. All models were controlled for age, GCS, ISS, and AIS head.

RESULTS

Administration of TXA was not associated with a change in biomarkers over 24 hours postinjury. Changes in biomarker levels were associated with AIS head and age. On admission, higher GFAP (odds ratio [OR], 1.75; confidence interval [CI], 1.31–2.38; p < 0.001) was associated with increased 28-day mortality. At 24 hours postinjury, higher levels of GFAP (OR, 2.09; CI, 1.37–3.30; p < 0.001 and UCHL-1 (OR, 2.98; CI, 1.77–5.25; p < 0.001) were associated with mortality. A change in UCH levels from 0 hour to 24 hours postinjury was also associated with increased mortality (OR, 1.68; CI, 1.15–2.49; p < 0.01).

CONCLUSION

Administration of TXA does not impact change in GFAP, UCHL-1, or MAP-2 during the first 24 hours after blunt TBI with ICH. Higher levels of GFAP and UCH early after injury may help identify patients at high risk for 28-day mortality.

LEVEL OF EVIDENCE

Therapeutic/Care Management; Level III.
Haemophilus influenzae blood-stream infection and third-generation cephalosporin susceptibility testing: a comparative case study using EUCAST and CLSI guidelines
Authors: Merlino John , Rizzo Sophia , English Suzanne , Baskar Sai Rupa , Siarakas Steven , Mckew Genevieve , Fernanado Shelanah , Gray Timothy
Published: October 2023

Introduction. In this comparative case study, we discuss clinically relevant discrepancies of antimicrobial susceptibility testing (AST) interpretation for ceftriaxone against a non-typable, beta-lactamase negative, ampicillin-resistant (BLNAR)

Haemophilus influenzae

isolated from a blood culture.

Case report. A 74-year-old man presented with a 3 day illness characterized by shortness of breath and dry cough, and was noted to be febrile and hypoxic on admission. A blood culture bottle flagged positive with Gram-negative coccobacilli, later identified as

Haemophilus influenzae

with the patient commenced on ceftriaxone. The isolate was beta-lactamase negative and antibiotic susceptibility testing (AST) using disc diffusion revealed the isolate resistant to ceftriaxone and ampicillin by EUCAST methodology, with the patient subsequently changed to amoxicillin/clavulanate. Further AST using the CLSI methodology in parallel demonstrated discrepant results between the two susceptibility methods. The patient recovered without complications.

Conclusion. This discrepancy could lead to inconsistent reporting of susceptibilities between laboratories, and consequently antibiotic prescribing, especially for invasive isolates. As more laboratories adopt EUCAST methodologies for AST interpretation in Australia and globally, it is important for clinicians to consider the clinical implications of these methodological discrepancies.
How do stochastic processes and genetic threshold effects explain incomplete penetrance and inform causal disease mechanisms?
Authors: Jenkins Dagan
Published: October 2023

Incomplete penetrance is the rule rather than the exception in Mendelian disease. In syndromic monogenic disorders, phenotypic variability can be viewed as the combination of incomplete penetrance for each of multiple independent clinical features. Within genetically identical individuals, such as isogenic model organisms, stochastic variation at molecular and cellular levels is the primary cause of incomplete penetrance according to a genetic threshold model. By defining specific probability distributions of causal biological readouts and genetic liability values, stochasticity and incomplete penetrance provide information about threshold values in biological systems. Ascertainment of threshold values has been achieved by simultaneous scoring of relatively simple phenotypes and quantitation of molecular readouts at the level of single cells. However, this is much more challenging for complex morphological phenotypes using experimental and reductionist approaches alone, where cause and effect are separated temporally and across multiple biological modes and scales. Here I consider how causal inference, which integrates observational data with high confidence causal models, might be used to quantify the relative contribution of different sources of stochastic variation to phenotypic diversity. Collectively, these approaches could inform disease mechanisms, improve predictions of clinical outcomes and prioritise gene therapy targets across modes and scales of gene function.
Heterogeneity in Functional Connectivity: Dimensional Predictors of Individual Variability during Rest and Task fMRI in Psychosis
Authors: Secara Maria T. , Oliver Lindsay D. , Gallucci Julia , Dickie Erin W. , Foussias George , Gold James , Malhotra Anil K. , Buchanan Robert W. , Voineskos Aristotle N. , Hawco Colin
Published: October 2023

Background

Individuals with schizophrenia spectrum disorders (SSD) often demonstrate cognitive impairments, associated with poor functional outcomes. While neurobiological heterogeneity has posed challenges when examining social cognition in SSD, it provides a unique opportunity to explore brain-behavior relationships. We examined the relationship between behavioral data and individual variability of functional connectivity at rest and during an emotional-processing task.

