The impact of weight gain on antipsychotic nonadherence or discontinuation: A systematic review and meta-analysis.

BACKGROUND: Nonadherence/discontinuation of antipsychotic (AP) medications represents an important clinical issue in patients across psychiatric disorders, including schizophrenia spectrum disorders (SSDs). While antipsychotic-induced weight gain (AIWG) is a reported contributor to nonadherence, a systematic review of the association between AIWG and medication nonadherence/discontinuation has not been explored previously. METHOD: A systematic search was conducted in MEDLINE, EMBASE, PsychINFO, CINAHL, and CENTRAL databases, among others, to help identify all studies which explored adherence, study dropouts, AP switching and/or discontinuations attributable to AIWG among individuals with severe mental illness. A meta-analysis was also completed where applicable. RESULTS: We identified two categories of studies for the meta-analysis. Category 1 included three studies, which compared measures of AP adherence or discontinuation across BMI classes/degrees of self-reported weight gain. When compared to normal weight individuals receiving APs or those who did not report AIWG, individuals who were either overweight or obese or reported weight gain in relation to AP use had an increased odds of AP nonadherence (OR 2.37; 95% CI 1.51-3.73; p = 0.0002). Category 2 had 14 studies which compared measures of discontinuation related to weight gain reported as an adverse effect across different APs. Olanzapine was associated with a 3.32 times (95% CI 2.32-4.74; p < 0.00001) increased likelihood of nonadherence or discontinuation when compared to other APs with lower weight gain liabilities. Similarly, APs with moderate weight gain liability (paliperidone, risperidone, and quetiapine) increased the odds of nonadherence or discontinuation by 2.25 (95% CI 1.31-3.87; p = 0.003) when compared to APs considered to have lower weight gain liability (i.e. haloperidol and aripiprazole). The qualitative summary also confirmed these findings. CONCLUSION: This review and meta-analysis suggests that AIWG influences medication nonadherence/discontinuation, whereby APs with higher weight gain liability are associated with nonadherence/discontinuation. Additional studies are needed to confirm these findings.

Identification of micrognathia by prenatal ultrasound may improve timely diagnosis and management of infants with Robin sequence.

OBJECTIVE: Robin sequence (RS) is a craniofacial anomaly characterized by small jaw (micrognathia) with associated tongue base airway obstruction. With advances in fetal imaging, micrognathia may be detected prenatally. This study aims to determine if prenatal recognition of micrognathia offers any advantage over being unaware of the condition until after delivery and to assess if prenatal consultation for micrognathia adds benefits beyond merely noting the presence of the condition. METHOD: Retrospective chart review examining cases from 01/01/2010 to 12/31/2020 at an urban tertiary medical center. RESULTS: Forty seven infants with RS were included. 40.4% (n = 19) had micrognathia/retrognathia noted on prenatal ultrasound. 47.4% (n = 9) of those 19 pregnancies saw a maternal fetal medicine (MFM) program with craniofacial consultation. Compared to 28 infants not diagnosed with micrognathia until after birth, the 19 infants identified prenatally required fewer transfers from birth hospital (p = 0.02). Additionally, those referred to MFM with craniofacial consultation had shorter lengths of stay when airway intervention was required (p = 0.05). CONCLUSION: Prenatal recognition of micrognathia may lead to early detection and management of RS. When RS is suspected, prenatal consultation with MFM and craniofacial team may further optimize care of the infant following delivery.

Life and death in a dynamic environment: Invasive trout, floods, and intraspecific drivers of translocated populations.

