Mixed Gonadal Dysgenesis: A Narrative Literature Review and Clinical Primer for the Urologist.

PURPOSE: Mixed gonadal dysgenesis is a difference of sex development that is often confused with other conditions. Individuals have a 45,X/46,XY karyotype. Gonads are characterized by a streak gonad and a dysgenetic testis at varying levels of descent. Persistent Müllerian structures are typical (eg, hemi-uterus). There is significant phenotypic heterogeneity of the internal and external genitalia that, together with different interpretations of the definition, have contributed to a poor understanding of the condition among pediatric urologists. Mixed gonadal dysgenesis is one manifestation of the 45,X/46,XY karyotype. 45,X/46,XY mosaicism can also be associated with typical female or male external genitalia. This review aims to clarify the mixed gonadal dysgenesis definition and to provide urologists with diagnostic and management considerations for affected individuals. MATERIALS AND METHODS: We searched 3 medical databases for articles related to mixed gonadal dysgenesis. 287 full-text abstracts and manuscripts were reviewed for content pertinent to: (1) Clarifying the definition of mixed gonadal dysgenesis, and (2) Describing the following related to the care of affected individuals: prenatal and neonatal evaluation and management, genital surgery, gonadal malignancy risk and management, fertility, gender dysphoria/incongruence, puberty and long-term outcomes, systemic comorbidities, and transitional care. RESULTS: 50 articles were included. Key points and implications for each of the above topics were summarized. CONCLUSIONS: Mixed gonadal dysgenesis exists on a wide phenotypic spectrum and management considerations reflect this heterogeneity. Care for individuals with mixed gonadal dysgenesis is complex, and decisions should be made in a multidisciplinary setting with psychological support.

Temporally resolved proteomics identifies nidogen-2 as a cotarget in pancreatic cancer that modulates fibrosis and therapy response.

Pancreatic ductal adenocarcinoma (PDAC) is characterized by increasing fibrosis, which can enhance tumor progression and spread. Here, we undertook an unbiased temporal assessment of the matrisome of the highly metastatic KPC (Pdx1-Cre, LSL-KrasG12D/+, LSL-Trp53R172H/+) and poorly metastatic KPflC (Pdx1-Cre, LSL-KrasG12D/+, Trp53fl/+) genetically engineered mouse models of pancreatic cancer using mass spectrometry proteomics. Our assessment at early-, mid-, and late-stage disease reveals an increased abundance of nidogen-2 (NID2) in the KPC model compared to KPflC, with further validation showing that NID2 is primarily expressed by cancer-associated fibroblasts (CAFs). Using biomechanical assessments, second harmonic generation imaging, and birefringence analysis, we show that NID2 reduction by CRISPR interference (CRISPRi) in CAFs reduces stiffness and matrix remodeling in three-dimensional models, leading to impaired cancer cell invasion. Intravital imaging revealed improved vascular patency in live NID2-depleted tumors, with enhanced response to gemcitabine/Abraxane. In orthotopic models, NID2 CRISPRi tumors had less liver metastasis and increased survival, highlighting NID2 as a potential PDAC cotarget.

Application of intraoperative structured light scanning to enable post-operative evaluation of digital and 3D-printed penile models.