Methods

Neuroimaging and behavioral data were analyzed for 193 individuals with SSD and 155 controls (total n = 348). Individual variability was quantified through mean correlational distance (MCD) of functional connectivity between participants; MCD was defined as a global ‘variability score’. Hierarchical regressions were performed on variability scores derived from resting state and Empathic Accuracy (EA) task functional connectivity data to determine potential predictors (e.g., age, sex, neurocognitive and social cognitive scores) of individual variability.

Results

SSD showed greater MCD during rest (p = 0.00013) and task (p = 0.022). In the hierarchical regression, diagnosis remained significant when social cognition was included during rest (p = 0.008), but not during task (p = 0.50); social cognition was significant during both rest and task (both p = 0.01).

Conclusions

Diagnostic differences were more prevalent during unconstrained resting scans, whereas the task pushed participants into a more common pattern which better emphasized transdiagnostic differences in cognitive abilities. Focusing on variability may provide new opportunities for interventions targeting specific cognitive impairments to improve functional outcomes.
Samsung Galaxy Watch5 Pro and Withings Body+ generate electrical interference on CRT-Ds
Authors: Hansen Nathan , Ha Gia-Bao , Colvin Penny , Freedman Roger A. , Bayés-Genís Antoni , Steinberg Benjamin A. , Sanchez Benjamin
Published: October 2023

Smart consumer devices with bioimpedance sensing technology apply an electrical current to the body for health and wellness. However, whether these smart devices interfere with cardiac implantable electronic devices (CIEDs) remains unknown. We report electrical interference with benchtop testing from the Galaxy Watch5 Pro and smart scale Body+ to cardiac resynchronization therapy device generators from different manufacturers. These results highlight the need of establishing standard testing procedures to assess the safety of smart devices with bioimpedance sensing in patients with CIEDs.
Asthma severity and corticosteroid response depend on variable type 1 and type 2 inflammation in the airway
Authors: Fahy John V. , Jackson Nathan D. , Sajuthi Satria P. , Pruesse Elmar , Moore Camille M. , Everman Jamie L. , Rios Cydney , Tang Monica , Gauthier Marc , Wenzel Sally E. , Bleecker Eugene R. , Castro Mario , Comhair Suzy A. , Erzurum Serpil C. , Hastie Annette T. , Moore Wendy , Israel Elliot , Levy Bruce D. , Denlinger Loren , Jarjour Nizar N. , Johansson Mats W. , Mauger David T. , Phillips Brenda R. , Sumino Kaharu , Woodruff Prescott G. , Peters Michael C. , Seibold Max A. ,   the National Heart, Lung, and Blood Institute Severe Asthma Research Program-3
Published: October 2023

The prevalence, inter-relationships, and longitudinal behavior of type 1 (T1) and type 2 (T2) immune responses in asthma are uncertain, as is the role of viruses as determinants of these responses. Here, we performed whole transcriptome network analysis on sputum cells collected from Severe Asthma Research Program (SARP)-3 patients before and after treatment with intramuscular corticosteroid and again at 1 and 3-year follow-up visits. We used network analysis to analyze whole-transcriptome gene expression and metagenomic analysis of these RNA-seq data to detect viruses. We identified T1 and T2 airway networks, the expression of which showed that 26% and 44% of patients had T1-high and T2-high asthma at baseline, respectively. Asthma severity outcomes were worse in T2-high asthma than in T1-high asthma and most severe in the subgroup of patients (14%) with combined T1- and T2-high disease. Corticosteroid treatment suppressed T2 but not T1 gene expression, and corticosteroid-associated improvements in FEV1 occurred only in patients with T1-L/T2-H disease and not in T1-H/T2-H patients. Although T1 and T2 inflammation at baseline was a significant predictor of T1 and T2 inflammation at follow-up visits, most patients had variable rather than persistent expression of T1 and T2 network genes. Viral metagenomic analyses uncovered that 24% of asthma sputum samples tested positive for a virus and high viral carriage was associated with an 11-fold increased risk of T1-high disease. Together our results uncover a relatively high burden of T1-high and T1/T2-high disease subtypes in severe asthma, which are corticosteroid-resistant and manifest with sub-clinical viral infection.
Polygenic associations with clinical and neuropathological trait heterogeneity across TDP-43 proteinopathies
Authors: Spencer Barbara E. , Irwin David J. , Van Deerlin Vivianna M. , Suh EunRan , Lee Edward B. , Elman Lauren B. , Quinn Colin C. , Amado Defne , Baer Michael , Grossman Murray , Wolk David A. , McMillan Corey T.
Published: October 2023