Understanding the relative strengths of intrinsic and extrinsic factors regulating populations is a long-standing focus of ecology and critical to advancing conservation programs for imperiled species. Conservation could benefit from an increased understanding of factors influencing vital rates (somatic growth, recruitment, survival) in small, translocated populations, which is lacking owing to difficulties in long-term monitoring of rare species. Translocations, here defined as the transfer of wild-captured individuals from source populations to new habitats, are widely used for species conservation, but outcomes are often minimally monitored, and translocations that are monitored often fail. To improve our understanding of how translocated populations respond to environmental variation, we developed and tested hypotheses related to intrinsic (density dependent) and extrinsic (introduced rainbow trout Oncorhynchus mykiss, stream flow and temperature regime) causes of vital rate variation in endangered humpback chub (Gila cypha) populations translocated to Colorado River tributaries in the Grand Canyon (GC), USA. Using biannual recapture data from translocated populations over 10 years, we tested hypotheses related to seasonal somatic growth, and recruitment and population growth rates with linear mixed-effects models and temporal symmetry mark-recapture models. We combined data from recaptures and resights of dispersed fish (both physical captures and continuously recorded antenna detections) from throughout GC to test survival hypotheses, while accounting for site fidelity, using joint live-recapture/live-resight models. While recruitment only occurred in one site, which also drove population growth (relative to survival), evidence supported hypotheses related to density dependence in growth, survival, and recruitment, and somatic growth and recruitment were further limited by introduced trout. Mixed-effects models explained between 67% and 86% of the variation in somatic growth, which showed increased growth rates with greater flood-pulse frequency during monsoon season. Monthly survival was 0.56-0.99 and 0.80-0.99 in the two populations, with lower survival during periods of higher intraspecific abundance and low flood frequency. Our results suggest translocations can contribute toward the recovery of large-river fishes, but continued suppression of invasive fishes to enhance recruitment may be required to ensure population resilience. Furthermore, we demonstrate the importance of flooding to population demographics in food-depauperate, dynamic, invaded systems.

Effects of cardiorespiratory fitness and exercise training on cerebrovascular blood flow and reactivity: a systematic review with meta-analyses.

We address two aims: Aim 1 (Fitness Review) compares the effect of higher cardiorespiratory fitness (CRF) (e.g., endurance athletes) with lower CRF (e.g., sedentary adults) on cerebrovascular outcomes, including middle cerebral artery velocity (MCAv), cerebrovascular reactivity and resistance, and global cerebral blood flow, as assessed by transcranial Doppler (TCD) or magnetic resonance imaging (MRI). Aim 2 (Exercise Training Review) determines the effect of exercise training on cerebrovascular outcomes. Systematic review of studies with meta-analyses where appropriate. Certainty of evidence was assessed by the Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Twenty studies (18 using TCD) met the eligibility criteria for Aim 1, and 14 studies (8 by TCD) were included for Aim 2. There was a significant effect of higher CRF compared with lower CRF on cerebrovascular resistance (effect size = -0.54, 95% confidence interval = -0.91 to -0.16) and cerebrovascular reactivity (0.98, 0.41-1.55). Studies including males only demonstrated a greater effect of higher CRF on cerebrovascular resistance than mixed or female studies (male only: -0.69, -1.06 to -0.32; mixed and female studies: 0.10, -0.28 to 0.49). Exercise training did not increase MCAv (0.05, -0.21 to 0.31) but showed a small nonsignificant improvement in cerebrovascular reactivity (0.60, -0.08 to 1.28; P = 0.09). Exercise training showed heterogeneous effects on regional but little effect on global cerebral blood flow as measured by MRI. High CRF positively effects cerebrovascular function, including decreased cerebrovascular resistance and increased cerebrovascular reactivity; however, global cerebral blood flow and MCAv are primarily unchanged following an exercise intervention in healthy and clinical populations.NEW & NOTEWORTHY Higher cardiorespiratory fitness is associated with lower cerebrovascular resistance and elevated cerebrovascular reactivity at rest. Only adults with a true-high fitness based on normative data exhibited elevated middle cerebral artery velocity. The positive effect of higher compared with lower cardiorespiratory fitness on resting cerebrovascular resistance was more evident in male-only studies when compared with mixed or female-only studies. A period of exercise training resulted in negligible changes in middle cerebral artery velocity and global cerebral blood flow, with potential for improvements in cerebrovascular reactivity.

The effect of heat therapy on blood pressure and peripheral vascular function: A systematic review and meta-analysis.