BACKGROUND: Penile phenotype in hypospadias is currently assessed visually or manually (e.g., ruler, goniometer) for clinical, education, and research applications. However, these methods lack precision and accuracy across raters and cannot be reevaluated retrospectively following a surgical repair. The project aim was to evaluate the precision and reliability of penile dimensions obtained from digital and three dimensional (3D) printed models created from intraoperative (OR) structured light scans (SLS) during primary pediatric penile procedures. METHODS: Boys ages 1 month to 6 years underwent first- or single-stage penile surgery at a single institution were enrolled in this prospective study (IRB #20-000143). For each patient, immediately following placement of a stay suture under consistent manual tension, intra-operative dimension measurements with a ruler were obtained. A digital 3D model was created prior to penile repositioning using an Artec Space Spider scanner and Artec Studio 13 software. Following the case, two different raters completed 10 digital measurements of each generated model in Autodesk Fusion 360. These digital models were subsequently 3D printed and two different raters completed 10 manual dimension measurements of each 3D printed model using a ruler. A one-way random effects intraclass correlation coefficient (ICC) evaluated measures of agreement between and within raters, respectively. Analyses were conducted in R version 4.2. RESULTS: Six scans were obtained (hypospadias: 4, circumcision: 2). Intra-rater assessments showed excellent precision across repeated digital measurements; manual measurements of 3D printed models had excellent reliability for glans width and penile length but poor to good reliability for glans height. Inter-rater reliability was good to excellent for glans width (0.77-0.95) and good for penile length (0.71-0.88). However, there was poor inter-rater reliability for glans height (0-0.14). Following training regarding glans height location, there was an improvement in precision and repeatability of manual and digital measurements. CONCLUSION: Digital measurement of OR-derived 3D models resulted in excellent repeatability for each rater and improved between-rater reliability over manual measurement of 3D printed models alone, ensuring that images can be compared by various surgeons both now and in the future. SLS is promising as a novel modality to digitally generate 3D models, thereby informing phenotypic analysis for research and education. Further development of digital measurement methods to ensure consistency between raters for quantitative assessment of additional parameters and assessment of the technology within the pre-operative environment for surgical planning is planned.

Observational study protocol for an arrhythmia notification feature.

INTRODUCTION: Screening for atrial fibrillation (AF) in the general population may help identify individuals at risk, enabling further assessment of risk factors and institution of appropriate treatment. Algorithms deployed on wearable technologies such as smartwatches and fitness bands may be trained to screen for such arrhythmias. However, their performance needs to be assessed for safety and accuracy prior to wide-scale implementation. METHODS AND ANALYSIS: This study will assess the ability of the WHOOP strap to detect AF using its WHOOP Arrhythmia Notification Feature (WARN) algorithm in an enriched cohort with a 2:1 distribution of previously diagnosed AF (persistent and paroxysmal) and healthy controls. Recruited participants will collect data for 7 days with the WHOOP wrist-strap and BioTel ePatch (electrocardiography gold-standard). Primary outcome will be participant level sensitivity and specificity of the WARN algorithm in detecting AF in analysable windows compared with the ECG gold-standard. Similar analyses will be performed on an available epoch-level basis as well as comparison of these findings in important subgroups. ETHICS AND DISSEMINATION: The study was approved by the ethics board at the study site. Participants will be enrolled after signing an online informed consent document. Updates will be shared via clinicaltrials.gov. The data obtained from the conclusion of this study will be presented in national and international conferences with publication in clinical research journals. TRIAL REGISTRATION NUMBER: NCT05809362.

Paediatric cerebellar glioblastoma - long-term survival following surgery and adjuvant chemoradiotherapy: A case report and literature review.

Introduction: Paediatric cerebellar glioblastoma is an exceptionally rare clinical entity, with very few cases described in the literature. In the majority of reported cases, prognosis is extremely poor, despite surgical and oncological management. The paucity of data results in lack of consensus as to the optimal management of these patients, with the objective of prolonging survival. Research question: Do patient or tumour characteristics suggest more favourable rates of progression-free survival in paediatric cerebellar glioblastoma? Material and methods: Tumour histopathology plus retrospective molecular analysis of archived samples, as well treatment strategy and patient characteristics of a six-year-old child with cerebellar glioblastoma and prolonged progression-free survival were assessed. Characteristics in the published literature that inferred prolonged survival were identified and compared. Results: Paediatric cerebellar glioblastoma is extremely rare, with only a handful of cases reported over several decades, during which time diagnostic and therapeutic techniques have evolved markedly. Consequently, the scarcity of data with sufficient granularity means that limited conclusions can be drawn. Specific clinical and histopathological factors (i.e. female sex, young age, EGFR negativity and surgical resection plus adjuvant chemoradiotherapy) may indicate a more favourable progression-free survival. Discussion and conclusion: Rates of progression-free survival in this rare condition are generally poor, however, several patient and tumour characteristics may infer more favourable prognosis. As increasingly refined means of diagnosis and characterisation are developed, particularly as a result of advances in molecular analyses, more adjuvant treatment options are likely to come on stream in future.

