Estimating the Distribution of True Rates of Visual Field Progression in Glaucoma.

Purpose: The purpose of this study was to estimate the distribution of the true rates of progression (RoP) of visual field (VF) loss. Methods: We analyzed the progression of mean deviation over time in series of ≥ 10 tests from 3352 eyes (one per patient) from 5 glaucoma clinics, using a novel Bayesian hierarchical Linear Mixed Model (LMM); this modeled the random-effect distribution of RoPs as the sum of 2 independent processes following, respectively, a negative exponential distribution (the "true" distribution of RoPs) and a Gaussian distribution (the "noise"), resulting in a skewed exGaussian distribution. The exGaussian-LMM was compared to a standard Gaussian-LMM using the Watanabe-Akaike Information Criterion (WAIC). The random-effect distributions were compared to the empirical cumulative distribution function (eCDF) of linear regression RoPs using a Kolmogorov-Smirnov test. Results: The WAIC indicated a better fit with the exGaussian-LMM (estimate [standard error]: 192174.4 [721.2]) than with the Gaussian-LMM (192595 [697.4], with a difference of 157.2 [22.6]). There was a significant difference between the eCDF and the Gaussian-LMM distribution (P < 0.0001), but not with the exGaussian-LMM distribution (P = 0.108). The estimated mean (95% credible intervals, CIs) "true" RoP (-0.377, 95% CI = -0.396 to -0.359 dB/year) was more negative than the observed mean RoP (-0.283, 95% CI = -0.299 to -0.268 dB/year), indicating a bias likely due to learning in standard LMMs. Conclusions: The distribution of "true" RoPs can be estimated with an exGaussian-LMM, improving model accuracy. Translational Relevance: We used these results to develop a fast and accurate analytical approximation for sample-size calculations in clinical trials using standard LMMs, which was integrated in a freely available web application.

Trial of Early Minimally Invasive Removal of Intracerebral Hemorrhage.

BACKGROUND: Trials of surgical evacuation of supratentorial intracerebral hemorrhages have generally shown no functional benefit. Whether early minimally invasive surgical removal would result in better outcomes than medical management is not known. METHODS: In this multicenter, randomized trial involving patients with an acute intracerebral hemorrhage, we assessed surgical removal of the hematoma as compared with medical management. Patients who had a lobar or anterior basal ganglia hemorrhage with a hematoma volume of 30 to 80 ml were assigned, in a 1:1 ratio, within 24 hours after the time that they were last known to be well, to minimally invasive surgical removal of the hematoma plus guideline-based medical management (surgery group) or to guideline-based medical management alone (control group). The primary efficacy end point was the mean score on the utility-weighted modified Rankin scale (range, 0 to 1, with higher scores indicating better outcomes, according to patients' assessment) at 180 days, with a prespecified threshold for posterior probability of superiority of 0.975 or higher. The trial included rules for adaptation of enrollment criteria on the basis of hemorrhage location. A primary safety end point was death within 30 days after enrollment. RESULTS: A total of 300 patients were enrolled, of whom 30.7% had anterior basal ganglia hemorrhages and 69.3% had lobar hemorrhages. After 175 patients had been enrolled, an adaptation rule was triggered, and only persons with lobar hemorrhages were enrolled. The mean score on the utility-weighted modified Rankin scale at 180 days was 0.458 in the surgery group and 0.374 in the control group (difference, 0.084; 95% Bayesian credible interval, 0.005 to 0.163; posterior probability of superiority of surgery, 0.981). The mean between-group difference was 0.127 (95% Bayesian credible interval, 0.035 to 0.219) among patients with lobar hemorrhages and -0.013 (95% Bayesian credible interval, -0.147 to 0.116) among those with anterior basal ganglia hemorrhages. The percentage of patients who had died by 30 days was 9.3% in the surgery group and 18.0% in the control group. Five patients (3.3%) in the surgery group had postoperative rebleeding and neurologic deterioration. CONCLUSIONS: Among patients in whom surgery could be performed within 24 hours after an acute intracerebral hemorrhage, minimally invasive hematoma evacuation resulted in better functional outcomes at 180 days than those with guideline-based medical management. The effect of surgery appeared to be attributable to intervention for lobar hemorrhages. (Funded by Nico; ENRICH ClinicalTrials.gov number, NCT02880878.).