Objective

TDP-43 proteinopathies, including amyotrophic lateral sclerosis (ALS), frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), and limbic-predominant age-related TDP-43 encephalopathy, encompass a spectrum of clinical and neuropathological traits. Despite mounting evidence for shared genetic risk across TDP-43 proteinopathies, the modifiers of individual-level traits are unknown. We aimed to identify polygenic contributions to trait heterogeneity across TDP-43 proteinopathies.

Methods

We used weighted correlation analysis of GWAS summary statistics for ALS, FTLD-TDP, and hippocampal sclerosis of aging (HS-Aging) to identify data-driven modules of highly correlated single nucleotide polymorphisms (SNPs). We performed gene ontology enrichment analysis for each identified module. We derived module-specific polygenic scores and evaluated their association with clinical and neuropathological traits in an independently evaluated sample of individuals who met neuropathological and/or genetic criteria for FTLD-TDP or ALS (n=260).

Results

We identified 5 distinct data-driven modules, including 3 GWAS phenotype-specific modules (FTLD-TDP, ALS, HS-Aging) and 2 modules representing the overlap between a pair of GWAS phenotypes (ALS-FTLD and FTLD-HS). Pathway analysis revealed biologically meaningful associations including distinct GWAS phenotype-specific processes within modules. Module-specific ALS and FTLD-TDP polygenic risk each associated with individual-level clinical traits, even within the context of autosomal dominant mutation carriers, where higher ALS polygenic risk associated with neuromuscular impairment and higher FTLD-TDP polygenic risk associated with cognitive-behavioral impairment. Moreover, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden within characteristic FTLD-TDP brain regions.Interpretation:We suggest that there are polygenic modifiers of clinical and neuropathological traits across TDP-43 proteinopathies that may contribute to individual-level differences, including likelihood for developing FTLD or ALS.
The Effects of Intensive Antihypertensive Treatment Targets on Cerebral Blood Flow and Orthostatic Hypotension in Frail Older Adults
Authors: Weijs Ralf W.J. , de Roos Bente M. , Thijssen Dick H.J. , Claassen Jurgen A.H.R.
Published: October 2023

Background

Guidelines recommend restrictive antihypertensive treatment (AHT) in hypertensive frail older adults, as intensive AHT is assumed to cause cerebral hypoperfusion and orthostatic hypotension (OH). However, studies directly examining these assumptions in older, frail individuals are lacking.

Methods

Fourteen frail hypertensive patients (six females; age 80.3±5.2 years; Clinical Frailty Scale 4-7; unattended SBP ≥150 mmHg) underwent measurements before and after a median of 7-weeks AHT (SBP target ≤140 mmHg). Transcranial Doppler measurements of middle cerebral artery velocity (MCAv), reflecting changes in cerebral blood flow (CBF), were combined with finger plethysmography recording of continuous BP. Transfer function analysis assessed cerebral autoregulation (CA). ANCOVA analyzed AHT-induced changes in CBF and CA, and evaluated non-inferiority of the relative change in CBF (margin: -10%; covariates: pre-AHT values and AHT-induced relative mean BP change). McNemar-tests analyzed whether the prevalence of (initial) OH, assessed by sit/supine-to-stand challenges, increased with AHT.

Results

Unattended mean arterial pressure decreased by 15 mmHg following AHT. Ten (71%) participants had good quality TCD assessments. Non-inferiority was confirmed for the relative change in MCAv (95%CI -2.7, 30.4). CA was normal and remained unchanged following AHT (P>0.05). None of the 14 participants had an increase in the prevalence of OH or initial OH (P≥0.655).

