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Purpose Oral delivery of therapeutic peptides has been challenging due to multiple physiological factors and physicochemical properties of peptides. We report a systematic approach to identify formulation compositions combining a permeation enhancer and a peptidase inhibitor that minimize proteolytic degradation and increase absorption of a peptide across the small intestine. Methods An acylated glucagon-like peptide-1/glucagon co-agonist peptide (4.5 kDa) was selected as a model peptide. Proteolytic stability of the peptide was investigated in rat and pig SIF. Effective PEs and multiple component formulations were identified in rats. Relative bioavailability of the peptide was determined in minipigs via intraduodenal administration (ID) of enteric capsules. Results The peptide degraded rapidly in the rat and pig SIF. Citric acid, SBTI, and SBTCI inhibited the enzymatic degradation. The peptide self-associated into trimers in solution, however, addition of PEs monomerized the peptide. C10 was the most effective PE among tested PEs (DPC, LC, rhamnolipid, C12-maltosides, and SNAC) to improve intestinal absorption of the peptide in the rat IJ-closed loop model. A combination of C10 and SBTI or SBTCI increased the peptide exposure 5–tenfold compared to the exposure with the PE alone in the rat IJ-cannulated model, and achieved 1.06 ± 0.76% bioavailability in minipigs relative to subcutaneous via ID administration using enteric capsules. Conclusion We identified SBTI and C10 as an effective peptidase inhibitor and PE for intestinal absorption of the peptide. The combination of SBTI and C10 addressed the peptide physiochemical properties and provides a formulation strategy to achieve intestinal delivery of this peptide.

Objective: Ultra-rapid insulin formulations control postprandial hyperglycemia; however, inadequate understanding of injection site absorption mechanisms is limiting further advancement. We used photoacoustic imaging to investigate the injection site dynamics of dye-labeled insulin lispro in the Humalog and Lyumjev formulations using the murine ear cutaneous model and correlated it with results from unlabeled insulin lispro in pig subcutaneous injection model. Methods: We employed dual-wavelength optical-resolution photoacoustic microscopy to study the absorption and diffusion of the near-infrared dye-labeled insulin lispro in the Humalog and Lyumjev formulations in mouse ears. We mathematically modeled the experimental data to calculate the absorption rate constants and diffusion coefficients. We studied the pharmacokinetics of the unlabeled insulin lispro in both the Humalog and Lyumjev formulations as well as a formulation lacking both the zinc and phenolic preservative in pigs. The association state of insulin lispro in each of the formulations was characterized using SV-AUC and NMR spectroscopy. Results: Through experiments using murine and swine models, we show that the hexamer dissociation rate of insulin lispro is not the absorption rate-limiting step. We demonstrated that the excipients in the Lyumjev formulation produce local tissue expansion and speed both insulin diffusion and microvascular absorption. We also show that the diffusion of insulin lispro at the injection site drives its initial absorption; however, the rate at which the insulin lispro crosses the blood vessels is its overall absorption rate-limiting step. Conclusions: This study provides insights into injection site dynamics of insulin lispro and the impact of formulation excipients. It also demonstrates photoacoustic microscopy as a promising tool for studying protein therapeutics. The results from this study address critical questions around the subcutaneous behavior of insulin lispro and the formulation excipients, which could be useful to make faster and better controlled insulin formulations in the future. Competing Interest Statement A.K., R.C., and J.S. declare no competing interests. C.D.P., F.A.V, A.E.S., A.M.C., P.L.B.A., E.L., R.L.B, R.M., S.A.B., J.M.B, and S.O. are employees and stockholders of Eli Lilly and Company. L.V.W. and K.M. have financial interests in Microphotoacoustics, Inc., CalPACT, LLC and Union Photoacoustic Technologies, Ltd, which did not support this work.

The hallmark of bipolar disorder is hypomania or mania, and the predominant phase of illness is depression. Affecting approximately 40 million individuals worldwide, bipolar disorder is associated with a substantial psychosocial, medical, and financial burden and increased mortality from suicide and other causes. Diagnosis can be challenging due to symptom overlap with attention-deficit hyperactivity disorder, major depressive disorder, psychotic spectrum disorders, and personality disorders, which often leads to a delay in diagnosis. Recent advancements in understanding disease risk and pathophysiology have identified multigene risk and possible infectious and mitochondrial causes. Treatment approaches include pharmacotherapy, psychotherapy, and lifestyle modifications, which should always be patient-centred and aligned with individual goals and priorities. Future directions for bipolar disorder care include increasing the availability of psychosocial interventions aimed at self-management, addressing treatment-resistant bipolar depression, deepening the understanding of pathophysiology, and exploring novel interventions, such as ketamine, esketamine, other rapid-acting antidepressants, and various neuromodulation approaches.