Genomic Landscape of Circulating Tumor DNA in Patients With Hormone Receptor-Positive/Human Epidermal Growth Factor Receptor-2-Negative Metastatic Breast Cancer Treated With Abemaciclib: Data From the SCRUM-Japan Cancer Genome Screening Project.

PURPOSE: To understand the mutational landscape of circulating tumor DNA (ctDNA) and tumor tissue of patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancer (MBC) treated with abemaciclib + endocrine therapy (ET). METHODS: Blood samples for ctDNA and/or tissue samples were collected from abemaciclib-treated patients with HR+/HER2- MBC enrolled in the SCRUM-Japan MONSTAR-SCREEN project. Blood samples were collected before abemaciclib initiation (baseline) and at disease progression/abemaciclib discontinuation (post abemaciclib treatment). Clinical and genomic characteristics including neoplastic burden (measured by shedding rate and maximum variant allele frequency [VAF]) were assessed at baseline. Genomic alterations in ctDNA were compared in paired baseline and post abemaciclib treatment samples. RESULTS: All patients (N = 97) were female (median age, 57 years [IQR, 50-67]). In baseline ctDNA (n = 77), PIK3CA (37%), TP53 (28%), ESR1 (16%), and GATA3 (11%) were the most frequently mutated genes. Baseline tissue samples (n = 79) showed similar alteration frequencies. Among patients with baseline ctDNA data, 30% had received previous ET. ESR1 alteration frequency (35% v 8%; P < .01), median shedding rate (3 v 2), and maximum somatic VAF (4 v 0.8; both P < .05) were significantly higher in ctDNA from patients with previous ET than those without previous ET. In paired ctDNA samples (n = 33), PIK3CA and ESR1 alteration frequencies were higher after abemaciclib treatment than at baseline, though not statistically significant. Among the post-treatment alterations, those newly acquired were detected most frequently in FGF3/4/19 (18%); PIK3CA, TP53, CCND1, and RB1 (all 15%); and ESR1 (12%). CONCLUSION: We summarized the ctDNA and cancer tissue mutational landscape, including overall neoplastic burden and PIK3CA and ESR1 hotspot mutations in abemaciclib-treated patients with HR+/HER2- MBC. The data provide insights that could help optimize treatment strategies in this population.

Association of alcohol use with olfactory function among older adults.

BACKGROUND/PURPOSE: Olfactory dysfunction (OD) has been recognized as an early biomarker for neurodegenerative diseases. Identifying behaviors that increase the risk of OD is crucial for early recognition of neurogenerative diseases. Alcohol consumption can potentially impact olfaction through its neurotoxic effects. This study aims to examine the relationship between alcohol consumption and OD, using data from the National Social Life, Health, and Aging Project (NSHAP). METHODS: This cross-sectional study was conducted on data for 2757 adults from Round 1 of NSHAP. OD was defined as correctly identifying 0-3 odors in the 5-item Sniffin' Sticks test while normal olfactory function was defined as correctly identifying 4-5 odors. Multivariable logistic regression was utilized to examine the association between alcohol consumption and OD, controlling for age, race, and comorbidities. Analyses were weighted to account for the sampling design. RESULTS: OD was present in 23.1 % of adults. The average age among those with OD was 71.2 ± 7.8 years, compared to 66.9 ± 7.2 years in those with normal olfaction. In terms of alcohol consumption, 31.1 % of adults with OD were light-to-moderate drinkers and 7.7 % were heavy drinkers, compared to 35.6 % light-to-moderate and 7.7 % heavy drinkers in the normal olfaction group. After adjusting for age, gender, race, and education, neither light-to-moderate drinking (aOR: 0.99; 95 % CI: 0.76-1.29) nor heavy drinking (aOR: 1.24; 95 % CI: 0.83-1.85) were significantly associated with OD. CONCLUSION: Alcohol consumption was not associated with OD after controlling for covariates. While this study provides insight into the relationship between alcohol consumption and OD, further research is needed due to conflicting results in previous studies.

