In vitro assessment of the Kirpa Kit™ modified manual single lumen alternating micro-batch (mSLAMB) dialysis device.

BACKGROUND: Access to pediatric dialysis is challenged in low-resource settings due to high costs, scarcity of equipment, and the lack of qualified personnel availability. We demonstrated the manual single lumen alternating micro-batch (mSLAMB) device can remove small solutes in vitro without the need for electricity, batteries, or pumps. We developed a new version (Kirpa Kit™) to address some of the technical limitations of mSLAMB. Here, we compare the in vitro clearance performance and ease of use of the Kirpa Kit™ with that of prior mSLAMB configurations. METHODS: A mixture of expired packed red blood cells, 0.9% NaCl, urea, and heparin was used to test the efficiency of two mSLAMB configurations and the Kirpa Kit™ in removing potassium and urea. Clearance was evaluated by measuring percent reduction after 25-min sessions with each device. A survey was used to evaluate the ease of use of each configuration. RESULTS: The Kirpa Kit™ achieved a median urea reduction of 82.4% and potassium reduction of 82.1%, which were higher than those achieved with the best-performing mSLAMB configuration (urea 71.9%, potassium 75.4%). The Kirpa Kit™ was easier to use with a shorter perceived time of use than the mSLAMB. CONCLUSIONS: The Kirpa Kit™, evolution of mSLAMB, is easy to use and may have improved efficacy, making it an optimal candidate for in vivo testing.

Profiles of alcohol intoxication and their associated risks in young adults' natural settings: A multilevel latent profile analysis applied to daily transdermal alcohol concentration data.

OBJECTIVE: Transdermal alcohol concentration (TAC) sensors capture aspects of drinking events that self-reports cannot. The multidimensional nature of TAC data allows novel classification of drinking days and identification of associated behavioral and contextual risks. We used multilevel latent profile analysis (MLPA) to create day-level profiles of TAC features and test their associations with (a) daily behaviors and contexts and (b) risk for alcohol use disorders at baseline. METHOD: Two hundred twenty-two regularly heavy-drinking young adults (Mage = 22.3) completed the Alcohol Use Disorders Identification Test (AUDIT) at baseline and then responded to mobile phone surveys and wore TAC sensors for six consecutive days. MLPA identified day-level profiles using four TAC features (peak, rise rate, fall rate, and duration). TAC profiles were tested as correlates of daily drinking behaviors, contexts, and baseline AUDIT. RESULTS: Four profiles emerged: (a) high-fast (8.5% of days), (b) moderate-fast (12.8%), (c) low-slow (20.4%), and (d) little-to-no drinking days (58.2%). Profiles differed in the odds of risky drinking behaviors and contexts. The highest risk occurred on high-fast days, followed by moderate-fast, low-slow, and little-to-no drinking days. Higher baseline AUDIT predicted higher odds of high-fast and moderate-fast days. CONCLUSIONS: Days with high and fast intoxication are reflective of high-risk drinking behaviors and were most frequent among those at risk for alcohol use disorders. TAC research using MLPA may offer novel and important insights to intervention efforts. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Biliary atresia.

Biliary atresia (BA) is a progressive inflammatory fibrosclerosing disease of the biliary system and a major cause of neonatal cholestasis. It affects 1:5,000-20,000 live births, with the highest incidence in Asia. The pathogenesis is still unknown, but emerging research suggests a role for ciliary dysfunction, redox stress and hypoxia. The study of the underlying mechanisms can be conceptualized along the likely prenatal timing of an initial insult and the distinction between the injury and prenatal and postnatal responses to injury. Although still speculative, these emerging concepts, new diagnostic tools and early diagnosis might enable neoadjuvant therapy (possibly aimed at oxidative stress) before a Kasai portoenterostomy (KPE). This is particularly important, as timely KPE restores bile flow in only 50-75% of patients of whom many subsequently develop cholangitis, portal hypertension and progressive fibrosis; 60-75% of patients require liver transplantation by the age of 18 years. Early diagnosis, multidisciplinary management, centralization of surgery and optimized interventions for complications after KPE lead to better survival. Postoperative corticosteroid use has shown benefits, whereas the role of other adjuvant therapies remains to be evaluated. Continued research to better understand disease mechanisms is necessary to develop innovative treatments, including adjuvant therapies targeting the immune response, regenerative medicine approaches and new clinical tests to improve patient outcomes.

