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The identification of targetable vulnerabilities in the context of therapeutic resistance is a key challenge in cancer treatment. We detected pervasive aberrant splicing as a characteristic feature of chronic lymphocytic leukemia (CLL), irrespective of splicing factor mutation status, which was associated with sensitivity to the spliceosome modulator, E7107. Splicing modulation affected CLL survival pathways, including members of the B cell lymphoma-2 (BCL2) family of proteins, remodeling antiapoptotic dependencies of human and murine CLL cells. E7107 treatment decreased myeloid cell leukemia-1 (MCL1) dependence and increased BCL2 dependence, sensitizing primary human CLL cells and venetoclax-resistant CLL-like cells from an Eμ-TCL1-based adoptive transfer murine model to treatment with the BCL2 inhibitor venetoclax. Our data provide preclinical rationale to support the combination of venetoclax with splicing modulators to reprogram apoptotic dependencies in CLL for treating venetoclax-resistant CLL cases.

Cardiovascular diseases (CVDs) are complex in their aetiology, arising due to a combination of genetics, lifestyle and environmental factors. By nature of this complexity, different CVDs vary in their molecular mechanisms, clinical presentation and progression. Although extensive efforts are being made to develop novel therapeutics for CVDs, genetic heterogeneity is often overlooked in the development process. By considering molecular mechanisms at an individual and ancestral level, a richer understanding of the influence of environmental and lifestyle factors can be gained and more refined therapeutic interventions can be developed. It is therefore expedient to understand the molecular and clinical heterogeneity in CVDs that exists across different populations. In this review, we highlight how the mechanisms underlying CVDs vary across diverse population ancestry groups due to genetic heterogeneity. We then discuss how such genetic heterogeneity is being leveraged to inform therapeutic interventions and personalised medicine, highlighting examples across the CVD spectrum. Finally, we present an overview of how polygenic risk scores and Mendelian randomisation can foster more robust insight into disease mechanisms and therapeutic intervention in diverse populations. Fulfilment of the vision of precision medicine requires more exhaustive leveraging of the genetic variability across diverse ancestry populations to improve our understanding of disease onset, progression and response to therapeutic intervention.

Purpose: Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. Methods: A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. Results: Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. Conclusion: EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. Trial registration: NCT03470259 [ABSTRACT FROM AUTHOR]

The G protein–coupled CXC chemokine receptor 4 (CXCR4) is a candidate therapeutic target for tissue fibrosis. A fully human single-domain antibody-like scaffold i-body AD-114-PA600 (AD-114) with specific high binding affinity to CXCR4 has been developed. To define its renoprotective role, AD-114 was administrated in a mouse model of renal fibrosis induced by folic acid (FA). Increased extracellular matrix (ECM) accumulation, macrophage infiltration, inflammatory response, TGF-β1 expression, and fibroblast activation were observed in kidneys of mice with FA-induced nephropathy. These markers were normalized or partially reversed by AD-114 treatment. In vitro studies demonstrated AD-114 blocked TGF-β1–induced upregulated expression of ECM, matrix metalloproteinase-2, and downstream p38 mitogen-activated protein kinase (p38 MAPK) and PI3K/AKT/mTOR signaling pathways in a renal proximal tubular cell line. Additionally, these renoprotective effects were validated in a second model of unilateral ureteral obstruction using a second generation of AD-114 (Fc-fused AD-114, also named AD-214). Collectively, these results suggest a renoprotective role of AD-114 as it inhibited the chemotactic function of CXCR4 as well as blocked CXCR4 downstream p38 MAPK and PI3K/AKT/mTOR signaling, which establish a therapeutic strategy for AD-114 targeting CXCR4 to limit renal fibrosis.

Mucopolysaccharidosis type II (MPS II) is a lysosomal storage disorder caused by deficiency of the iduronate-2-sulfatase (IDS) enzyme, resulting in cellular accumulation of glycosaminoglycans (GAGs) throughout the body. Treatment of MPS II remains a considerable challenge as current enzyme replacement therapies do not adequately control many aspects of the disease, including skeletal and neurological manifestations. We developed an IDS transport vehicle (ETV:IDS) that is engineered to bind to the transferrin receptor; this design facilitates receptor-mediated transcytosis of IDS across the blood-brain barrier and improves its distribution into the brain while maintaining distribution to peripheral tissues. Here we show that chronic systemic administration of ETV:IDS in a mouse model of MPS II reduced levels of peripheral and central nervous system GAGs, microgliosis, and neurofilament light chain, a biomarker of neuronal injury. Additionally, ETV:IDS rescued auricular and skeletal abnormalities when introduced in adult MPS II mice. These effects were accompanied by improvements in several neurobehavioral domains, including motor skills, sensorimotor gating, and learning and memory. Together, these results highlight the therapeutic potential of ETV:IDS for treating peripheral and central abnormalities in MPS II. DNL310, an investigational ETV:IDS molecule, is currently in clinical trials as a potential treatment for patients with MPS II.

PURPOSE Complementary and alternative medicine (CAM) use during cancer treatment is controversial. We aim to evaluate contemporary CAM use, patient perceptions and attitudes, and trust in various sources of information regarding CAM. METHODS A multi-institutional questionnaire was distributed to patients receiving cancer treatment. Collected information included respondents' clinical and demographic characteristics, rates of CAM exposure/use, information sources regarding CAM, and trust in each information source. Comparisons between CAM users and nonusers were performed with chi-squared tests and one-way analysis of variance. Multivariable logistic regression models for trust in physician and nonphysician sources of information regarding CAM were evaluated. RESULTS Among 749 respondents, the most common goals of CAM use were management of symptoms (42.2%) and treatment of cancer (30.4%). Most CAM users learned of CAM from nonphysician sources. Of CAM users, 27% reported not discussing CAM with their treating oncologists. Overall trust in physicians was high in both CAM users and nonusers. The only predictor of trust in physician sources of information was income >$100,000 in US dollars per year. Likelihood of trust in nonphysician sources of information was higher in females and lower in those with graduate degrees. CONCLUSION A large proportion of patients with cancer are using CAM, some with the goal of treating their cancer. Although patients are primarily exposed to CAM through nonphysician sources of information, trust in physicians remains high. More research is needed to improve patient-clinician communication regarding CAM use. [ABSTRACT FROM AUTHOR]