Antiviral discovery in toxic cyanobacteria: Low hanging fruit in the age of pandemics.

The power of novel vaccination technologies and their rapid development were elucidated clearly during the COVID-19 pandemic. At the same time, it also became clear that there is an urgent need to discover and manufacture new antivirals that target emerging viral threats. Toxic species of cyanobacteria produce a range of bioactive compounds that makes them good candidates for drug discovery. Nevertheless, few studies demonstrate the antiviral potential of cyanobacteria. This is partly due to the lack of specific and simple protocols designed for the rapid detection of antiviral activity in cyanobacteria and partly because specialized facilities for work with pathogenic viruses are few and far between. We therefore developed an easy method for the screening of cyanobacterial cultures for antiviral activity and used our private culture collection of non-pathogenic virus isolates to show that antiviral activity is a prominent feature in the cyanobacterium Microcystis aeruginosa. In this proof-of-concept study, we show that M. aeruginosa extracts from three different cyanobacterial strains delay infection of diatom-infecting single-stranded DNA and single-stranded RNA viruses by up to 2 days. Our work shows the ease with which cyanobacteria from culture collections can be screened for antiviral activity and highlights the potential of cyanobacteria as an excellent source for the discovery of novel antiviral compounds, warranting further investigation.

Incidence of Sinusitis Postoperatively in Orthognathic Surgery: A Systematic Review and Meta-Analysis.

Maxillary osteotomies as a component of orthognathic surgery disrupt the normal anatomy and function of the sinus. The osteotomy with advancement of the inferior component of the sinus leaves a bony and mucosal opening in the sinus. Immediately after surgery, nasal drainage is impeded because of intranasal swelling. Acute and chronic maxillary sinusitis would be expected; however, its incidence as an expected complication is not well documented. A systematic review and meta-analysis was completed using PubMed to determine the incidence of sinusitis after maxillary orthognathic surgery. Studies were reviewed by two authors, and incidence data were extracted. Two hundred six articles were identified with 24 meeting the criteria for analysis. The incidence of sinusitis was based on 4213 participants who had undergone orthognathic surgery. Twenty-three studies reported a total number of sinusitis cases, and the results demonstrated a pooled incidence of 3.3% (95% confidence interval: 1.77, 6.06). One study did not report a total number of cases but reported chronic sinusitis survey-duration-based and Lund-Mackay scores. These scores, respectively, worsened from 7.6 to 14.8 and from 1.58 to 2.90 postoperatively. Despite the variability of maxillary surgery, the surgical technique, and the postoperative management, the incidence is low but sinusitis does occur. Prospective studies with validated questionnaires within the context of a specific protocol may further elucidate the causality of sinusitis. Further, patients with sinonasal symptoms postsurgery should be encouraged to consult with an otolaryngologist to ensure prompt treatment.

Trends and Frequencies of Antibiotic Prescriptions for Acute Sinusitis Outpatient Visits in Adults.