Developing a core outcome set for evaluating medication adherence interventions for adults prescribed long-term medication in primary care.

BACKGROUND: Approximately half of people prescribed medications do not take them as prescribed. There is a significant unmet need regarding the barriers to medication adherence not being addressed in primary care. There is no agreement on which outcomes should be measured and reported in trials of medication adherence interventions. OBJECTIVE: To develop a core outcome set (COS) for trials of medication adherence interventions in primary care for adults prescribed medications for long-term health conditions. METHODS: A list of potentially relevant outcomes from the literature was developed. Using a two-round Delphi survey of stakeholder groups representing patients and their carers; primary care staff; and academic researchers with an interest in medication adherence; each outcome was scored in terms of importance for determining the effectiveness of medication adherence interventions in primary care. This was followed by two consensus workshops, where importance, as well as feasibility and acceptability of measurement, were considered in order to finalise the COS. RESULTS: One hundred and fifty people took part in Delphi Round 1 and 101 took part in Round 2. Eight people attended the workshops (four attendees per workshop). Seven outcomes were identified as most important, feasible and acceptable to collect in medication adherence trials: Health-related quality of life, number of doses taken, persistence with medicines, starting (initiating) a medicine, relevance of the medication adherence intervention for an individual, mortality, and adverse medicine events. CONCLUSIONS: This COS represents the minimum outcomes that should be collected and reported in all medication adherence trials undertaken in primary care. When developing and finalizing the COS, feasibility and acceptability of collection of outcomes has been considered. In addition to the COS, medication adherence trials can choose to include outcomes to suit their specific context such as the health condition associated with their medication adherence intervention.

No increase in corticospinal excitability during motor simulation provides a platform to explore the neurophysiology of aphantasia.

This scientific commentary refers to 'Explicit and implicit motor simulations are impaired in individuals with aphantasia', by Dupont  et al. (https://doi.org/10.1093/braincomms/fcae072) in Brain Communications.

The Increasing Burden of Emergency Department and Inpatient Consultations for "Papilledema".

BACKGROUND: Increasing incidence of idiopathic intracranial hypertension (IIH), overreported radiologic signs of intracranial hypertension, difficult access to outpatient neuro-ophthalmology services, poor insurance coverage, and medicolegal concerns have lowered the threshold for emergency department (ED) visits for "papilledema." Our objective was to examine referral patterns and outcomes of neuro-ophthalmology ED and inpatient consultations for concern for papilledema. METHODS: At one university-based quaternary care center, all adults referred for "papilledema" over one year underwent a standardized ED "papilledema protocol." We collected patient demographics, final diagnoses, and referral patterns. RESULTS: Over 1 year, 153 consecutive patients were referred for concern for papilledema. After papilledema protocol, 89 of 153 patients (58%) had bilateral optic disc edema, among whom 89% (79/89) had papilledema (intracranial hypertension). Of the 38 of 153 (25%) consultations for suspected disorder of intracranial pressure without previous fundus examination (Group 1), 74% (28/38) did not have optic disc edema, 21% (8/38) had papilledema, and 5% (2/38) had other causes of bilateral disc edema. Of the 89 of 153 (58%) consultations for presumed papilledema seen on fundus examination (Group 2), 58% (66/89) had confirmed papilledema, 17% (15/89) had pseudopapilledema, and 9% (8/89) had other causes of bilateral optic disc edema. Of the 26 of 153 (17%) patients with known IIH (Group 3), 5 had papilledema and 4 required urgent intervention. The most common diagnosis was IIH (58/79). Compared with IIH, patients with secondary causes of intracranial hypertension were older (P = 0.002), men (P < 0.001), not obese (P < 0.001), and more likely to have neurologic symptoms (P = 0.002). CONCLUSION: Inpatient and ED consultations for "papilledema" are increasing. Of the 153 ED and inpatient neuro-ophthalmology consultations seen for "papilledema" over 1 year, one-third of patients with optic disc edema of unknown cause before presentation to our ED had new vision- or life-threatening disease, supporting the need for prompt identification and evaluation of optic disc edema in the ED. In the face of limited access to neuro-ophthalmologists, this study supports the need for emergency department access to expert eye-care evaluation or ocular fundus camera for prompt identification of optic disc edema and standardized evaluation for neurologic emergencies.