Conclusions

We found that AHT in frail, older patients does not reduce CBF, is not associated with impaired CA, and does not increase (initial) OH prevalence. These observations may open doors for more intensive AHT targets upon individualized evaluation and monitoring of hypertensive frail patients.

Clinical Trial Registration

ClinicalTrials.gov(NCT05529147) and EudraCT (2022-001283-10).
Computational divergence analysis reveals the existence of regulatory degeneration and supports HDAC1 as a potential drug target for Alzheimer’s disease
Authors: Wang Qun , Zhao Zhenzhen , Lu Dong , Xu Hong , Xia Jianhua , Zhang Weidong , Meng Guofeng
Published: October 2023

Epigenetic dysregulation has been widely reported in patients of Alzheimer’s disease (AD) and epigenetic drugs are gaining particular interest as a potential candidate therapy target. However, it is less clear how epigenetic dysregulation contributes to AD development. In this work, we performed regulatory divergence analysis using large-scale AD brain RNA-seq data and reported a widespread existence of regulatory degeneration among AD patients. It seems that transcription factor (TF)-mediated regulations get weakened or lost during AD development, resulting in disruption of normal neuronal function, especially including protein degradation, neuroinflammation, mitochondria and synaptic dysfunction. The regulatory degeneration burden (RDB) is well correlated with the detrimental clinical manifestations of AD patients. Studies of epigenetic marks, including histone modification, open chromatin accessibility and three TF binding sites supported the existence of regulatory degeneration. It suggested that epigenetic dysregulation contributed to regulatory degeneration, which also explained the consequence of epigenetic dysregulation. Among the epigenetic regulators, HDAC1 was proposed as a potential participator in such a process. Overall, our computational analysis suggested a novel causal mechanism of AD development and proposed HDAC1 as a drug target to treat AD.
Securing diagonal integration of multimodal single-cell data against ambiguous mapping
Authors: Zhou Han , Cao Kai , Lu Yang Young
Published: October 2023

Recent advances in single-cell multimodal omics technologies enable the exploration of cellular systems at unprecedented resolution, leading to the rapid generation of multimodal datasets that require sophisticated integration methods. Diagonal integration has emerged as a flexible solution for integrating heterogeneous single-cell data without relying on shared cells or features. However, the absence of anchoring elements introduces the risk of artificial integrations, where cells across modalities are incorrectly aligned due to ambiguous mapping. To address this challenge, we propose SONATA, a novel diagnostic method designed to detect potential artificial integrations resulting from ambiguous mappings in diagonal data integration. SONATA identifies ambiguous alignments by quantifying cell-cell ambiguity within the data manifold, ensuring that biologically meaningful integrations are distinguished from spurious ones. It is worth noting that SONATA is not designed to replace any existing pipelines for diagonal data integration; instead, SONATA works simply as an add-on to an existing pipeline for achieving more reliable integration. Through comprehensive evaluation on both simulated and real multimodal single-cell datasets, we observe that artificial integrations in diagonal data integration are widespread yet surprisingly overlooked, occurring across all mainstream diagonal integration methods. We demonstrate SONATA’s ability to safeguard against misleading integrations and provide actionable insights into potential integration failures across mainstream methods. Our approach offers a robust framework for ensuring the reliability and interpretability of multimodal single-cell data integration.1
Conditional Requirement for Dimerization of the Membrane-Binding Module of BTK
Authors: Eisen Timothy J. , Ghaffari-Kashani Sam , Groves Jay T. , Weiss Arthur , Kuriyan John
Published: October 2023