OBJECTIVE: The objective of this study was to analyze the trends and frequency in which recommended first-line therapy, amoxicillin with or without clavulanate, was prescribed for acute sinusitis based on current otolaryngology and other gold standard guidelines, as well as analyze differences in prescription behaviors of otolaryngologists compared with non-otolaryngologists for outpatient adult acute sinusitis visits. METHODS: Weighted patient data from the National Ambulatory Medical Care Survey were analyzed to calculate visit rates and trends of antibiotic prescriptions for adults diagnosed with acute sinusitis from 2007 to 2019. Visits with multiple prescribed antibiotics or concomitant diagnoses requiring antibiotics were excluded. Each visit was classified based on the type of antibiotic prescribed. RESULTS: Acute sinusitis was diagnosed in 0.63% of all outpatient visits from 2007 to 2019 (95% confidence interval: 0.56%-0.71%). Amoxicillin had the greatest increase in prescription frequency (13.4%), whereas macrolides had the largest decrease in prescription frequency (13.9%). Among adult acute sinusitis outpatient visits in which antibiotics were prescribed, recommended first-line antibiotic therapy of amoxicillin-clavulanate or amoxicillin alone was prescribed in 40.4% of visits. The most common antibiotic prescribed was amoxicillin-clavulanate at otolaryngologist visits (20.5%) and macrolides at non-otolaryngologist visits (26.0%). A greater proportion of otolaryngologist visits resulted in no antibiotics prescribed for acute sinusitis (36.8% vs. 22.5%, p < 0.001). CONCLUSION: Otolaryngologists engage in watchful waiting more than non-otolaryngologists. Broader dissemination of existing guidelines for acute sinusitis treatment to non-Otolaryngologist (ENT) primary care specialties that take care of acute sinusitis to improve antibiotic stewardship and appropriate antibiotic selection is needed. LEVEL OF EVIDENCE: 4 Laryngoscope, 134:2622-2625, 2024.

Nurse-delivered sleep restriction therapy in primary care for adults with insomnia disorder: a mixed-methods process evaluation.

BACKGROUND: Sleep restriction therapy (SRT) is a behavioural therapy for insomnia. AIM: To conduct a process evaluation of a randomised controlled trial comparing SRT delivered by primary care nurses plus a sleep hygiene booklet with the sleep hygiene booklet only for adults with insomnia disorder. DESIGN AND SETTING: A mixed-methods process evaluation in a general practice setting. METHOD: Semi-structured interviews were conducted in a purposive sample of patients receiving SRT, the practice nurses who delivered the therapy, and also GPs or practice managers at the participating practices. Qualitative data were explored using framework analysis, and integrated with nurse comments and quantitative data, including baseline Insomnia Severity Index score and serial sleep efficiency outcomes to investigate the relationships between these. RESULTS: In total, 16 patients, 13 nurses, six practice managers, and one GP were interviewed. Patients had no previous experience of behavioural therapy, needed flexible appointment times, and preferred face-to-face consultations; nurses felt prepared to deliver SRT, accommodating patient concerns, tailoring therapy, and negotiating sleep timings despite treatment complexity and delays between training and intervention delivery. How the intervention produced change was explored, including patient and nurse interactions and patient responses to SRT. Difficulties maintaining SRT, negative attitudes towards treatment, and low self-efficacy were highlighted. Contextual factors, including freeing GP time, time constraints, and conflicting priorities for nurses, with suggestions for alternative delivery options, were raised. Participants who found SRT a positive process showed improvements in sleep efficiency, whereas those who struggled did not. CONCLUSION: SRT was successfully delivered by practice nurses and was generally well received by patients, despite some difficulties delivering and applying the intervention in practice.

Effect of insulin insufficiency on ultrastructure and function in skeletal muscle.

BACKGROUND: Decreased insulin availability and high blood glucose levels, the hallmark features of poorly controlled diabetes, drive disease progression and are associated with decreased skeletal muscle mass. We have shown that mice with ß-cell dysfunction and normal insulin sensitivity have decreased skeletal muscle mass. This project asks how insulin deficiency impacts on the structure and function of the remaining skeletal muscle in these animals. METHODS: Skeletal muscle function was determined by measuring exercise capacity and specific muscle strength prior to and after insulin supplementation for 28 days in 12-week-old mice with conditional ß-cell deletion of the ATP binding cassette transporters ABCA1 and ABCG1 (ß-DKO mice). Abca1 and Abcg1 floxed (fl/fl) mice were used as controls. RNAseq was used to quantify changes in transcripts in soleus and extensor digitorum longus muscles. Skeletal muscle and mitochondrial morphology were assessed by transmission electron microscopy. Myofibrillar Ca2+ sensitivity and maximum isometric single muscle fibre force were assessed using MyoRobot biomechatronics technology. RESULTS: RNA transcripts were significantly altered in ß-DKO mice compared with fl/fl controls (32 in extensor digitorum longus and 412 in soleus). Exercise capacity and muscle strength were significantly decreased in ß-DKO mice compared with fl/fl controls (P = 0.012), and a loss of structural integrity was also observed in skeletal muscle from the ß-DKO mice. Supplementation of ß-DKO mice with insulin restored muscle integrity, strength and expression of 13 and 16 of the dysregulated transcripts in and extensor digitorum longus and soleus muscles, respectively. CONCLUSIONS: Insulin insufficiency due to ß-cell dysfunction perturbs the structure and function of skeletal muscle. These adverse effects are rectified by insulin supplementation.