ComBating inter-site differences in field strength: harmonizing preclinical traumatic brain injury MRI data.

Integrating datasets from multiple sites and scanners can increase statistical power for neuroimaging studies but can also introduce significant inter-site confounds. We evaluated the effectiveness of ComBat, an empirical Bayes approach, to combine longitudinal preclinical MRI data acquired at 4.7 or 9.4 T at two different sites in Australia. Male Sprague Dawley rats underwent MRI on Days 2, 9, 28, and 150 following moderate/severe traumatic brain injury (TBI) or sham injury as part of Project 1 of the NIH/NINDS-funded Centre Without Walls EpiBioS4Rx project. Diffusion-weighted and multiple-gradient-echo images were acquired, and outcomes included QSM, FA, and ADC. Acute injury measures including apnea and self-righting reflex were consistent between sites. Mixed-effect analysis of ipsilateral and contralateral corpus callosum (CC) summary values revealed a significant effect of site on FA and ADC values, which was removed following ComBat harmonization. Bland-Altman plots for each metric showed reduced variability across sites following ComBat harmonization, including for QSM, despite appearing to be largely unaffected by inter-site differences and no effect of site observed. Following harmonization, the combined inter-site data revealed significant differences in the imaging metrics consistent with previously reported outcomes. TBI resulted in significantly reduced FA and increased susceptibility in the ipsilateral CC, and significantly reduced FA in the contralateral CC compared with sham-injured rats. Additionally, TBI rats also exhibited a reversal in ipsilateral CC ADC values over time with significantly reduced ADC at Day 9, followed by increased ADC 150 days after injury. Our findings demonstrate the need for harmonizing multi-site preclinical MRI data and show that this can be successfully achieved using ComBat while preserving phenotypical changes due to TBI.

Face-down positioning or posturing after pars plana vitrectomy for macula-involving rhegmatogenous retinal detachments.