NEW FINDINGS: What is the topic of this review? We have conducted a systematic review and meta-analysis on the current evidence for the effect of heat therapy on blood pressure and vascular function. What advances does it highlight? We found that heat therapy reduced mean arterial, systolic and diastolic blood pressure. We also observed that heat therapy improved vascular function, as assessed via brachial artery flow-mediated dilatation. Our results suggest that heat therapy is a promising therapeutic tool that should be optimized further, via mode and dose, for the prevention and treatment of cardiovascular disease risk factors. ABSTRACT: Lifelong sauna exposure is associated with reduced cardiovascular disease risk. Recent studies have investigated the effect of heat therapy on markers of cardiovascular health. We aimed to conduct a systematic review with meta-analysis to determine the effects of heat therapy on blood pressure and indices of vascular function in healthy and clinical populations. Four databases were searched up to September 2020 for studies investigating heat therapy on outcomes including blood pressure and vascular function. Grading of Recommendations, Assessment, Development and Evaluations (GRADE) was used to assess the certainty of evidence. A total of 4522 titles were screened, and 15 studies were included. Healthy and clinical populations were included. Heat exposure was for 30-90 min, over 10-36 sessions. Compared with control conditions, heat therapy reduced mean arterial pressure [n = 4 studies; mean difference (MD): -5.86 mmHg, 95% confidence interval (CI): -8.63, -3.10; P < 0.0001], systolic blood pressure (n = 10; MD: -3.94 mmHg, 95% CI: -7.22, -0.67; P = 0.02) and diastolic blood pressure (n = 9; MD: -3.88 mmHg, 95% CI: -6.13, -1.63; P = 0.0007) and improved flow-mediated dilatation (n = 5; MD: 1.95%, 95% CI: 0.14, 3.76; P = 0.03). Resting heart rate was unchanged (n = 10; MD: -1.25 beats/min; 95% CI: -3.20, 0.70; P = 0.21). Early evidence also suggests benefits for arterial stiffness and cutaneous microvascular function. The certainty of evidence was moderate for the effect of heat therapy on systolic and diastolic blood pressure and heart rate and low for the effect of heat therapy on mean arterial pressure and flow-mediated dilatation. Heat therapy is an effective therapeutic tool to reduce blood pressure and improve macrovascular function. Future research should aim to optimize heat therapy, including the mode and dose, for the prevention and management of cardiovascular disease.

Association between physical activity and subjective memory decline triggered by the COVID-19 pandemic: Findings from the PAMPA cohort.

Implementation of social distancing reduced the incidence of coronavirus disease (COVID-19) cases. Nevertheless, this strategy has other undesirable effects such as physical inactivity and psychological distress, which are associated with cognitive impairment. We aimed to examine whether physical activity during social distancing restrictions could reduce the risk of subjective memory decline in adults. Participants (n=2321) completed the baseline assessment of PAMPA cohort (Prospective Study About Mental and Physical Health), a ambispective cohort study conducted in southern Brazil. An online-based, self-administered questionnaire assessed physical activity and self-rated memory in two different periods: before and during social distancing. Data collection was executed from June 22nd to July 23rd 2020. Adjusted Poisson regression models were performed and values reported in prevalence ratio (PR) with 95% confidence interval (CI). Participants presented with a mean age of 38.2 (95%CI: 37.5, 38.9) years. Most were women (76.6%), had at least a university degree (66.7%), and were overweight or obese (53.3%). Subjective memory decline was reported by 30.0% (95%CI: 27.7%, 32.4%) of respondents. Most individuals with subjective memory decline reported being physically inactive during the pandemic of COVID-19. Participants were less likely to experience subjective memory decline if they either became (PR: 0.56; 95%CI: 0.36, 0.89) or remained (PR: 0.68; 95%CI: 0.49, 0.93) physically active compared to inactive respondents. Physical activity participation during social distancing reduced the likelihood of subjective memory decline in adults. Physical activity should be highlighted as a potential alternative to reduce the burden of the COVID-19 pandemic on cognitive function and mental health.

Two-minute exercise testing is sufficient to estimate maximal cardiorespiratory fitness in people with epilepsy.

We aimed to examine the agreement between submaximal cardiopulmonary exercise testing (CPET) measures and peak oxygen consumption (VO2peak) in adults with epilepsy. Data from a randomized controlled trial with adults with epilepsy (N = 21) were analyzed. VO2peak was assessed using indirect calorimetry during a treadmill graded maximal CPET. Oxygen uptake efficiency slope (OUES) was calculated from the relationship between oxygen uptake and minute ventilation during the entire test (OUESpeak) and the first 2 (OUES2min), 3 (OUES3min), and 4 (OUES4min) minutes of the CPET. The strength of the association between measures was tested by Pearson correlation. Linear regression models were used to predict VO2peak based on OUES from the different testing durations. Agreement between measured and predicted maximal values was tested using intraclass correlation coefficient (ICC) and Bland-Altman plots. OUES2min, OUES3min, and OUES4min were highly associated with absolute (r = 0.84, r = 0.76, r = 0.75, respectively) and relative (r = 0.84, r = 0.78, r = 0.78, respectively) VO2peak. Agreement (ICC = 0.83) between CPET-measured and OUES-predicted VO2peak values was stronger with OUES2min than the other time-based OUES markers. Bland-Altman plot showed satisfactory agreement between predicted and measured CPET measures with the narrowest limits of agreement observed with the OUES2min. No potential bias was identified between these two measurements (p = 0.33). Changes in absolute (r = 0.77) and relative (r = 0.88) VO2peak were highly associated with the change in OUES2min. OUES2min can be used as a surrogate for maximal cardiorespiratory fitness in adults with epilepsy. Studies with larger samples size are encouraged to confirm our findings in a more heterogeneous population.