miR-9 utilizes precursor pathways in adaptation to alcohol in mouse striatal neurons.

microRNA-9 (miR-9) is one of the most abundant microRNAs in the mammalian brain, essential for its development and normal function. In neurons, it regulates the expression of several key molecules, ranging from ion channels to enzymes, to transcription factors broadly affecting the expression of many genes. The neuronal effects of alcohol, one of the most abused drugs in the world, seem to be at least partially dependent on regulating the expression of miR-9. We previously observed that molecular mechanisms of the development of alcohol tolerance are miR-9 dependent. Since a critical feature of alcohol action is temporal exposure to the drug, we decided to better understand the time dependence of alcohol regulation of miR-9 biogenesis and expression. We measured the effect of intoxicating concentration of alcohol (20 mM ethanol) on the expression of all major elements of miR-9 biogenesis: three pri-precursors (pri-mir-9-1, pri-mir-9-2, pri-mir-9-3), three pre-precursors (pre-mir-9-1, pre-mir-9-2, pre-mir-9-3), and two mature microRNAs: miR-9-5p and miR-9-3p, using digital PCR and RT-qPCR, and murine primary medium spiny neurons (MSN) cultures. We subjected the neurons to alcohol based on an exposure/withdrawal matrix of different exposure times (from 15 min to 24 h) followed by different withdrawal times (from 0 h to 24 h). We observed that a short exposure increased mature miR-9-5p expression, which was followed by a gradual decrease and subsequent increase of the expression, returning to pre-exposure levels within 24 h. Temporal changes of miR-9-3p expression were complementing miR-9-5p changes. Interestingly, an extended, continuous presence of the drug caused a similar pattern. These results suggest the presence of the adaptive mechanisms of miR-9 expression in the presence and absence of alcohol. Measurement of miR-9 pre- and pri-precursors showed further that the primary effect of alcohol on miR-9 is through the mir-9-2 precursor pathway with a smaller contribution of mir-9-1 and mir-9-3 precursors. Our results provide new insight into the adaptive mechanisms of neurons to alcohol exposure. It would be of interest to determine next which microRNA-based mechanisms are involved in a transition from the acute, intoxicating effects of alcohol to the chronic, addictive effects of the drug.

Ancient Clostridium DNA and variants of tetanus neurotoxins associated with human archaeological remains.

The analysis of microbial genomes from human archaeological samples offers a historic snapshot of ancient pathogens and provides insights into the origins of modern infectious diseases. Here, we analyze metagenomic datasets from 38 human archaeological samples and identify bacterial genomic sequences related to modern-day Clostridium tetani, which produces the tetanus neurotoxin (TeNT) and causes the disease tetanus. These genomic assemblies had varying levels of completeness, and a subset of them displayed hallmarks of ancient DNA damage. Phylogenetic analyses revealed known C. tetani clades as well as potentially new Clostridium lineages closely related to C. tetani. The genomic assemblies encode 13 TeNT variants with unique substitution profiles, including a subgroup of TeNT variants found exclusively in ancient samples from South America. We experimentally tested a TeNT variant selected from an ancient Chilean mummy sample and found that it induced tetanus muscle paralysis in mice, with potency comparable to modern TeNT. Thus, our ancient DNA analysis identifies DNA from neurotoxigenic C. tetani in archaeological human samples, and a novel variant of TeNT that can cause disease in mammals.

Adverse Childhood Experiences and Aging-Associated Functional Impairment in a National Sample of Older Community-Dwelling Adults.