Purpose: The Internet is a ubiquitous source of medical information, and natural language processors are gaining popularity as alternatives to traditional search engines. However, suitability of their generated content for patients is not well understood. We aimed to evaluate the appropriateness and readability of natural language processor-generated responses to urology-related medical inquiries. Materials and Methods: Eighteen patient questions were developed based on Google Trends and were used as inputs in ChatGPT. Three categories were assessed: oncologic, benign, and emergency. Questions in each category were either treatment or sign/symptom-related questions. Three native English-speaking Board-Certified urologists independently assessed appropriateness of ChatGPT outputs for patient counseling using accuracy, comprehensiveness, and clarity as proxies for appropriateness. Readability was assessed using the Flesch Reading Ease and Flesh-Kincaid Reading Grade Level formulas. Additional measures were created based on validated tools and assessed by 3 independent reviewers. Results: Fourteen of 18 (77.8%) responses were deemed appropriate, with clarity having the most 4 and 5 scores (P [ .01). There was no significant difference in appropriateness of the responses between treatments and symptoms or between different categories of conditions. The most common reason from urologists for low scores was responses lacking information dsometimes vital information. The mean (SD) Flesch Reading Ease score was 35.5 (SD[10.2) and the mean Flesh-Kincaid Reading Grade Level score was 13.5 (1.74). Additional quality assessment scores showed no significant differences between different categories of conditions. Conclusions: Despite impressive capabilities, natural language processors have limitations as sources of medical information. Refinement is crucial before adoption for this purpose. [ABSTRACT FROM AUTHOR]

Background: Recent efforts to repurpose existing drugs to different indications have been accompanied by a number of computational methods, which incorporate protein-protein interaction networks and signaling pathways, to aid with prioritizing existing targets and/or drugs. However, many of these existing methods are focused on integrating additional data that are only available for a small subset of diseases or conditions. Methods: We have designed and implemented a new R-based open-source target prioritization and repurposing method that integrates both canonical intracellular signaling information from five public pathway databases and target information from public sources including OpenTargets.org. The Pathway2Targets algorithm takes a list of significant pathways as input, then retrieves and integrates public data for all targets within those pathways for a given condition. It also incorporates a weighting scheme that is customizable by the user to support a variety of use cases including target prioritization, drug repurposing, and identifying novel targets that are biologically relevant for a different indication. Results: As a proof of concept, we applied this algorithm to a public colorectal cancer RNA-sequencing dataset with 144 case and control samples. Our analysis identified 430 targets and ~700 unique drugs based on differential gene expression and signaling pathway enrichment. We found that our highest-ranked predicted targets were significantly enriched in targets with FDA-approved therapeutics for colorectal cancer (p-value < 0.025) that included EGFR, VEGFA, and PTGS2. Interestingly, there was no statistically significant enrichment of targets for other cancers in this same list suggesting high specificity of the results. We also adjusted the weighting scheme to prioritize more novel targets for CRC. This second analysis revealed epidermal growth factor receptor (EGFR), phosphoinositide-3-kinase (PI3K), and two mitogen-activated protein kinases (MAPK14 and MAPK3). These observations suggest that our open-source method with a customizable weighting scheme can accurately prioritize targets that are specific and relevant to the disease or condition of interest, as well as targets that are at earlier stages of development. We anticipate that this method will complement other approaches to repurpose drugs for a variety of indications, which can contribute to the improvement of the quality of life and overall health of such patients. [ABSTRACT FROM AUTHOR]

People with type 2 diabetes receiving a second-generation basal insulin (BI) analog may be switched to a first-generation formulation for financial reasons or changes in health insurance. However, because second-generation BI analogs have more even pharmacokinetic profiles, longer durations of action (>24 vs. ≤24 hours), and more stable action profiles than first-generation BI analogs, such a change may result in suboptimal treatment persistence and/or adherence. This study compared treatment persistence, treatment adherence, rates of hypoglycemia, and health care resource utilization outcomes in people with type 2 diabetes who either continued treatment with the second-generation BI Gla-300 or switched to a first-generation BI. The study showed that continuing with Gla-300 was associated with a lower risk of discontinuing therapy, fewer emergency department visits, and lower hypoglycemia event rates than switching to a first-generation BI. [ABSTRACT FROM AUTHOR]

We examined oral PrEP interest among adolescents and its association with perceived parental support and PrEP stigma. Cross-sectional data were collected during baseline procedures of the "Our Family Our Future" intervention trial in South Africa. Adolescents (14–16 years) at elevated risk for acquiring HIV and their parents or caregivers were dyadically enrolled from 2018 to 2021. There were 879 complete adolescent-parent dyads. Among adolescents, 27% had heard about PrEP, 67% reported they would want to use PrEP, and 58% thought their parent would want them to use PrEP. Among parents, 33% had heard about PrEP and 85% reported they would want their adolescent to use PrEP. Adolescents who thought their parent would want them to use PrEP were more likely to be interested in PrEP than adolescents who thought their parent would not want them to use PrEP (adjusted prevalence ratio (aPR) = 2.11, 95% CI 1.82, 2.44). Further, adolescents with higher average PrEP stigma scores above the adolescent sample median were less likely to be interested in PrEP than adolescents with lower average PrEP stigma scores (aPR = 0.81, 95% CI 0.72, 0.91). In conclusion, parents were more supportive of their adolescent taking PrEP than adolescents perceived they would be, and perceptions of low parental support and greater PrEP stigma were associated with reduced PrEP interest among adolescents. Interventions should aim to improve adolescent-parent communication around sexual health and effective HIV prevention tools. [ABSTRACT FROM AUTHOR]