High-sodium diet does not worsen endothelial function in female patients with postural tachycardia syndrome.

PURPOSE: Postural tachycardia syndrome (POTS), a syndrome characterized by orthostatic symptoms and a heart rate increase of at least 30 beats per minute in the absence of hypotension upon standing, is often accompanied by increased sympathetic activity and low blood volume. A common non-pharmacologic recommendation for patients with POTS is a high-sodium (HS) diet with the goal of bolstering circulating blood volume. The objective of this study is to assess the effects of 6 days of a HS diet on endothelial function in POTS. METHODS: A total of 14 patients with POTS and 13 age-matched healthy controls, all females, were studied following 6 days on a low-sodium (LS) diet (10 mEq/day) and 6 days on a HS diet (300 mEq/day) in a crossover design. We measured endothelial function following reactive hyperemia in the brachial artery using flow-mediated dilation (FMD), leg blood flow (LBF) using strain gauge plethysmography in the calf, and reactive hyperemic index (RHI) in the microcirculation of the hand using pulsatile arterial tonometry. RESULTS: On the LS diet, FMD% did not differ between patients with POTS and the healthy controls although peak brachial artery diameter was lower for the patient group. RHI was higher for the patient group than for the controls, but there were no differences in post-ischemic LBF increase. On the HS diet, there were no between-group differences in FMD%, LBF increase, or RHI. CONCLUSION: In summary, a HS diet for 6 days did not induce endothelial dysfunction. This non-pharmacologic treatment used for patients with POTS does not negatively affect endothelial function when used for a sub-acute duration. TRIAL REGISTRATION: ClinicalTrials.gov NCT01550315; March 9, 2012.

Hybrid Perovskites with Larger Organic Cations Reveal Autocatalytic Degradation Kinetics and Increased Stability under Light.

Hybrid organic-inorganic perovskites have shown incredible promise as active materials for photovoltaic devices, but their instability to light remains a significant roadblock in realizing these applications. Changing the organic cation has been shown to affect light-induced degradation. As a strategy for increasing the stability of these materials, we replaced varying percentages of methylammonium ion in the archetypical methylammonium lead iodide (MAPbI3) hybrid organic-inorganic perovskite with three significantly larger organic ammonium cations: imidazolium, dimethylammonium, and guanidinium. We were able to synthesize hybrid organic-inorganic perovskites with the same 3D perovskite structure as MAPbI3 with substitution of the larger ions as high as 20-30%. These substituted hybrid organic-inorganic perovskites retained similar optoelectronic properties. We discovered that the light-induced degradation in MAPbI3 and its substituted derivatives is autocatalytic, and we calculated rate coefficients for the degradation. All of the substituted hybrid organic-inorganic perovskites showed light-induced degradation slower than that of MAPbI3, up to a 62% decrease in degradation rate coefficient, at all substitution percentages up to 20%. This work provides evidence that a high percentage of a variety of large ammonium cations can be substituted into the hybrid organic-inorganic perovskite lattice without compromising its desirable optoelectronic properties. Insight into the autocatalytic mechanism of light-induced degradation will be valuable for designing additional strategies to improve the stability of hybrid organic-inorganic perovskites. We also offer insights into how factors other than size, such as hydrogen bonding, influence the stability of the materials. Overall, we have shown that substitution of methylammonium ion for the much larger imidazolium, dimethylammonium, and guanidinium cations in MAPbI3 is a valid strategy for creating stable hybrid organic-inorganic perovskite derivatives by slowing the rate of light-induced degradation.

The use of ion-selective membranes to study cation transport in hybrid organic-inorganic perovskites.