BACKGROUND: Prior research on the health implications of adverse childhood experiences (ACEs) has focused on early or midlife adults, not older adults who bear the greatest burden of health-related functional impairment. OBJECTIVE: To examine associations between ACEs, objectively measured physical mobility and cognitive impairment, and functional disability in older community-dwelling adults. DESIGN: Cross-sectional analysis. PARTICIPANTS: Community-dwelling older U.S. adults ages 50 years and older. MAIN MEASURES: Participants completed structured questionnaires assessing history of ACEs (childhood experience of violence/abuse, witnessing of violence, financial insecurity, parental separation, or serious illness), underwent standardized physical performance testing (tandem balance, 3-m walk, chair stand test) and cognitive testing (survey adaptation of the Montreal Cognitive Assessment), and reported functional disability (difficulty with activities of daily living). KEY RESULTS: Among the 3387 participants (aged 50 to 97 years; 54% female), 44% reported a history of one or more types of ACEs. Thirty-five percent met criteria for physical mobility impairment, 24% for cognitive impairment, and 24% for functional disability. After adjusting for age, gender, race, and ethnicity, participants reporting any ACE history were more likely to demonstrate physical mobility impairment (OR 1.30, 95% CI 1.11-1.52) and cognitive impairment (OR 1.26, 95% CI 1.03-1.54) and report functional disability (OR 1.69, 95% CI 1.38-2.07), compared to those with no ACE history. Childhood experience of violence was associated with greater physical mobility impairment (OR 1.38, 95% CI 1.11-1.71) and functional disability (OR 1.86, 95% CI 1.49-2.33). CONCLUSIONS: Older adults with a history of ACEs are more likely to experience physical and cognitive functional impairment, suggesting that efforts to mitigate ACEs may have implications for aging-associated functional decline. Findings support the need for trauma-informed approaches to geriatric care that consider the potential role of early life traumatic experiences in shaping or complicating late-life functional challenges.

Development and validation of qPCR methods for nucleic acid biomarkers as a drug development tool: points to consider.

Nucleic acid (NA) biomarkers play critical roles in drug development. However, the global regulatory guidelines for assessing quantification methods specific to NA biomarkers are limited. The validation of analytical methods is crucial for the use of biomarkers in clinical and post-marketing evaluations of drug efficacy and adverse reactions. Given that quantitative polymerase chain reaction (qPCR) and reverse transcription qPCR (RT-qPCR) methods are the gold standards for the quantification of NA biomarkers, the Biomarker Analytical Method Validation Study Group in Japan has discussed considerations and made recommendations for the development and validation of qPCR- and RT-qPCR-based analytical methods for endogenous NA biomarkers as drug development tools. This white paper aims to contribute to the global harmonization of NA biomarker assay validation.

Clinical and cost-effectiveness of nurse-delivered sleep restriction therapy for insomnia in primary care (HABIT): a pragmatic, superiority, open-label, randomised controlled trial.