This pilot study assessed the feasibility and potential effectiveness of a single-session workshop in modifying parental beliefs/knowledge about attention-deficit/hyperactivity disorder (ADHD) in children and impact on treatment acceptance/utilization. Concerns raised by school professionals about lack of treatment follow-through after ADHD diagnosis and parental misinformation about medication usage catalyzed this project. A single-group pre-post quasi-experimental design was used. Sixty-eight parents completed ADHD knowledge/belief scales and stress inventories, and pre-ADHD and post-ADHD information workshop. Follow-up calls were made after the workshop to assess treatment utilization. Parents/caregivers experienced significant knowledge and belief changes regarding medication efficacy, willingness to accept physician treatment recommendations, and rejection of non-empirically based treatments. Follow-up data showed that 41% of contacted participants met with physicians to discuss medication utilization and behavioral treatments. Brief, one-session psycho-educational workshops were feasible and impacted parental beliefs and behaviors regarding scientifically supported interventions for ADHD. [ABSTRACT FROM AUTHOR]

The COVID‐19 pandemic has placed unprecedented pressure on biopharmaceutical companies to develop efficacious preventative and therapeutic treatments, which is unlikely to abate in the coming years. The importance of fast progress to clinical evaluation for treatments, which tackle unmet medical needs puts strain on traditional product development timelines, which can take years from start to finish. Although previous work has been successful in reducing phase 1 timelines for recombinant antibodies, through utilization of the latest technological advances and acceptance of greater business risk or costs, substantially faster development is likely achievable without increased risk to patients during initial clinical evaluation. To optimize lessons learned from the pandemic and maximize multi‐stakeholder (i.e., patients, clinicians, companies, regulatory agencies) benefit, we conducted an industry wide benchmarking survey in September/October 2021. The aims of this survey were to: (i) benchmark current technical practices of key process and product development activities related to manufacturing of therapeutic proteins, (ii) understand the impact of changes implemented in COVID‐19 accelerated Ab programs, and whether any such changes can be retained as part of sustainable long‐term business practices and (iii) understand whether any accelerative action(s) taken have (negatively) impacted the wider development process. This article provides an in‐depth analysis of this data, ultimately highlighting an industry perspective of how biopharmaceutical companies can sustainably adopt new approaches to therapeutic protein development and production. [ABSTRACT FROM AUTHOR]

Cardiovascular diseases (CVDs) are complex in their aetiology, arising due to a combination of genetics, lifestyle and environmental factors. By nature of this complexity, different CVDs vary in their molecular mechanisms, clinical presentation and progression. Although extensive efforts are being made to develop novel therapeutics for CVDs, genetic heterogeneity is often overlooked in the development process. By considering molecular mechanisms at an individual and ancestral level, a richer understanding of the influence of environmental and lifestyle factors can be gained and more refined therapeutic interventions can be developed. It is therefore expedient to understand the molecular and clinical heterogeneity in CVDs that exists across different populations. In this review, we highlight how the mechanisms underlying CVDs vary across diverse population ancestry groups due to genetic heterogeneity. We then discuss how such genetic heterogeneity is being leveraged to inform therapeutic interventions and personalised medicine, highlighting examples across the CVD spectrum. Finally, we present an overview of how polygenic risk scores and Mendelian randomisation can foster more robust insight into disease mechanisms and therapeutic intervention in diverse populations. Fulfilment of the vision of precision medicine requires more exhaustive leveraging of the genetic variability across diverse ancestry populations to improve our understanding of disease onset, progression and response to therapeutic intervention. [ABSTRACT FROM AUTHOR]

Clinical trials to address the COVID-19 public health emergency have broadly excluded pregnant people from participation, illustrating a long-standing trend of clinical trial exclusion that has led to a clear knowledge gap and unmet need in the treatment and prevention of medical conditions experienced during pregnancy and of pregnancy-related conditions. Drugs (includes products such as drugs, biologics, biosimilars and vaccines) approved for a certain medical condition in adults are also approved for use in pregnant adults with the same medical condition, unless contraindicated for use in pregnancy. However, there are limited pregnancy-specific data on risks and benefits of drugs in pregnant people, despite their approval for all adults. The United States Food and Drug Administration-approved medical products are used widely by pregnant people, 90% of whom take at least 1 medication during the course of their pregnancy despite there being sparse data from clinical trials on these products in pregnancy. This overall lack of clinical data precludes informed decision-making, causing clinicians and pregnant patients to have to decide whether to pursue treatment without an adequate understanding of potential effects. Although some United States Food and Drug Administration initiatives and other federal efforts have helped to promote the inclusion of pregnant people in clinical research, broader collaboration and reforms are needed to address challenges related to the design and conduct of trials that enroll pregnant people, and to forge a culture of widespread inclusion of pregnant people in clinical research. This article summarizes the scientific, ethical, and legal considerations governing research conducted during pregnancy, as discussed during a recent subject matter expert convening held by the Duke-Margolis Center for Health Policy and the United States Food and Drug Administration on this topic. This article also recommends strategies for overcoming impediments to inclusion and trial conduct. [ABSTRACT FROM AUTHOR]