Bruton’s tyrosine kinase (BTK) is a major drug target in immune cells. The membrane-binding pleckstrin-homology and tec-homology (PH–TH) domains of BTK are required for signaling. In vitro, dimerization of the PH–TH module strongly stimulates BTK kinase activity. Whether BTK dimerizes in cells via the PH–TH module, and whether this dimerization is necessary for signaling, is unknown. To address this question, we developed high-throughput mutagenesis assays for BTK function in B cells and T cells. We measured the fitness costs for thousands of point mutations in the PH–TH module and kinase domain, allowing us to assess whether dimerization of the PH–TH module and BTK kinase activity are necessary for function. In Ramos B cells we find that neither PH–TH dimerization nor kinase activity is required for BTK signaling. Instead, in Ramos cells, BTK signaling is enhanced by mutations in the PH–TH module that increase membrane adsorption, even at the cost of reduced PH–TH dimerization. In contrast, in Jurkat T cells, we find that BTK signaling depends on both PH–TH dimerization and kinase activity. Evolutionary analysis shows that BTK proteins in fish and lower organisms, like all Tec kinases other than BTK, lack PH–TH dimerization but have active kinase domains. Thus, PH–TH dimerization is not intrinsically required for Tec-kinase activity, and is a special feature that evolved to exert stricter regulatory control on BTK kinase activity as adaptive immune systems gained increased complexity.
Healthcare and long-term care for older people with cognitive impairment in the US: A latent transition analysis
Authors: Hu Bo , Wang Pengyun , Chen Xi
Published: October 2023

Background

Healthcare and long-term care are crucial to the well-being of people with mild cognitive impairment (MCI) or dementia. This study investigates the clustering patterns of healthcare and long-term care use in people with MCI or dementia and the relationships between changes in cognitive functioning and transitions of care.

Methods

The study used longitudinal data from three recent waves of the Health and Retirement Study (HRS 2014-2018, N=10,152). MCI and dementia were measured based on the Langa-Weir Classifications. The outcome measures included five types of healthcare and three types of long-term care services. Latent transition analyses were conducted to identify the clustering patterns of care use and map out the transition pathways between different care classes over time. Multilevel regression analyses were conducted to investigate the relationships between changes in cognitive functioning and care transitions.

Results

We identified three user groups: medium healthcare and low long-term care (MM-LC, 56%, n=5,653), high healthcare and high long-term care (HM-HC, 37%, n=3,743), and low healthcare and low long-term care (LM-LC, 7%, n=736). The progression of cognitive impairment was associated with a higher probability of transitioning from MM-LC to HM-HC class (β=0.070; p<0.001). An improvement in cognitive functioning was associated with a higher probability of transitioning from HM-HC to MM-LC class (β=0.039, p<0.05).

Conclusions

Our findings underscore the importance of integration between healthcare and long-term care. Changes in cognitive functioning are useful indicators for care planning, resource allocation, and care coordination from diverse care providers.

Key points

Three classes of healthcare and long-term care services were identified in the latent transition analyses.

The progression of cognitive impairment was associated with transitioning to a class characterized by more use of healthcare and long-term care services,

An improvement in cognitive functioning was associated with transitioning to a class characterized by less use of care in both sectors.
Genomics in nephrology: identifying informatics opportunities to improve diagnosis of genetic kidney disorders using a human-centered design approach
Authors: Romagnoli Katrina M. , Salvati Zachary M. , Johnson Darren K. , Ramey Heather M. , Chang Alexander R. , Williams Marc S.
Published: October 2023

Background

Genomic conditions in nephrology often have a long lag between onset of symptoms and diagnosis. To design a real time genetic diagnosis process that meets the needs of nephrologists, we need to understand the current state of the diagnostic process of genomic kidney disorders, barriers and facilitators nephrologists experience, and identify areas of opportunity for improvement and innovation.

Methods

Qualitative in-depth interviews were conducted with 16 nephrologists from 7 health systems across the US, with variable levels of experience with genetic testing and diagnosis. Rapid analysis identified themes in the interviews. Themes were then used to develop service blueprints (visual diagrams representing relationships between components of a service) and process maps depicting the current state of genetic diagnosis of kidney disease, helping visualize the current state, along with associated barriers and facilitators.

Results

Themes from the interviews included the importance of trustworthy resources, guidance on how to order tests, and evidence-based recommendations on what to do with results. Barriers included lack of knowledge, lack of access, and complexity surrounding the case and disease. Facilitators, based on current genetic testing services used by participants, included good user experience, straightforward diagnoses, and support from colleagues.

Discussion

The current state of diagnosis of genetic kidney diseases is suboptimal, with information gaps, complexity of genetic testing process, and complexity of disease impeding efficiency. This study highlights opportunities for improvement and innovation to address these barriers and empower clinicians who treat nephrological disease to access and use real time genetic information.