Using a methylammonium selective membrane in conjunction with electrochemical impedance spectroscopy, we measured ion migration in methylammonium lead triiodide (MAPbI3) with a millisecond (ms) time constant under illumination. These values were consistent with the reported values of ionic conduction in thin-film perovskite solar cells. We monitored an electrochemical impedance response arising from ionic conductivity through MAPbI3 and a methylammonium selective layer. We could fit this complex impedance response to an intuitive circuit model, which revealed an ionic species moving on a ms time scale. Electrospray ionization mass spectrometry (ESI-MS) revealed direct chemical evidence of methylammonium diffusion into the ion-selective layer. We found no experimental evidence indicating the mobility of lead ions or protons, suggesting that the mobile species observed under illumination is likely methylammonium.

Correction: The use of ion-selective membranes to study cation transport in hybrid organic-inorganic perovskites.

Correction for 'The use of ion-selective membranes to study cation transport in hybrid organic-inorganic perovskites' by Emily C. Smith et al., Phys. Chem. Chem. Phys., 2019, 21, 20720-20726.

Therapeutic vaccination expands and improves the function of the HIV-specific memory T-cell repertoire.

BACKGROUND: The licensing of herpes zoster vaccine has demonstrated that therapeutic vaccination can help control chronic viral infection. Unfortunately, human trials of immunodeficiency virus (HIV) vaccine have shown only marginal efficacy. METHODS: In this double-blind study, 17 HIV-infected individuals with viral loads of <50 copies/mL and CD4(+) T-cell counts of >350 cells/µL were randomly assigned to the vaccine or placebo arm. Vaccine recipients received 3 intramuscular injections of HIV DNA (4 mg) coding for clade B Gag, Pol, and Nef and clade A, B, and C Env, followed by a replication-deficient adenovirus type 5 boost (10(10) particle units) encoding all DNA vaccine antigens except Nef. Humoral, total T-cell, and CD8(+) cytotoxic T-lymphocyte (CTL) responses were studied before and after vaccination. Single-copy viral loads and frequencies of latently infected CD4(+) T cells were determined. RESULTS: Vaccination was safe and well tolerated. Significantly stronger HIV-specific T-cell responses against Gag, Pol, and Env, with increased polyfunctionality and a broadened epitope-specific CTL repertoire, were observed after vaccination. No changes in single-copy viral load or the frequency of latent infection were observed. CONCLUSIONS: Vaccination of individuals with existing HIV-specific immunity improved the magnitude, breadth, and polyfunctionality of HIV-specific memory T-cell responses but did not impact markers of viral control. CLINICAL TRIALS REGISTRATION: NCT00270465.

Acute Sympathetic Blockade Improves Insulin-Mediated Microvascular Blood Flow in the Forearm of Adult Human Subjects With Obesity.

BACKGROUND: Obesity is associated with resistance to the metabolic (glucose uptake) and vascular (nitric-oxide mediated dilation and microvascular recruitment) actions of insulin. These vascular effects contribute to insulin sensitivity by increasing tissue delivery of glucose. Studies by us and others suggest that sympathetic activation contributes to insulin resistance to glucose uptake. Here we tested the hypothesis that sympathetic activation contributes to impaired insulin-mediated vasodilation in adult subjects with obesity. METHODS AND RESULTS: In a randomized crossover study, we used a euglycemic hyperinsulinemic clamp in 12 subjects with obesity to induce forearm arterial vasodilation (forearm blood flow) and microvascular recruitment (contrast-enhanced ultrasonography) during an intrabrachial infusion of saline (control) or phentolamine (sympathetic blockade). Insulin increased forearm blood flow on both study days (from 2.21±1.22 to 4.89±4.21 mL/100 mL per min, P=0.003 and from 2.42±0.89 to 7.19±3.35 mL/100 mL per min, P=0.002 for the intact and blocked day, respectively). Sympathetic blockade with phentolamine resulted in a significantly greater increase in microvascular flow velocity (∆microvascular flow velocity: 0.23±0.65 versus 2.51±3.01 arbitrary intensity units (AIU/s) for saline and phentolamine respectively, P=0.005), microvascular blood volume (∆microvascular blood volume: 1.69±2.45 versus 3.76±2.93 AIU, respectively, P=0.05), and microvascular blood flow (∆microvascular blood flow: 0.28±0.653 versus 2.51±3.01 AIU2/s, respectively, P=0.0161). To evaluate if this effect was not due to nonspecific vasodilation, we replicated the study in 6 subjects with obesity comparing intrabrachial infusion of phentolamine to sodium nitroprusside. At doses that produced similar increases in forearm blood flow, insulin-induced changes in microvascular flow velocity were greater during phentolamine than sodium nitroprusside (%microvascular flow velocity=58% versus 29%, respectively, P=0.031). CONCLUSIONS: We conclude that sympathetic activation impairs insulin-mediated microvascular recruitment in adult subjects with obesity.