Comparative pharmacokinetics of a single oral dose of meloxicam in the California sea lion (Zalophus californianus) and Pacific harbor seal (Phoca vitulina richardii).

Pharmacokinetics studies have investigated meloxicam, a non-steroidal anti-inflammatory drug, dosing strategies in a wide variety of non-domestic animals; however, there is no prior study examining well-founded dosing for pinnipeds. To develop dosing protocols, pharmacokinetic information is needed, with an examination of differences between pinniped species. Apparently, healthy California sea lions (Zalophus californianus: CSL; n = 13) and Pacific harbor seals (Phoca vitulina richardii: PHS; n = 17) that had completed rehabilitation were enrolled into a population-based pharmacokinetic study. Each animal was administered a single oral dose of meloxicam at 0.1 mg/kg, and two blood samples were collected from each animal at varying intervals during a 96-h study period. Plasma concentrations of meloxicam were determined by high-pressure liquid chromatography. Data were analyzed with nonlinear mixed effects modeling (Phoenix® NLME™, Certara, St. Louis, MO 63105, USA). The results indicated that in PHS, peak plasma concentration (Cmax) was 0.33 µg/mL with an elimination half-life (Ke t½) of 31.53 h. In CSL, Cmax was 0.17 µg/mL with Ke t½ of 32.71 h. All animals enrolled completed the study without outward adverse clinical signs. The elimination half-life was longer than previously recommended dosing intervals for pinnipeds; however, we cannot speculate in the optimum clinical dose from these results.

Preexisting maternal immunity to AAV but not Cas9 impairs in utero gene editing in mice.

In utero gene editing (IUGE) is a potential treatment for inherited diseases that cause pathology before or soon after birth. Preexisting immunity to adeno-associated virus (AAV) vectors and Cas9 endonuclease may limit postnatal gene editing. The tolerogenic fetal immune system minimizes a fetal immune barrier to IUGE. However, the ability of maternal immunity to limit fetal gene editing remains a question. We investigated whether preexisting maternal immunity to AAV or Cas9 impairs IUGE. Using a combination of fluorescent reporter mice and a murine model of a metabolic liver disease, we demonstrated that maternal anti-AAV IgG antibodies were efficiently transferred from dam to fetus and impaired IUGE in a maternal titer-dependent fashion. By contrast, maternal cellular immunity was inefficiently transferred to the fetus, and neither maternal cellular nor humoral immunity to Cas9 impaired IUGE. Using human umbilical cord and maternal blood samples collected from mid- to late-gestation pregnancies, we demonstrated that maternal-fetal transmission of anti-AAV IgG was inefficient in midgestation compared with term, suggesting that the maternal immune barrier to clinical IUGE would be less relevant at midgestation. These findings support immunologic advantages for IUGE and inform maternal preprocedural testing protocols and exclusion criteria for future clinical trials.

Acarbose ameliorates Western diet-induced metabolic and cognitive impairments in the 3xTg mouse model of Alzheimer's disease.

Age is the greatest risk factor for Alzheimer's disease (AD) as well as for other disorders that increase the risk of AD such as diabetes and obesity. There is growing interest in determining if interventions that promote metabolic health can prevent or delay AD. Acarbose is an anti-diabetic drug that not only improves glucose homeostasis, but also extends the lifespan of wild-type mice. Here, we test the hypothesis that acarbose will not only preserve metabolic health, but also slow or prevent AD pathology and cognitive deficits in 3xTg mice, a model of AD, fed either a Control diet or a high-fat, high-sucrose Western diet (WD). We find that acarbose decreases the body weight and adiposity of WD-fed 3xTg mice, increasing energy expenditure while also stimulating food consumption, and improves glycemic control. Both male and female WD-fed 3xTg mice have worsened cognitive deficits than Control-fed mice, and these deficits are ameliorated by acarbose treatment. Molecular and histological analysis of tau and amyloid pathology identified sex-specific effects of acarbose which are uncoupled from the dramatic improvements in cognition, suggesting that the benefits of acarbose on AD are largely driven by improved metabolic health. In conclusion, our results suggest that acarbose may be a promising intervention to prevent, delay, or even treat AD, especially in individuals consuming a Western diet.