Ectonucleotidases modulate inflammatory responses by balancing extracellular ATP and adenosine (ADO) and might be involved in COVID-19 immunopathogenesis. Here, we explored the contribution of extracellular nucleotide metabolism to COVID-19 severity in mild and severe cases of the disease. We verified that the gene expression of ectonucleotidases is reduced in the whole blood of patients with COVID-19 and is negatively correlated to levels of CRP, an inflammatory marker of disease severity. In line with these findings, COVID-19 patients present higher ATP levels in plasma and reduced levels of ADO when compared to healthy controls. Cell type-specific analysis revealed higher frequencies of CD39+ T cells in severely ill patients, while CD4+ and CD8 + expressing CD73 are reduced in this same group. The frequency of B cells CD39+CD73+ is also decreased during acute COVID-19. Interestingly, B cells from COVID-19 patients showed a reduced capacity to hydrolyze ATP into ADP and ADO. Furthermore, impaired expression of ADO receptors and a compromised activation of its signaling pathway is observed in COVID-19 patients. The presence of ADO in vitro, however, suppressed inflammatory responses triggered in patients' cells. In summary, our findings support the idea that alterations in the metabolism of extracellular purines contribute to immune dysregulation during COVID-19, possibly favoring disease severity, and suggest that ADO may be a therapeutic approach for the disease. [ABSTRACT FROM AUTHOR]

Further information is needed on how community exercise facilities can be effectively utilised to engage people living with chronic health conditions in exercise. The aim of this study was to identify the exercise barriers, facilitators and needs of patients with chronic disease in the community; and to provide recommendations to support the transition from hospital‐based to community‐based exercise. Using a qualitative approach, four focus groups were conducted with patients who had completed hospital‐based exercise programmes (n = 11) and fitness instructors (n = 10). Data were audio recorded, member checked and transcribed verbatim for thematic analysis using NVivo. The side effects of chronic health conditions, the gym environment and a need for support when joining/attending a gym were perceived as barriers to exercising in the community. In contrast, the presence of supportive staff was perceived by patients as a facilitator to engaging in exercise in the community. A total of three themes emerged from participants views on exercise needs in the community; the referral and induction process in community gyms, fitness instructor training and experience and creating a supportive exercise environment. Themes informed eight key recommendations to support patients to exercise in the community, including supportive gym referral and induction processes for patients with chronic conditions, increased professional training for fitness instructors in the area of chronic disease management and exercise prescription, and exercise support at regular intervals for those with chronic conditions attending community gyms. This study found that there is potential for community gyms to play a key role in promoting health among people with chronic conditions. However, more can be done to foster an inclusive atmosphere in this space. Patients living with chronic conditions need information and advice on exercising in their communities. Community gyms require further support to ensure that facilities meet the exercise needs of people with chronic conditions. [ABSTRACT FROM AUTHOR]

Background: The aim of this review was to identify relevant randomized controlled trials (RCTs) and non-RCTs to evaluate the existing knowledge on the effect of antibiotic treatment for infants with necrotizing enterocolitis (NEC).Objective: Identifying 1) the best antibiotic regimen to avoid disease progression as assessed by surgery or death, 2) the best antibiotic regimen for infants operated for NEC as assessed by re-operation or death.Methods: Embase, MEDLINE and Cochrane were searched systematically for human studies using antibiotics for patients with NEC, Bell's stage II and III.Results: Five studies were included, with a total of 375 infants. There were 2 RCT and 3 cohort studies. Four main antibiotic regimens appeared. Three with a combination of ampicillin + gentamycin (or similar) with an addition of 1) clindamycin 2) metronidazole or 3) enteral administration of gentamycin. One studied investigated cefotaxime + vancomycin. None of the included studies had a specific regimen for infants undergoing surgery.Conclusions: No sufficient evidence was found for any recommendation on the choice of antibiotics, the route of administration or the duration in infants treated for NEC with Bell's stage II and III. [ABSTRACT FROM AUTHOR]

The application of nanocarriers in medicine and pharmaceuticals suggests a new procedure in nanotechnology terminology, nanomedicine. DNA has been significantly highlighted due to its amazing functionality and nature as a nanomaterial in biomedicine. Given that DNA is biocompatible, its use as a nanomaterial in medicine provides an excellent prospect for the rational engineering of DNA nanostructures. According to new approaches in disease treatment at gene levels, gene therapy, DNA as a nanomedicine plays an essential role in the medical sciences. In this field, researchers have published enormous documents regarding the applications of DNA and DNA-based nanostructures as drug or gene nanocarriers, DNA-based diagnostics, and DNA nano vaccines. In this review, the novelty of DNA-based nanomedicine has been considered. [ABSTRACT FROM AUTHOR]

Background: The impact of multiple coexisting medical comorbidities on treatment outcomes in chronic rhinosinusitis (CRS) is unknown. In this study we sought to evaluate the effect of comorbidities on sinonasal quality of life (QOL) and general health utility values by utilizing the Functional Comorbidity Index (FCI) in CRS patients. Methods: Patients with CRS were prospectively enrolled in a cross‐sectional study of medical and surgical therapies. The 22‐item Sino‐Nasal Outcome Test (SNOT‐22) and Medical Outcomes Study Short‐Form 6D (SF‐6D) scores were recorded at enrollment and 6‐month follow‐up; Lund‐Kennedy endoscopy and Lund‐Mackay computed tomography scores were recorded at enrollment. The FCI was calculated using the electronic medical record. The impact of cumulative comorbidity burden on baseline and posttreatment outcomes was assessed using univariate and bivariate correlations. Results: A total of 428 participants with CRS were included. The average (mean standard ± deviation) FCI score was 3.03 ± 2.28 (range, 0‐12). Significant linear correlations were identified between increasing FCI score and baseline SNOT‐22 and SF‐6D scores (R = 0.166, p = 0.001 and R = −0.245, p < 0.001, respectively). There was no correlation between FCI and change in SNOT‐22 or SF‐6D scores after CRS treatment (R = 0.066, p = 0.17 and R = −0.087, p = 0.074, respectively). Achievement of a minimally clinically important difference was also independent of FCI. Conclusion: Although cumulative comorbidity burden, as measured by FCI, is associated with worse baseline SNOT‐22 and SF‐6D scores, it does not appear to limit posttreatment improvement in either outcome measure. On average, patients with high comorbidity burden report substantial improvement in both QOL and health utility after CRS treatment, similar to those with fewer comorbidities. [ABSTRACT FROM AUTHOR]