Peripheral Lipid Signatures, Metabolic Dysfunction, and Pathophysiology in Schizophrenia Spectrum Disorders.

Metabolic dysfunction is commonly observed in schizophrenia spectrum disorders (SSDs). The causes of metabolic comorbidity in SSDs are complex and include intrinsic or biological factors linked to the disorder, which are compounded by antipsychotic (AP) medications. The exact mechanisms underlying SSD pathophysiology and AP-induced metabolic dysfunction are unknown, but dysregulated lipid metabolism may play a role. Lipidomics, which detects lipid metabolites in a biological sample, represents an analytical tool to examine lipid metabolism. This systematic review aims to determine peripheral lipid signatures that are dysregulated among individuals with SSDs (1) with minimal exposure to APs and (2) during AP treatment. To accomplish this goal, we searched MEDLINE, Embase, and PsychINFO databases in February 2024 to identify all full-text articles written in English where the authors conducted lipidomics in SSDs. Lipid signatures reported to significantly differ in SSDs compared to controls or in relation to AP treatment and the direction of dysregulation were extracted as outcomes. We identified 46 studies that met our inclusion criteria. Most of the lipid metabolites that significantly differed in minimally AP-treated patients vs. controls comprised glycerophospholipids, which were mostly downregulated. In the AP-treated group vs. controls, the significantly different metabolites were primarily fatty acyls, which were dysregulated in conflicting directions between studies. In the pre-to-post AP-treated patients, the most impacted metabolites were glycerophospholipids and fatty acyls, which were found to be primarily upregulated and conflicting, respectively. These lipid metabolites may contribute to SSD pathophysiology and metabolic dysfunction through various mechanisms, including the modulation of inflammation, cellular membrane permeability, and metabolic signaling pathways.

Hepatic artery infusion pump (HAIP) therapy in combination with targeted delivery of IL-12 for patients with metastatic colorectal cancer or intrahepatic cholangiocarcinoma: a phase II trial protocol.

Background: Treatment of advanced liver tumors remains challenging. Although immune checkpoint inhibition has revolutionized treatment for many cancers, responses in colorectal liver metastases and biliary tract cancers remain suboptimal. Investigation into additional immunomodulatory therapies for these cancers is needed. Interleukin-12 (IL-12) is a pro-inflammatory cytokine with robust anti-tumor activity, but systemic adverse effects largely terminated therapeutic development of recombinant human IL-12 (rhIL-12). PDS01ADC is a novel human monoclonal antibody (NHS76) conjugated to two IL-12 heterodimers with established safety in phase I trials. The NHS76 antibody specifically targets histone/DNA complexes which are accessible only in regions of cell death and this antibody has been shown to accumulate locally in tumors. Methods: Patients with unresectable metastatic colorectal cancer (mCRC) or unresectable intrahepatic cholangiocarcinoma (ICC) will receive synchronization of subcutaneous PDS01ADC with floxuridine delivered via a hepatic artery infusion pump (HAIP). The primary outcome measured in this study will be overall response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. Secondary outcomes measured in this study will include hepatic and non-hepatic progression-free survival (PFS), overall survival, and safety of PDS01ADC combination therapy with HAIP. Discussion: Poor clinical response of these liver tumors to immunotherapy is likely due to various factors, including poor immune infiltrate into the tumor and immunosuppression by the tumor microenvironment. By exploiting the tumor cell death induced by HAIP locoregional therapy in combination with systemic chemotherapy, PDS01ADC is poised to modulate the tumor immune microenvironment to improve outcomes for patients undergoing HAIP therapy. Trial Registration: ClinicalTrials.gov (ID NCT05286814 version 2023-10-18); https://clinicaltrials.gov/study/NCT05286814?term=NCT05286814&rank=1.

High-velocity resistance training improves executive function in mobility-limited older adults.