Dietary isoleucine content defines the metabolic and molecular response to a Western diet.

The amino acid composition of the diet has recently emerged as a critical regulator of metabolic health. Consumption of the branched-chain amino acid isoleucine is positively correlated with body mass index in humans, and reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice. However, it is unknown how sex, strain, and dietary isoleucine intake may interact to impact the response to a Western Diet (WD). Here, we find that although the magnitude of the effect varies by sex and strain, reducing dietary levels of isoleucine protects C57BL/6J and DBA/2J mice of both sexes from the deleterious metabolic effects of a WD, while increasing dietary levels of isoleucine impairs aspects of metabolic health. Despite broadly positive responses across all sexes and strains to reduced isoleucine, the molecular response of each sex and strain is highly distinctive. Using a multi-omics approach, we identify a core sex- and strain- independent molecular response to dietary isoleucine, and identify mega-clusters of differentially expressed hepatic genes, metabolites, and lipids associated with each phenotype. Intriguingly, the metabolic effects of reduced isoleucine in mice are not associated with FGF21 - and we find that in humans plasma FGF21 levels are likewise not associated with dietary levels of isoleucine. Finally, we find that foods contain a range of isoleucine levels, and that consumption of dietary isoleucine is lower in humans with healthy eating habits. Our results demonstrate that the dietary level of isoleucine is critical in the metabolic and molecular response to a WD, and suggest that lowering dietary levels of isoleucine may be an innovative and translatable strategy to protect from the negative metabolic consequences of a WD.

Immune Modulation Permits Tolerance and Engraftment in a Murine Model of Late-Gestation Transplantation.

In utero hematopoietic cell transplantation (IUHCT) is an experimental non-myeloablative therapy with potential application to hematologic disorders including Sickle cell disease. Its clinical utility has been limited due to the early acquisition of T cell immunity beginning at approximately 14 weeks gestation, posing significant technical challenges and excluding from treatment fetuses evaluated after the first trimester. Using murine neonatal transplantation at 20 days post-coitum (DPC) as a model for late-gestation transplantation (LGT) in humans, we investigated whether immune modulation with anti-CD3 monoclonal antibody (mAb) could achieve donor-specific tolerance and sustained allogeneic engraftment comparable to the early-gestation fetal recipient at 14 DPC. In allogeneic wild-type strain combinations, administration of anti-CD3 mAb with transplantation resulted in transient T cell depletion followed by central tolerance induction confirmed by donor-specific clonal deletion and skin graft tolerance. Normal immune responses to third-party major histocompatibility complex and viral pathogens were preserved, and graft-versus-host disease did not occur. We further demonstrate successful application of this approach to the Townes mouse model of Sickle cell disease. These findings confirm the developing fetal T cell response as a barrier to LGT and support transient T cell depletion as a safe and effective immunomodulatory strategy by which to overcome it.

Protocol for the Evaluation of Data-Related Processes and Challenges at Level 1-4 Trauma Centers in Arkansas: A Mixed-Methods Case Study.