BACKGROUND: Insomnia is prevalent and distressing but access to the first-line treatment, cognitive behavioural therapy (CBT), is extremely limited. We aimed to assess the clinical and cost-effectiveness of sleep restriction therapy, a key component of CBT, which has the potential to be widely implemented. METHODS: We did a pragmatic, superiority, open-label, randomised controlled trial of sleep restriction therapy versus sleep hygiene. Adults with insomnia disorder were recruited from 35 general practices across England and randomly assigned (1:1) using a web-based randomisation programme to either four sessions of nurse-delivered sleep restriction therapy plus a sleep hygiene booklet or a sleep hygiene booklet only. There was no restriction on usual care for either group. Outcomes were assessed at 3 months, 6 months, and 12 months. The primary endpoint was self-reported insomnia severity at 6 months measured with the insomnia severity index (ISI). The primary analysis included participants according to their allocated group and who contributed at least one outcome measurement. Cost-effectiveness was evaluated from the UK National Health Service and personal social services perspective and expressed in terms of incremental cost per quality-adjusted life year (QALY) gained. The trial was prospectively registered (ISRCTN42499563). FINDINGS: Between Aug 29, 2018, and March 23, 2020 we randomly assigned 642 participants to sleep restriction therapy (n=321) or sleep hygiene (n=321). Mean age was 55·4 years (range 19-88), with 489 (76·2%) participants being female and 153 (23·8%) being male. 580 (90·3%) participants provided data for at least one outcome measurement. At 6 months, mean ISI score was 10·9 (SD 5·5) for sleep restriction therapy and 13·9 (5·2) for sleep hygiene (adjusted mean difference -3·05, 95% CI -3·83 to -2·28; p<0·0001; Cohen's d -0·74), indicating that participants in the sleep restriction therapy group reported lower insomnia severity than the sleep hygiene group. The incremental cost per QALY gained was £2076, giving a 95·3% probability that treatment was cost-effective at a cost-effectiveness threshold of £20 000. Eight participants in each group had serious adverse events, none of which were judged to be related to intervention. INTERPRETATION: Brief nurse-delivered sleep restriction therapy in primary care reduces insomnia symptoms, is likely to be cost-effective, and has the potential to be widely implemented as a first-line treatment for insomnia disorder. FUNDING: The National Institute for Health and Care Research Health Technology Assessment Programme.

Collagen Vascular Diseases: A Review of Cutaneous and Systemic Lupus Erythematosus, Dermatomyositis, and Distinguishing Features in Skin of Color.

Collagen vascular diseases such as lupus erythematosus and dermatomyositis (DM) occur 2 to 3 times more often among patients with skin of color. In this article, the authors review DM and cutaneous lupus erythematosus, including acute cutaneous lupus erythematosus, subacute cutaneous lupus erythematosus, and discoid lupus erythematosus. They discuss the distinguishing features between these entities and highlight distinct presentations and management considerations in patients with skin of color to aid in prompt and correct diagnoses in this patient population.

Cost-Effectiveness and Budget Impact of a Novel Antithrombotic Drug Removal System to Reduce Bleeding Risk in Patients on Preoperative Ticagrelor Undergoing Cardiac Surgery.

BACKGROUND: Antithrombotic drugs, including the P2Y12 inhibitor ticagrelor, increase the risk of perioperative bleeding in patients requiring urgent cardiac surgery. Perioperative bleeding can lead to increased mortality and prolong intensive care unit and hospital stays. A novel sorbent-filled hemoperfusion cartridge that intraoperatively removes ticagrelor via hemoadsorption can reduce the risk of perioperative bleeding. We estimated the cost-effectiveness and budget impact of using this device versus standard practices to reduce the risk of perioperative bleeding during and after coronary artery bypass grafting from the US healthcare sector perspective. METHODS: We used a Markov model to analyze the cost-effectiveness and budget impact of the hemoadsorption device in three cohorts: (1) surgery within 1 day from last ticagrelor dose; (2) surgery between 1 and 2 days from last ticagrelor dose; and (3) a combined cohort. The model analyzed costs and quality-adjusted life years (QALYs). Results were interpreted as both incremental cost-effectiveness ratios and net monetary benefits (NMBs) at a cost-effectiveness threshold of $100,000/QALY. We analyzed parameter uncertainty using deterministic and probabilistic sensitivity analyses. RESULTS: The hemoadsorption device was dominant for each cohort. Patients with less than 1 day of washout in the device arm gained 0.017 QALYs at a savings of $1748 (USD), for an NMB of $3434. In patients with 1-2 days of washout, the device arm yielded 0.014 QALYs and a cost savings of $151, for an NMB of $1575. In the combined cohort, device gained 0.016 QALYs and a savings of $950 for an NMB of $2505. Per-member-per-month cost savings associated with device was estimated to be $0.02 for a one-million-member health plan. CONCLUSION: This model found the hemoadsorption device to provide better clinical and economic outcomes compared with the standard of care in patients who required surgery within 2 days of ticagrelor discontinuation. Given the increasing use of ticagrelor in patients with acute coronary syndrome, incorporating this novel device may represent an important part of any bundle to save costs and reduce harm.