OBJECTIVES: To examine the effect of high-velocity resistance training (HVRT) on the executive function of middle-aged and older adults with and without mobility limitations. METHODS: Participants (n = 41, female: 48.9%) completed a supervised 12-week HVRT intervention (2 sessions/week; at 40-60% of one-repetition maximum). The sample included 17 middle-aged adults (40-55 years); 16 older adults (>60 years) and 8 mobility-limited older adults (LIM). Executive function was assessed before and after the intervention period and was reported as z-scores. Maximal dynamic strength, peak power, quadriceps muscle thickness, maximal isometric voluntary contraction (MVIC), and functional performance were also measured pre and post intervention. Training-related adaptations in cognitive measures were calculated using a Generalized Estimating Equation model. RESULTS: HVRT improved executive function in LIM (adjusted marginal mean differences [AMMD]: 0.21; 95%CI: 0.04, 0.38; p = 0.040) although no effect on middle-aged (AMMD: 0.04; 95%CI: -0.09; 0.17; p = 0.533) and older (AMMD: -0.11; 95%CI: -0.25; 0.02; p = 0.107) participants was observed. Improvements in maximal dynamic strength, peak power, MVIC, quadriceps muscle thickness, and functional performance were all associated with changes in executive function, and changes in the first four also seem to mediate the association between changes in functional performance and executive function. CONCLUSIONS: HVRT-induced improvement in executive function of mobility-limited older adults were mediated by changes in lower-body muscle strength, power, and muscle thickness. Our findings reinforce the relevance of muscle-strengthening exercises to preserve cognition and mobility in older adults.

Continuous Positive Airway Pressure for the Treatment of Supine Hypertension and Orthostatic Hypotension in Autonomic Failure.

BACKGROUND: Supine hypertension affects most patients with orthostatic hypotension (OH) due to autonomic failure, but it is often untreated for fear of worsening OH. We hypothesized that increasing intrathoracic pressure with continuous positive airway pressure (CPAP) had a Valsalva-like blood-pressure-lowering effect that could be used to treat nocturnal supine hypertension in these patients, while reducing nocturnal pressure diuresis and improving daytime OH. METHODS: In Protocol 1, we determined the acute hemodynamic effects of increasing levels of CPAP (0, 4, 8, 12, and 16 cm H2O, 3 minutes each) in 26 patients with autonomic failure and supine hypertension studied while awake and supine. In Protocol 2 (n=11), we compared the effects of overnight therapy with CPAP (8-12 cm H2O for 8 hours) versus placebo on nocturnal supine hypertension, nocturnal diuresis and daytime OH in a 2-night crossover study. RESULTS: In Protocol 1, acute CPAP (4-16 cm H2O) decreased systolic blood pressure in a dose-dependent manner (maximal drop 22±4 mmHg with CPAP 16) due to reductions in stroke volume (-16+3%) and cardiac output (-14±3%). Systemic vascular resistance and heart rate remained unchanged. In Protocol 2, overnight CPAP lowered nighttime systolic blood pressure (maximal change -23±5 versus placebo -1±7 mmHg; P=0.023) and was associated with lower nighttime diuresis (609±84 versus placebo 1004±160 mL; P=0.004) and improved morning orthostatic tolerance (AUC upright SBP 642±121 versus placebo 410±109 mmHg*min; P=0.014). CONCLUSIONS: CPAP is a novel nonpharmacologic approach to treat the supine hypertension of autonomic failure while improving nocturia and daytime OH. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03312556.

The Safety and Efficacy of Mandibular Distraction Osteogenesis Among Infants Less Than 3 kg.

OBJECTIVES/HYPOTHESIS: Mandibular distraction osteogenesis (MDO) is a safe and effective surgery to address respiratory and feeding issues due to micrognathia in patients with Robin Sequence (RS). Previous studies examining postoperative complications in neonates receiving MDO have considered 4 kg as the cut-off for low weight; however, an increasing number of MDO interventions are performed in infants <4 kg. To determine if a weight <3 kg at time of MDO is a risk factor for postoperative complications or need for subsequent tracheostomy or gastrostomy tube (G-tube). STUDY DESIGN: Retrospective chart review. METHODS: A retrospective review of all infants <6 months of age undergoing MDO at two tertiary pediatric hospitals from 2008 to 2018. Demographic data, syndromic status, weight, and age at time of surgery, length of postoperative hospital stay, and postoperative outcomes were recorded including tracheostomy placement, G-tube placement, hardware infection, reintubation, facial/marginal mandibular nerve damage, and need for revision MDO. RESULTS: Sixty-nine patients with RS were included. The mean age at MDO was 25 ± 20 days and mean weight was 3.32 ± 0.44 kg. There was no statistically significant correlation between weight (P = .699) or age (P = .422) and unfavorable postoperative outcomes. No patients (0%) underwent tracheostomy pre-MDO. Two patients (2.9%) required tracheostomy postsurgery; neither was <3 kg. Eight patients (11.6%) required a G-tube postoperatively. CONCLUSION: Newborns <3 kg who undergo MDO experience the same rates of success and complication as larger infants, suggesting that MDO is a safe and efficacious procedure in infants less than 3 kg. Laryngoscope, 132:1295-1299, 2022.