Background: In the following manuscript, we describe the detailed protocol for a mixed-methods, observational case study conducted to identify and evaluate existing data-related processes and challenges currently faced by trauma centers in a rural state. The data will be utilized to assess the impact of these challenges on registry data collection. Methods: The study relies on a series of interviews and observations to collect data from trauma registry staff at level 1-4 trauma centers across the state of Arkansas. A think-aloud protocol will be used to facilitate observations to gather keystroke-level modeling data and insight into site processes and workflows for collecting and submitting data to the Arkansas Trauma Registry. Informal, semi-structured interviews will follow the observation period to assess the participant's perspective on current processes, potential barriers to data collection or submission to the registry, and recommendations for improvement. Each session will be recorded, and de-identified transcripts and session notes will be used for analysis. Keystroke level modeling data derived from observations will be extracted and analyzed quantitatively to determine time spent performing end-to-end registry-related activities. Qualitative data from interviews will be reviewed and coded by 2 independent reviewers following a thematic analysis methodology. Each set of codes will then be adjudicated by the reviewers using a consensus-driven approach to extrapolate the final set of themes. Discussion: We will utilize a mixed methods approach to understand existing processes and barriers to data collection for the Arkansas Trauma Registry. Anticipated results will provide a baseline measure of the data collection and submission processes at various trauma centers across the state. We aim to assess strengths and limitations of existing processes and identify existing barriers to interoperability. These results will provide first-hand knowledge on existing practices for the trauma registry use case and will provide quantifiable data that can be utilized in future research to measure outcomes of future process improvement efforts. The potential implications of this study can form the basis for identifying potential solutions for streamlining data collection, exchange, and utilization of trauma registry data for clinical practice, public health, and clinical and translational research.

Protein restriction slows the development and progression of pathology in a mouse model of Alzheimer's disease.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer's disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD.

Recurrent Duplication and Diversification of a Vital DNA Repair Gene Family Across Drosophila.

Maintaining genome integrity is vital for organismal survival and reproduction. Essential, broadly conserved DNA repair pathways actively preserve genome integrity. However, many DNA repair proteins evolve adaptively. Ecological forces like UV exposure are classically cited drivers of DNA repair evolution. Intrinsic forces like repetitive DNA, which also imperil genome integrity, have received less attention. We recently reported that a Drosophila melanogaster-specific DNA satellite array triggered species-specific, adaptive evolution of a DNA repair protein called Spartan/MH. The Spartan family of proteases cleave hazardous, covalent crosslinks that form between DNA and proteins ("DNA-protein crosslink repair"). Appreciating that DNA satellites are both ubiquitous and universally fast-evolving, we hypothesized that satellite DNA turnover spurs adaptive evolution of DNA-protein crosslink repair beyond a single gene and beyond the D. melanogaster lineage. This hypothesis predicts pervasive Spartan gene family diversification across Drosophila species. To study the evolutionary history of the Drosophila Spartan gene family, we conducted population genetic, molecular evolution, phylogenomic, and tissue-specific expression analyses. We uncovered widespread signals of positive selection across multiple Spartan family genes and across multiple evolutionary timescales. We also detected recurrent Spartan family gene duplication, divergence, and gene loss. Finally, we found that ovary-enriched parent genes consistently birthed functionally diverged, testis-enriched daughter genes. To account for Spartan family diversification, we introduce a novel mechanistic model of antagonistic coevolution that links DNA satellite evolution and adaptive regulation of Spartan protease activity. This framework promises to accelerate our understanding of how DNA repeats drive recurrent evolutionary innovation to preserve genome integrity.

Experiences of sexist discrimination as a potential explanatory factor for alcohol and drug misuse among Latina young adult women.

RATIONALE: Marianismo beliefs, or traditional female gender role beliefs among Latinas, have been found to serve as risk or protective factors linked with health risk behaviors in prior studies, including alcohol and drug misuse. However, limited research has examined potential factors that may contribute to or explain these associations. Sexist discrimination, which can serve as a significant stressor that may contribute to substance misuse, is one potential factor that may link marianismo beliefs and substance misuse among Latina young adult women. OBJECTIVE: This study examined sexism as a potential mediator of hypothesized negative associations between five marianismo beliefs (Family Pillar, Virtuous and Chaste, Subordinate to Others, Silencing Self to Maintain Harmony, and Spiritual Pillar) and alcohol and drug misuse using structural equation modeling. METHOD: Participants included 611 cisgender Latina full-time college student young adult women in the U.S. ages 18-26 who participated in an online cross-sectional survey about their health and behaviors. RESULTS: Results delineated experiences of sexism as a significant risk factor for alcohol and drug misuse and as a potential explanatory factor that may partly explain associations between certain marianismo beliefs (i.e., Virtuous and Chaste beliefs) and substance misuse. Specifically, experiences of sexism partially accounted for the negative association between endorsement of the Virtuous and Chaste belief and increased alcohol and drug misuse among Latina young adults. CONCLUSIONS: Prevention and intervention efforts should take a culturally responsive, gender-informed approach to address substance misuse among Latina young adults and address the negative influence of sexism on health.