The emergence of dual therapy for antiretroviral (ARV)-experienced persons living with HIV (PWH) offers the opportunity to reduce lifetime exposure to unnecessary ARV drugs while maintaining viral suppression and reducing the cost of care. Our objective, using retrospective analysis of a quality care initiative, was to examine in routine clinical practice the clinical impact of switching PWH stable on a three-drug to a two-drug single-tablet formulation (STF) ARV regimen. We also examined the cost implications of this STF adjustment. Between January 1, 2020 and January 1, 2021 eligible patients (i.e., virally suppressed, no active hepatitis B infection, no documented nucleoside reverse transcriptase inhibitors/integrase strand transfer inhibitor resistance) were offered, on a convenience basis and as part of routine care, the opportunity to adjust their current three-drug STF to a two-drug STF (dolutegarvair/lamivudine). The acceptance, clinical efficacy, safety, tolerability, and cost of treatment were measured for patients who switched in 2020. Of 989 eligible PWH, 408 were approached and 391 (39.5%) switched to two-drug regimen; 99% remained on the two-drug STF at year's end (median 240 days follow-up). Only 2/391 patients who switched lost viral control. The total ARV drug cost for all 989 patients decreased by 10.3% generating an actual savings of $1,596,666 among patients approached and switched in 2020. Patient interest and uptake in switching to two-drug STF was substantial and resulted in few discontinuations for any reason. It provided significant and immediate cost savings within the first year. Our results bring clarity to discussions on whether using two-drug regimens would be practical and acceptable in nonclinical trial settings. [ABSTRACT FROM AUTHOR]

The movement system was identified as the focus of our expertise as physical therapists in the revised vision statement for the profession adopted by the American Physical Therapy Association in 2013. Attaining success with the profession's vision requires the development of movement system diagnoses that will be useful in clinical practice, research, and education. To date, only a few movement system diagnoses have been identified and described, and none of these specifically address balance dysfunction. Over the past 2 years, a Balance Diagnosis Task Force, a subgroup of the Movement System Task Force of the Academy of Neurologic Physical Therapy, focused on developing diagnostic labels (or diagnoses) for individuals with balance problems. This paper presents the work of the task force that followed a systematic process to review available diagnostic frameworks related to balance, identify 10 distinct movement system diagnoses that reflect balance dysfunction, and develop complete descriptions of examination findings associated with each balance diagnosis. A standardized approach to movement analysis of core tasks, the Framework for Movement Analysis developed by the Academy of Neurologic Physical Therapy Movement Analysis Task Force, was integrated into the examination and diagnostic processes. The aims of this perspective paper are to (1) summarize the process followed by the Balance Diagnosis Task Force to develop an initial set of movement system (balance) diagnoses; (2) report the recommended diagnostic labels and associated descriptions; (3) demonstrate the clinical decision-making process used to determine a balance diagnosis and develop a plan of care; and (4) identify next steps to validate and implement the diagnoses into physical therapist practice, education, and research. Impact The development and use of diagnostic labels to classify distinct movement system problems is needed in physical therapy. The 10 balance diagnosis proposed can aid in clinical decision making regarding intervention. [ABSTRACT FROM AUTHOR]

To examine the feasibility and acceptability of NIDUS-Family, a 6–8 session manualised, individually tailored, modular intervention supporting independence at home for people with dementia; and explore participants' and facilitators' experiences of the intervention. In this single group multi-site feasibility study, trained, supervised non-clinically qualified graduates (facilitators) delivered NIDUS-Family to family carer and people living with dementia dyads. We recruited participants from GP practices and memory services in London and Bradford. We completed quantitative outcomes pre- and post-intervention; and conducted qualitative interviews with participants and facilitators. Our pre-specified main outcomes were proportion of potential participants approached who agreed to participate, intervention adherence and acceptability to family carers, and facilitator fidelity to the manual. We recruited 16 dyads (57% of those approached); 12 (75%) completed the intervention. Of 12 participants rating intervention acceptability, 9 (75%) agreed or strongly agreed that it had helped; 2 (18%) neither agreed nor disagreed and 1 (8%) disagreed. Mean facilitator fidelity was high (81.5%). Dyads set on average 3.9 goals; these most commonly related to getting out and about and increasing activity/hobby participation (n = 10); carer wellbeing (n = 6), managing physical complaints (n = 6); meal preparation/cooking (n = 5); and reducing irritability, frustration or aggression (n = 5). Almost all secondary outcomes changed in a direction indicating improvement. In our qualitative analysis we identified three overarching themes; relationships facilitate change, goal-focused versus manualised approach and balancing the needs of carers and people with dementia. NIDUS-Family was feasible and acceptable to participants. Following refinements, testing in a pragmatic trial is underway. [ABSTRACT FROM AUTHOR]

Background: There exist functional deficits in motor, sensory, and olfactory abilities in dementias. Measures of these deficits have been discussed as potential clinical markers.Objective: We measured the deficit of motor, sensory, and olfactory functions on both the left and right body side, to study potential body lateralizations.Methods: This IRB-approved study (N = 84) performed left/right clinical tests of gross motor (dynamometer test), sensory (Von Frey test), and olfactory (peppermint oil test) ability. The Mini-Mental Status Exam was administered to determine level of dementia; medical and laboratory data were collected.Results: Sensory and olfactory deficits lateralized to the left side of the body, while motor deficits lateralized to the right side. We found clinical correlates of motor lateralization: female, depression, MMSE <15, and diabetes. While clinical correlates of sensory lateralization: use of psychotherapeutic agent, age ≥85, MMSE <15, and male. Lastly, clinical correlates of olfactory lateralization: age <85, number of medications >10, and male.Conclusion: These lateralized deficits in body function can act as early clinical markers for improved diagnosis and treatment. Future research should identify correlates and corresponding therapies to strengthen at-risk areas. [ABSTRACT FROM AUTHOR]