Study protocol for the BRAIN Training Trial: a randomised controlled trial of Balance, Resistance, And INterval training on cognitive function in older adults with mild cognitive impairment.

INTRODUCTION: Epidemiological evidence suggests that both poor cardiovascular fitness and low muscle mass or strength markedly increase the rate of cognitive decline and incident dementia in older adults. Results from exercise trials for the improvement of cognition in older adults with mild cognitive impairment (MCI) have reported mixed results. This is possibly due to insufficient exercise intensities. The aim of the Balance, Resistance, And INterval (BRAIN) Training Trial is to determine the effects of two forms of exercise, high-intensity aerobic interval training (HIIT) and high-intensity power training (POWER) each compared with a sham exercise control group on cognition in older adults with MCI. METHODS AND ANALYSIS: One hundred and sixty community-dwelling older (≥ 60 years) people with MCI have been randomised into the trial. Interventions are delivered supervised 2-3 days per week for 12 months. The primary outcome measured at baseline, 6 and 12 months is performance on a cognitive composite score measuring the executive domain calculated from a combination of computerised (NeuroTrax) and paper-and-pencil tests. Analyses will be performed via repeated measures linear mixed models and generalised linear mixed models of baseline, 6-month and 12-month time points, adjusted for baseline values and covariates selected a priori. Mixed models will be constructed to determine the interaction of GROUP × TIME. ETHICS AND DISSEMINATION: Ethical approval was obtained from the University of Sydney (HREC Ref.2017/368), University of Queensland (HREC Ref. 2017/HE000853), University of British Columbia (H16-03309), and Vancouver Coastal Health Research Institute (V16-03309) Human Research Ethics. Dissemination will be via publications, conference presentations, newsletter articles, social media, talks to clinicians and consumers and meetings with health departments/managers.It is expected that communication of results will allow for the development of more effective evidence-based exercise prescription guidelines in this population while investigating the benefits of HIIT and POWER on subclinical markers of disease. TRIAL REGISTRATION NUMBER: ACTRN12617001440314 Australian New Zealand Clinical Trials Registry.

Physical activity attenuates the risk for dementia associated with aging in older adults with mild cognitive impairment. Findings from a population-based cohort study.

From 2016 to 2040 the number of people with dementia in the United Kingdom is expected to increase by 57%, while 70% percent of it is due to a higher life expectancy. Thus, we analyzed the overall and age-stratified effect of physical activity on risk of dementia in participants with mild cognitive impairment (MCI) of the English Longitudinal Study of Ageing (ELSA). Participants of the ELSA, aged over 50 with MCI, were followed-up nine times between 2002 and 2019. Physical activity was assessed using a self-reported, validated questionnaire and participants were classified as inactive, low, or moderate-to-high active. Medical diagnosis of dementia was self-reported or determined using the Informant Questionnaire on Cognitive Decline in the Elderly. Data from 521 participants with MCI were analyzed (56% women; mean [SD] age, 68.7 [10.6]). Over 17-year follow-up, 20.5 (95%CI: 17.3 to 24.2)% were diagnosed with dementia. The risk of incident dementia was reduced in participants engaging in low (HR: 0.34; 95%CI: 0.22 to 0.54) or moderate-to-high (HR: 0.16; 95%CI: 0.08 to 0.33) levels of physical activity. Risk of dementia in adults aged 80 or more engaging in low or moderate-to-high levels of physical activity was not different from inactive adults aged between 50 and 69 years. Results were sustained after competing risk regression model and sensitivity analyses to reduce the impact of reverse causality. Physical activity appears to minimize the risk associated with aging in older adults with MCI.