Analysis of data from forest plants worldwide shows that margins between threshold xylem pressures at which plants suffer damage and the lowest xylem pressures experienced are small, with no difference between dry and wet forests, providing insight into why drought-induced forest decline is occurring in both arid and wet forests. Forests facing threat of drought Forest dieback resulting from extreme drought events has the potential to cause widespread loss of biodiversity, with a major impact on the global carbon balance. Plants undergoing drought stress experience reduced xylem pressure, and each species can tolerate a different degree of reduction before xylem damage and, eventually, hydraulic failure occur. This study looks at the safety margin between minimum experienced xylem pressure and the damage threshold for 226 forest species from 81 sites worldwide and shows that most species across both dry and wet biomes have small safety margins against injurious levels of drought stress. These plants are potentially vulnerable to the combination of rising temperatures and declining rainfall that is predicted to cause droughts of increasing intensity and duration in the near future. Shifts in rainfall patterns and increasing temperatures associated with climate change are likely to cause widespread forest decline in regions where droughts are predicted to increase in duration and severity 1 . One primary cause of productivity loss and plant mortality during drought is hydraulic failure 2 , 3 , 4 . Drought stress creates trapped gas emboli in the water transport system, which reduces the ability of plants to supply water to leaves for photosynthetic gas exchange and can ultimately result in desiccation and mortality. At present we lack a clear picture of how thresholds to hydraulic failure vary across a broad range of species and environments, despite many individual experiments. Here we draw together published and unpublished data on the vulnerability of the transport system to drought-induced embolism for a large number of woody species, with a view to examining the likely consequences of climate change for forest biomes. We show that 70% of 226 forest species from 81 sites worldwide operate with narrow (<1 megapascal) hydraulic safety margins against injurious levels of drought stress and therefore potentially face long-term reductions in productivity and survival if temperature and aridity increase as predicted for many regions across the globe 5 , 6 . Safety margins are largely independent of mean annual precipitation, showing that there is global convergence in the vulnerability of forests to drought, with all forest biomes equally vulnerable to hydraulic failure regardless of their current rainfall environment. These findings provide insight into why drought-induced forest decline is occurring not only in arid regions but also in wet forests not normally considered at drought risk 7 , 8 .

Veterans who identify as lesbian, gay, bisexual, transgender, queer, questioning, and related identities (LGBTQ+) have faced discrimination that puts them at increased risk for depression, anxiety, and suicide. Upstream interventions like the PRIDE in All Who Served program can improve internalized prejudice, suicidality, symptoms of depression, and symptoms of anxiety by addressing minority stress, facilitating social connection, and promoting engagement with the healthcare system. Yet, little is known about who benefits most from these types of services. Sixty-six US military veterans (Mean age = 47.06, SD = 13.74) provided outcome surveys before and after a 10-week health promotion group for LGBTQ+ individuals at one of 10 Veterans Health Administration (VA) Medical Centers. Subscales of a coping self-efficacy measure (e.g., problem-solving, social support, thought-stopping), and demographic factors were examined as moderators of treatment outcomes. Coping self-efficacy moderated effects across treatment outcomes with those lower in coping self-efficacy beliefs reporting the greatest benefit of the intervention. Reduction in anxiety symptoms was moderated only by problem-solving coping self-efficacy, while suicidality was moderated only by social support. Reduction of internalized prejudice and depression symptoms were moderated by both problem-solving and social support coping self-efficacy, while thought-stopping (a frequent target of traditional cognitive therapies) only moderated internalized prejudice, but not clinical symptom indicators. Most demographic factors (e.g., age, race, gender) did not impact treatment outcomes; however, sexual orientation was significant such that those who identified as bisexual, queer, or something else (e.g., pansexual) had greater reductions in internalized prejudice than their single gender-attracted peers. Individual differences like coping self-efficacy and sexual orientation are rarely considered in clinical care settings when shaping policy or implementing tailored programs. Understanding implications for who is most likely to improve could inform program refinement and implementation of affirming interventions for minoritized people.

Purpose of Review Cardiovascular disease (CVD) is the leading cause of death among women in the USA, accounting for one of every three deaths. Physical activity (PA) has been shown to have numerous beneficial effects for CVD risk reduction in women. Nonetheless, much of the previous research on the impact of PA on CVD risk factors has been measured using self-report questionnaires. The purpose of this review was to summarize the main findings for the association between objectively measured PA and PA interventions on traditional and nontraditional CVD risk factors from randomized controlled trials (RCT), cohort, and cross-sectional studies published in or after 2011. Traditional risk factors included hypertension, lipids, diabetes mellitus, and obesity whereas nontraditional risk factors included hypertension during pregnancy, gestational diabetes mellitus (GDM), polycystic ovary syndrome (PCOS), and depression. Recent Findings Shifting from traditional CVD risk factors to nontraditional, researchers have been assessing objective PA and PA interventions on pregnancy-related CVD risk factors. A recent meta-analysis and RCT found that exercise during pregnancy reduces the risk of GDM compared to standard maternity care. Recent intervention studies show the beneficial effects of strength training and high-intensity interval training on insulin resistance in women with PCOS. Summary More research looking at PA interventions with objectively measured compliance to PA (actual number of minutes, intensity, etc.) and observational studies using objective measures for PA (accelerometers, pedometers, etc.) are necessary at this time due to the difficulty of measuring light PA and the overestimation of MVPA through self-report.