Report on Proceedings of the Sixteenth Annual European CME Forum, the Hague, Netherlands, November 2023.

There was a renewed vigour among the participants attending the 16th Annual European CME Forum (#16ECF), which took place in the Hague, the Netherlands from 8-10 November 2023. This emanated from the meeting having reverted to an in-person format to promote engagement among attendees. The meeting was subdivided into three main sections to address this year's theme "Voices in CME-CPD": 1) Listening to others; 2) Listening to ourselves; 3) Listening to each other. The Forum unofficially began with the pre-meeting sessions led by two special interest groups and was then formally opened by the programme director. There were panel discussions on designing and implementing CME-CPD programmes, measuring and reporting outcomes, and valuing and defining independence, as well as smaller workshop and breakout sessions led by international presenters. Representatives for the Journal of CME presented on the 2023 Special Collection of articles, with this year's topic "Expanding the voices in CME-CPD" mirroring the meeting theme. Participants interacted with providers, accreditors and grantors, as well as poster authors and a local physician who attended to share a learner's perspective. The meeting concluded with the now familiar "CME unsession" to ensure everyone's voices were heard and no one left the meeting with any unanswered questions.

The landscape of real-world evidence of rituximab utilization and clinical outcomes in patients with cancer, rheumatoid arthritis, and multiple sclerosis: A scoping review.

BACKGROUND: Rituximab (RTX) is an anti-CD20 monoclonal antibody that is used to treat various conditions in cancer, rheumatoid arthritis (RA), and multiple sclerosis (MS). Although RTX has been used in the United States for almost 3 decades, questions remain regarding its real-world utilization and effectiveness. OBJECTIVE: To describe the state of observational research and real-world evidence evaluating RTX in oncology, RA, and off-label use in MS. METHODS: A broad search was conducted in MEDLINE, Embase, and CINAHL covering the period of January 2010 to June 2022. Two reviewers independently screened all identified records for each disease category (cancer, RA, MS) beginning with title review, followed by abstract, and full-text review to identify relevant publications to include in the final analysis. Data were extracted and summarized for each disease based on overall trends, similarities, and differences across included studies and stratified by disease state. RESULTS: A total of 260 studies met eligibility criteria, with 79 studies for the RA cohort, 144 for cancer, and 37 for MS. Across all disease cohorts, most studies (n = 189; 72.7%) were retrospective. 171 (65.8%) studies used hospital or electronic health record data as their data source and 65 (23.2%) used registry databases. Most studies (n = 153; 58.8%) assessed the effectiveness of RTX measured by disease-specific endpoints, followed by safety (n = 60; 23.1%), treatment patterns (n = 32; 12.3%), and descriptive analyses assessing treatment adherence and economic burden of disease (n = 16; 6.2%). Although safety was not the primary outcome for most studies, the majority of studies across all disease states still reported some form of safety measure. Conclusive statements on RTX's benefit varied across disease states, with MS having the most (n = 30; 81.1%) studies suggesting the drug's positive benefit. There were limited studies assessing RTX use, associated economic burden, and biosimilar switching. CONCLUSIONS: The findings underscore the need for health care providers to better understand the treatment landscape and utilization of RTX, particularly in terms of patient selection, timing of initiation, and long-term outcomes. Real-world evidence can help support health care decisions and treatment using rituximab.

Back Pain in the Era of Opioid Restriction and Implications for Neurosurgeons Based on Qualitative Findings From a Rural State.