Over 30,000 adult cardiac operations are carried out in the UK annually. A small number of these patients need to return to theatre in the first few days after the initial surgery, but the exact proportion is unknown. The majority of these resternotomies are for bleeding or cardiac tamponade. The Association of Cardiothoracic Anaesthesia and Critical Care carried out a 1-year national audit of resternotomy in 2018. Twenty-three of the 35 centres that were eligible participated. The overall resternotomy rate (95%CI) within the period of admission for the initial operation in these centres was 3.6% (3.37-3.85). The rate varied between centres from 0.69% to 7.6%. Of the 849 patients who required resternotomy, 127 subsequently died, giving a mortality rate (95%CI) of 15.0% (12.7-17.5). In patients who underwent resternotomy, the median (IQR [range]) length of stay on ICU was 5 (2-10 [0-335]) days, and time to tracheal extubation was 20 (12-48 [0-2880]) hours. A total of 89.3% of patients who underwent resternotomy were transfused red cells, with a median (IQR [range]) of 4 (2-7 [1-1144]) units of red blood cells. The rate (95%CI) of needing renal replacement therapy was 23.4% (20.6-26.5). This UK-wide audit has demonstrated that resternotomy after cardiac surgery is associated with prolonged intensive care stay, high rates of blood transfusion, renal replacement therapy and very high mortality. Further research into this area is required to try to improve patient care and outcomes in patients who require resternotomy in the first 24 h after cardiac surgery. [ABSTRACT FROM AUTHOR]

Background: The efficacy of naltrexone, baclofen, and acamprosate in the treatment of alcohol dependence has been successfully established over the past several years. The knowledge about their relative efficacies can facilitate in developing relapse prevention strategies that would give rise to a greater personal and socioeconomic benefits. Aims and Objective: To assess and compare the safety and efficacy profile of naltrexone, baclofen, and acamprosate in the treatment of alcohol dependence. In addition to this, the pattern of relapse and attitude of patients toward the treatment were also assessed. Materials and Methods: This was a prospective study carried out at a tertiary care center. It comprised of thirty alcohol-dependent patients each assigned to naltrexone, baclofen, and acamprosate group after detoxification. The patients were assessed for craving, relapse risk, and medication adherence using the respective scales and questionnaires. Results: In terms of Obsessive Compulsive Drinking Scale score decline, the decline seen in the naltrexone group (26.72 ± 13.05) was maximum, followed by baclofen and acamprosate. In terms of decreasing Advance Warning of Relapse (AWARE) questionnaire score, again naltrexone was most effective, with the maximum decline in AWARE score (64.72 ± 45.65), followed by baclofen and acamprosate. The attitude toward treatment with all the three medications was positive, as per the Hogan Drug Attitude Inventory score. Conclusion: Naltrexone was most effective in decreasing craving and drinking behavior. Baclofen showed best tolerability in terms of liver function tests and least number of side effects reported. Naltrexone group reported the least number of relapses but maximum number of side effects. Acamprosate group had the maximum dropout rate. [ABSTRACT FROM AUTHOR]

To describe the population of young people in Ireland diagnosed with narcolepsy with regards to vaccine exposure, symptomatology, investigation results and experience of medical treatment. Retrospective review of medical records at the single tertiary referral centre for young people with narcolepsy in Ireland. Sixty-seven patients were diagnosed with narcolepsy between July 2006 and July 2017. Sixty-one (91%) of these developed symptoms after receiving the Pandemrix vaccine. The population was largely homogeneous with low hypocretin (87.5%), HLA DQB1∗0602 positivity (95%) and unremarkable findings on MRI Brain (100%). 77.6% experienced cataplexy; we also measured high levels of obesity, school non-attendance and psychosocial complexity. Symptoms often continued despite treatment, with multiple medications prescribed in 76.1% of patients. Prescription of sodium oxybate was associated with a significant reduction in BMI standard deviation scores at 6 months, with improved IOTF obesity scores seen at 36 month follow-up. This paper describes the experience of narcolepsy in children and young people in Ireland from 2006 – 2017 at the national tertiary referral centre. Narcolepsy in children and young people in Ireland carries a significant burden of illness, with impact on participation in education as well as physical and mental health. Symptoms can be refractory to medical treatment. Referral to tertiary centres for prompt treatment and multidisciplinary input is essential. • This study describes the Irish national experience of narcolepsy in children and young people since 2009. • The population was largely homogeneous with low hypocretin, HLA DQBQ∗0602 positivity, and normal MRI Brain. • Pandemrix vaccine exposure preceded symptom onset in the majority of cases. • Symptoms of narcolepsy were resistant to treatment with single agents; medication side-effects were common. • High levels of obesity, school non-attendance and psychosocial complexity are described. [ABSTRACT FROM AUTHOR]

Background Falls are the leading cause of injuries among older adults, and trips and slips are major contributors to falls. Objective The authors sought to compare the effectiveness of adding a component of surface perturbation training to usual gait/balance training for reducing falls and fall-related injury in high-risk older adults referred to physical therapy. Design This was a multi-center, pragmatic, randomized, comparative effectiveness trial. Setting Treatment took place within 8 outpatient physical therapy clinics. Patients This study included 506 patients 65+ years of age at high fall risk referred for gait/balance training. Intervention This trial evaluated surface perturbation treadmill training integrated into usual multimodal exercise-based balance training at the therapist's discretion versus usual multimodal exercise-based balance training alone. Measurements Falls and injurious falls were assessed with a prospective daily fall diary, which was reviewed via telephone interview every 3 months for 1 year. A total of 211/253 (83%) patients randomized to perturbation training and 210/253 (83%) randomized to usual treatment provided data at 3-month follow-up. At 3 months, the perturbation training group had a significantly reduced chance of fall-related injury (5.7% versus 13.3%; relative risk 0.43) but no significant reduction in the risk of any fall (28% versus 37%, relative risk 0.78) compared with usual treatment. Time to first injurious fall showed reduced hazard in the first 3 months but no significant reduction when viewed over the entire first year. Limitations The limitations of this trial included lack of blinding and variable application of interventions across patients based on pragmatic study design. Conclusion The addition of some surface perturbation training to usual physical therapy significantly reduced injurious falls up to 3 months posttreatment. Further study is warranted to determine the optimal frequency, dose, progression, and duration of surface perturbation aimed at training postural responses for this population. [ABSTRACT FROM AUTHOR]