IntroductionGiven the increasing prevalence of both obesity and pre-diabetes in pregnant adults, there is growing interest in identifying hyperglycaemia in early pregnancy to optimise maternal and perinatal outcomes. Multiple organisations recommend first-trimester diabetes screening for individuals with risk factors; however, the benefits and drawbacks of detecting glucose abnormalities more mild than overt diabetes in early gestation and the best screening method to detect such abnormalities remain unclear.Methods and analysisThe goal of the Glycemic Observation and Metabolic Outcomes in Mothers and Offspring study (GO MOMs) is to evaluate how early pregnancy glycaemia, measured using continuous glucose monitoring and oral glucose tolerance testing, relates to the diagnosis of gestational diabetes (GDM) at 24–28 weeks’ gestation (maternal primary outcome) and large-for-gestational-age birth weight (newborn primary outcome). Secondary objectives include relating early pregnancy glycaemia to other adverse pregnancy outcomes and comprehensively detailing longitudinal changes in glucose over the course of pregnancy. GO MOMs enrolment began in April 2021 and will continue for 3.5 years with a target sample size of 2150 participants.Ethics and disseminationGO MOMs is centrally overseen by Vanderbilt University’s Institutional Review Board and an Observational Study Monitoring Board appointed by National Institute of Diabetes and Digestive and Kidney Diseases. GO MOMs has potential to yield data that will improve understanding of hyperglycaemia in pregnancy, elucidate better approaches for early pregnancy GDM screening, and inform future clinical trials of early GDM treatment.Trial registration numberNCT04860336.

Background Extremely preterm (EPT) birth has been related to dysregulation of stress responses and behavioral/learning problems at school age. Early adverse experiences can blunt HPA axis reactivity. We hypothesized that an attenuated cortisol awakening response would be associated with developmental and behavioral problems at school age in EPT children. Methods This secondary analysis of a sub-cohort of the SUPPORT study included children born between 24 and 27 weeks, evaluated at 6–7 years with a neurodevelopmental battery and cortisol measures. Differences were tested between EPT and a term-born group. Relationships of cortisol awakening response to test scores were analyzed. Results Cortisol was measured in 110 EPT and 29 term-born 6–7 year olds. Unadjusted WISC-IV and NEPSY-II scores were significantly worse among EPT children only. Conners Parent Rating Scale behavior scores were significantly worse among EPT children. After adjusting for covariates, blunted cortisol awakening responses were found to be associated with poorer scores on memory tests and greater problems with inattention for the EPT group ( p  < 0.05) only. Conclusions Among children born EPT, we identified an association of blunted cortisol awakening response with memory and inattention problems. This may have implications related to stress reactivity and its relationship to learning problems in children born EPT. ClinicalTrials.gov ID Extended Follow-up at School Age for the SUPPORT Neuroimaging and Neurodevelopmental Outcomes (NEURO) Cohort: NCT00233324. Impact In children born EPT, stress reactivity may have a relationship to learning problems. Cortisol awakening response should be a component for follow-up in EPT born children. Components of executive function, such as memory and attention, are related to stress reactivity.

We aimed to describe the preventability and provider specificity of surgical intensive care unit (SICU) deaths and complications compared with those in a cohort of trauma patients. Data were collected on all trauma and SICU admissions from July 1, 2001, to June 30, 2004, from administrative (Trauma Base and Project Impact) and morbidity databases. Services were protocol driven and staffed by in-house attendings. Performance improvement assessments were made by consensus. Deaths and complications were classified as preventable, potentially preventable, or nonpreventable, and provider-specific or not. Statistical significance was established at the P < .05 level. One hundred sixty-eight deaths (5.6% rate), 464 procedure-related, and 694 non–procedure-related complications were noted in 2969 SICU patients compared with 166 deaths (3.6% rate), 178 procedure-related, and 261 non–procedure-related complications in 4,655 trauma patients. Thirty-one percent of SICU deaths were preventable/potentially preventable compared with 14% of trauma deaths, but only 1.9% was attributable to the SICU provider. SICU complications were less frequently preventable/potentially preventable than in trauma patients (52% versus 61%) and less often provider-specific (5% versus 19%). SICU complications are deemed preventable less often than in trauma patients and, if so, infrequently incriminate the SICU provider. Preventable and potentially preventable SICU deaths are rarely attributed to SICU care. These data suggest that SICU performance improvement should focus on systems solutions and pre-SICU care.