Historically, back pain has been an inciting complaint for the initiation of opioids. Aggressive marketing of opioids to treat back pain coupled with the initiation of pain being treated as "the fifth vital sign" contributed to the emerging opioid crisis in the USA. West Virginia (WV) has long been considered the epicenter of the crisis. In 2018, the WV legislature passed a bill that placed prescribing limits on opioids. Our group set out to investigate the impacts of opioid prescribing restrictions through a sequential, mixed methods study evaluating prescription trends and stakeholder experiences. These stakeholder experiences generated emergent themes regarding the evolution of the opioid crisis up to and beyond the implementation of the bill, which is of relevance to neurosurgeons and back pain treatment. This study explores those findings for a neurosurgical audience. This study consisted of open-ended, semi-structured interviews with a purposive sample of 50 physicians, pharmacists, and patients in WV. Interviews were recorded and transcribed verbatim. Content analysis was utilized as the methodological orientation. Five theoretical domains relevant to the treatment of back pain emerged, describing the prevalence of opioid use, barriers to access care, the importance of opioids for function in resource-poor rural areas, disconnected and siloed care, and patient views on the impacts of pain care gaps and solutions. Spinal pain care in rural WV is complex due to identified challenges. Care siloing factors in suboptimal spinal pain care. Future work should define, implement, and assess the real-world effectiveness of treatment paradigms for the full spectrum of surgical and non-surgical back pain complaints. Neurosurgeons should be present in this arena.

A modified technique for simplifying full-arch screw-retained implant rehabilitation with rapid digital conversion: a case report.

In this case report, a novel technique is described for an efficient, simple, and effective digital approach to immediate provisionalization of the implant-supported full-arch prosthesis. Today's patient population is increasingly educated about treatment options and expects efficient, esthetic, and comfortable results. This novel technique delivers on these aims while eliminating the many challenges posed by previously described digital and analog techniques to the immediate provisionalization of the implant- supported full-arch prosthesis. This technique requires minimal chair time and cost to the provider and reduces patient discomfort and complication risk. Combining the best features of analog and digital methods to conversion of the implant-supported full-arch, this novel method presents a promising new protocol for this popular procedure.

Current approach to genetic testing and genetic evaluation referrals for adults with congenital heart disease.

Background: Congenital heart disease (CHD) is the most common congenital anomaly. Up to 33% have an identifiable genetic etiology. Improved medical and surgical management of CHD has translated into longer life expectancy and a rapidly growing population of adults living with CHD. The adult CHD (ACHD) population did not have access during childhood to the genetic technologies available today and therefore have not had a robust genetic evaluation that is currently recommended for infants with CHD. Given this potential benefit; the aims of this study were to determine how ACHD cardiologists offer genetics services to patients and identify the indications that influence decision-making for genetics care. Methods: We performed a descriptive cross-sectional study of ACHD cardiologists. A study-developed questionnaire was distributed via emailed REDCap link. The recruitment email was sent to 104 potential respondents. The survey was open from 06/2022 to 01/2023. Results: Thirty-five cardiologists participated in the study (response rate of 34%). Most cardiologists identified as white (77%) and male (66%). Cardiologists were more likely to refer patients to genetics (91%) than to order testing themselves (57%). Of the testing ordered, chromosomal testing (55%) was ordered more than gene sequencing (14%). Most cardiologists would refer a patient with a conotruncal lesion (interrupted aortic arch) over other indications for a genetics evaluation. There were more reported barriers to ordering genetic testing (66%) compared to referring to genetics for a genetics evaluation (23%). Cardiologists were more confident recognizing features suggestive of a genetic syndrome than ordering the correct test (p = 0.001). Regarding associations between clinical factors and current practices, more years in practice trended towards less referrals and testing. Evaluating a greater number of patients (p = 0.11) and greater confidence recognizing syndromic features (p = 0.12) and ordering the correct test (p = 0.09) were all associated with ordering more testing. Conclusion: Testing for microdeletion syndromes is being offered and completed in the ACHD population, however testing for single-gene disorders associated with CHD is being under-utilized. Developing guidelines for genetic testing in adults with CHD could increase access to genetic services, impact medical management, reduce uncertainty regarding prognosis, and inform recurrence risk estimates.