Amid rising trends in opioid use, hospitalizations for health conditions secondary to intravenous drug use are becoming more common. Such patients often require prolonged hospitalizations and frequently present with substance use histories, co-occurring mental health diagnoses, and unique behavioral health needs. These issues can adversely impact completion of medical treatment and place added burden on hospital staff. There is a growing need for medical institutions to develop policies and procedures which address the specific emotional, behavioral, and substance use needs of this patient population. Because guidelines for doing so are sparse in the literature, this study outlines the University of Vermont Medical Center's process of developing an in-hospital care agreement intended to (1) increase patient access to in-hospital need assessments, psychotherapy, and medication for opioid use disorders, (2) increase referrals for opioid use treatment beyond hospitalization, (3) standardize staff response to common challenging behaviors, and (4) provide staff with education and support for interacting with patients in effective ways. The multidisciplinary process of developing this care agreement, its specific details, lessons learned, and anticipated future directions are also discussed. [ABSTRACT FROM AUTHOR]

Objective: Hypotension in the prehospital environment is common and linked to dose-dependent mortality. Bolus dose epinephrine (BDE) may reverse hypotension. We tested if BDE use to treat profound hypotension is associated with 24-hour survival. Methods: We performed a retrospective case-cohort study of critical care transport patients with systolic blood pressure (SBP) <70 mmHg from January 2011 to January 2017. To account for baseline differences between treated and untreated patients, we used nearest neighbor matching to estimate the average treatment effect of BDE on 24-hour survival. Included covariates were age, gender, shock type (cardiogenic, distributive, obstructive or hypovolemic), weight, type of service, vitals (heart rate, SBP and diastolic blood pressure, respiratory rate, oxygen saturation, end-tidal carbon dioxide, and Glasgow Coma Scale score) at the time of the first hypotensive episode, as well as pretreatment characteristics including cardiopulmonary resuscitation, defibrillation, transcutaneous pacing, needle thoracostomy, vasopressors, intubation, or arrhythmias. After statistical analysis, we assessed for residual bias by selecting random matched patient records and asking 2 blinded physicians to rate overall illness severity on a Likert scale. We compared perceived illness severity between cases and matched controls using a rank-sum test. Results: There were 6,992 patients transported with SBP <70 mmHg at least once and 4,374 meet inclusion criteria. Of the 1,620 patients transported after protocol implementation, 574 (35%) received BDE. Overall 24-hour survival, survival to discharge and 30-day survival were 80, 57, and 54%, respectively. Survival at 24 hours differed between the BDE group (66%) and controls (82%). These differences persisted at both discharge and 30 days. Administration of BDE was associated with increased post-treatment SBP. BDE treated patients were also more likely to receive cardiopulmonary resuscitation and vasopressors after treatment than untreated hypotensive patients, but there was no association with tachydysrhythmias requiring defibrillation. Conclusions: Bolus dose epinephrine increases blood pressure in the prehospital setting. Despite robust efforts to control for confounding, BDE remained associated with increased mortality in this observational cohort. This association may be due to unmeasured confounding and a randomized controlled trial is necessary to establish a causal relationship between bolus dose vasopressors and mortality. [ABSTRACT FROM AUTHOR]

Background: Cotrimoxazole is associated with the development of hyponatremia, hyperkalemia and elevated serum creatinine, especially when combined with inhibitors of the renin–angiotensin–aldosterone system (RAAS). Pneumocystis jirovecii pneumonia (PJP) prophylaxis is the standard of care for high-grade glioma (HGG) patients receiving temozolomide concurrently with radiotherapy, low-dose cotrimoxazole being the preferred agent. Many of these patients are also taking renin–angiotensin–aldosterone system inhibitors, however the risk of significant laboratory disturbance in these patients remains undescribed. Objective: We evaluated whether high-grade glioma patients taking renin–angiotensin–aldosterone system inhibitors receiving low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis are at additional risk of laboratory disturbances in comparison with their non-renin–angiotensin–aldosterone system counterparts. Methods: We conducted a retrospective chart review of adult neuro-oncology patients treated for WHO Grade III or IV glioma between 2013 and 2016. Patient serum Na, K, creatinine, and eGFR were compared (renin–angiotensin–aldosterone system vs. non-renin–angiotensin–aldosterone system) using the chi-square test. Binary logistic regression analysis was then performed to account for differences between cohorts. Results: Of 63 patients (35 non-renin–angiotensin–aldosterone system, 28 renin–angiotensin–aldosterone system), patients in the renin–angiotensin–aldosterone system cohort were more likely to experience a laboratory disturbance (odds ratio=3.17, p = 0.03). Overall, these disturbances were moderate, but were slightly more common and slightly more severe in the renin–angiotensin–aldosterone system cohort. Conclusion: Adding low-dose cotrimoxazole for Pneumocystis jirovecii pneumonia prophylaxis to the regimens of patients with high-grade glioma taking renin–angiotensin–aldosterone system inhibitors increases the risk of laboratory disturbances. While these are generally moderate, some patients are at risk of significant electrolyte abnormalities requiring intervention. [ABSTRACT FROM AUTHOR]

Background there is little research on how people with dementia are involved in treatment decisions at diagnosis. Objective to measure shared decision making when starting cholinesterase inhibitors, investigate associations with contextual factors and explore satisfaction and experience of the diagnostic meeting. Setting nine UK memory clinics in two geographical locations. Subjects 74 people receiving dementia diagnoses (with 69 companions) and 21 doctors. Methods we video-recorded 74 memory clinic consultations and rated doctor-shared decision making behaviours using the Observing Patient Involvement in Decision Making scale (OPTION-5 scale). Patients and companions rated their satisfaction and experience. Mixed-effects regressions investigated involvement and (i) number people present, meeting length, capacity, cognitive functioning, diagnosis; and (ii) patient/companion satisfaction and consultation experience. Results mean consultation time was 26.7 min. Mean OPTION-5 score was 22.5/100 (Standard Deviation = 17.3). Doctors involved patients in decisions more often when patients had mixed dementia (β = 10.13, 95% confidence interval 1.25–19.0, P = 0.025) and in shorter meetings (β = −0.51, 95% CI −0.87 to −0.15, P = 0.006). Patient and companion satisfaction were high and not associated with whether doctors invited patient involvement. Half of patients and one-third companions were uncertain about the meeting outcome, experienced communication barriers and negative emotions. Conclusions consultations scored low on shared decision making, but were comparable to other settings and were not lower with more cognitively impaired patients. Negative patient and companion experiences reflect the importance of supporting healthcare providers to address patient and companion emotions and need for information. [ABSTRACT FROM AUTHOR]

Epidemiologic studies have demonstrated an association between acetaminophen (APAP) use and the development of asthma symptoms. However, few studies have examined relationships between APAP-induced signaling pathways associated with the development of asthma symptoms. We tested the hypothesis that acute APAP exposure causes airway hyper-responsiveness (AHR) in human airways. Precision cut lung slice (PCLS) airways from humans and mice were used to determine the effects of APAP on airway bronchoconstriction and bronchodilation and to assess APAP metabolism in lungs. APAP did not promote AHR in normal or asthmatic human airways ex vivo. Rather, high concentrations mildly bronchodilated airways pre-constricted with carbachol (CCh), histamine (His), or immunoglobulin E (IgE) cross-linking. Further, the addition of APAP prior to bronchoconstrictors protected the airways from constriction. Similarly, in vivo treatment of mice with APAP (200 mg/kg IP) resulted in reduced bronchoconstrictor responses in PCLS airways ex vivo. Finally, in both mouse and human PCLS airways, exposure to APAP generated only low amounts of APAP-protein adducts, indicating minimal drug metabolic activity in the tissues. These findings indicate that acute exposure to APAP does not initiate AHR, that high-dose APAP is protective against bronchoconstriction, and that APAP is a mild bronchodilator. [ABSTRACT FROM AUTHOR]

Background: Cholinesterase inhibitors (ChEIs) are one of only two drug therapies available to manage cognitive decline in dementia. Given sex-specific differences in medication access and effects, it is important to understand how ChEIs are used by women and men. Objective: The objective of this study was to provide contemporary sex-stratified evidence on patterns of ChEI use by community-dwelling older adults with dementia to inform opportunities to optimize drug prescribing. Methods: We conducted a population-based cross-sectional study examining ChEI use in older adults with dementia in Ontario, Canada. We identified all community-dwelling individuals aged 66 years and older with a pre-existing diagnosis of dementia as of 1 April, 2016. We examined the prevalence of ChEI use among women and men separately, and explored the association between ChEI use and age, sex, income status, geographic location of residence, use of palliative care services, comorbidity, and polypharmacy. Concurrent use of drugs known to impair cognition (including antipsychotics, benzodiazepines, and medications with strong anticholinergic properties) was separately assessed among women and men using multivariable analyses and prevalence risk ratios. Results: Of 74,799 women and 52,231 men living with dementia in the community, nearly 30% currently were using a ChEI (29.3% women, 28.6% men). Close to 70% of users were receiving the target therapeutic dose. Compared to men, women were less often taking the target therapeutic dose (67.8% women vs. 71.6% men, p < 0.001). Over 20% of users also were using drugs known to impair cognition, while being treated for cognitive decline using ChEIs. Compared to men, women were more often concurrently using drugs known to impair cognition (23.9% women vs. 21.8% men, p < 0.001). Conclusions: This is one of the first studies of ChEI use to account for important sex differences. The results remind clinicians and researchers that patterns of ChEI therapy use differ by sex, as women were less likely to receive target therapeutic doses and more vulnerable to potentially problematic polypharmacy than men. [ABSTRACT FROM AUTHOR]

Aim: To compare part-time and full-time Essix-type retainer wear regimens following fixed appliance treatment, with respect to dental alignment and occlusal changes. Methods: In this prospective study, 60 patients were randomly allocated to either full-time or part-time Essix retainer wear following fixed appliance therapy. Study casts were taken before treatment, at debonding, and 6 months following debonding. Little's irregularity index, the intercanine width, intermolar width, overjet, and overbite were measured blindly on both the maxillary and mandibular casts. Results: Both groups showed pretreatment equivalence for start age, duration of fixed appliance treatment, Little's index, intercanine width, intermolar width, overjet, and overbite. The number of patients completing the trial was 29 (1 dropout) in the part-time group and 28 in the full-time group (2 dropouts). There was a significant reduction in both the maxillary and mandibular Little's index and mandibular intermolar width in both groups during active treatment. There was a significant reduction in overjet and overbite in only the part-time retention group during fixed appliance treatment. Between debonding and 6 months after debonding, there was no significant change in any of the intra- or intergroup study cast measurements. Conclusions: Night-time-only Essix retainer wear may be an acceptable retention regimen following the use of fixed appliances. [ABSTRACT FROM AUTHOR]