BACKGROUND: A macula-involving rhegmatogenous retinal detachment (RRD) is one of the most common ophthalmic surgical emergencies and causes significant visual morbidity. Pars plana vitrectomy (PPV) with gas tamponade is often performed to repair primary macula-involving RRDs with a high rate of anatomical retinal reattachment. It has been advocated by some ophthalmologists that face-down positioning after PPV and gas tamponade helps reduce postoperative retinal displacement. Retinal displacement can cause metamorphopsia and binocular diplopia. OBJECTIVES: The primary objective of this review is to determine whether face-down positioning reduces the risk of retinal displacement following PPV and gas tamponade for primary macula-involving RRDs. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (which contains the Cochrane Eyes and Vision Trials Register) (2022, Issue 11), MEDLINE (January 1946 to 28 November 2022), Embase.com (January 1947 to 28 November 2022), PubMed (1948 to 28 November 2022), Latin American and Caribbean Health Sciences Literature database (1982 to 28 November 2022), ClinicalTrials.gov, and the World Health Organization International Clinical Trials Registry Platform. We did not use any date or language restrictions in the electronic search. We last searched the electronic databases on 28 November 2022. SELECTION CRITERIA: We included randomized controlled trials (RCTs) in which face-down positioning was compared with no positioning or another form of positioning following PPV and gas tamponade for primary macula-involving RRDs. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology and assessed the certainty of the body of evidence for the prespecified outcomes using the GRADE approach. MAIN RESULTS: We identified three RCTs (369 eyes of 368 participants) that met the eligibility criteria. Two RCTs provided data on postoperative retinal displacement, one reported on postoperative distortion and quality of life outcomes, two on postoperative best-corrected visual acuity (BCVA) in logMAR, and two on postoperative ocular adverse events such as outer retinal folds. Study characteristics and risk of bias All the trials involved predominantly male participants (range: 68% to 72%). Only one trial provided race and ethnicity information, was registered on a trial registry, and reported funding sources. Using the RoB 2 tool, we assessed the risk of bias for proportion of eyes with retinal displacement, mean change in visual acuity, objective distortion scores, quality of life assessments, and ocular adverse events, with most domains judged to be at low risk of bias. Findings Immediate face-down positioning may result in a lower proportion of participants with postoperative retinal displacement compared with support-the-break positioning at six months (risk ratio [RR] 0.73, 95% confidence interval [CI] 0.54 to 0.99; 1 RCT; 239 eyes of 239 participants; very low certainty evidence). One study found no evidence of a difference in BCVA at three months when comparing postoperative face-up with face-down positioning with or without perfluorocarbon liquid (mean difference [MD] -0.03, 95% CI -0.09 to 0.02; I2 = 0; 56 eyes of 56 participants; very low certainty evidence). Immediate face-down positioning appears to have little to no effect on postoperative distortion scores at week 26 (MD 1.80, 95% CI -1.92 to 5.52; 1 RCT; 219 eyes of 219 participants; very low certainty evidence) and postoperative quality of life assessment scores at week 26 (MD -1.80, 95% CI -5.52 to 1.92; 1 RCT; 217 eyes of 217 participants; very low certainty evidence). Adverse events One study that enrolled 262 participants with macula-involving RRDs suggested that immediate face-down positioning after PPV and gas tamponade may reduce the ocular adverse event of postoperative outer retinal folds at six months (RR 0.39, 95% CI 0.17 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) and binocular diplopia (RR 0.20, 95% CI 0.04 to 0.90; 1 RCT; 262 eyes of 262 participants; very low certainty evidence) compared with support-the-break positioning. Immediate face-down positioning may increase the ocular adverse event of elevated intraocular pressure compared with support-the-break positioning (RR 1.74, 95% CI 1.11 to 2.73; 1 RCT; 262 eyes of 262 participants; very low certainty evidence). Another study found no evidence of a difference in postoperative outer retinal folds when comparing face-down versus face-up positioning at one and three months (RR 1.00, 95% CI 0.50 to 2.02; RR 1.00, 95% CI 0.28 to 3.61; 1 RCT; 56 eyes of 56 participants; very low certainty evidence). No studies reported non-ocular adverse events. AUTHORS' CONCLUSIONS: Very low certainty evidence suggests that immediate face-down positioning after PPV and gas tamponade may result in a reduction in postoperative retinal displacement, outer retinal folds, and binocular diplopia, but may increase the chance of postoperative raised intraocular pressure compared with support-the-break positioning at six months. We identified two ongoing trials that compare face-down positioning with face-up positioning following PPV and gas tamponade in participants with primary macula-involving RRDs, whose results may provide relevant evidence for our stated objectives. Future trials should be rigorously designed, and investigators should analyze outcome data appropriately and report adequate information to provide evidence of high certainty. Quality of life and patient preferences should be examined in addition to clinical and adverse event outcomes.

Celebrating a decade of exercise physiology and metabolism research in physiological reports.

During its first decade of life, Physiological Reports has become a home for well-conceived and rigorously performed exercise physiology and metabolism studies. The breadth of research within this area is impressive, covering exercise-induced increases in skeletal muscle gene expression to the effects of exercise on the gut microbiome. The purpose of the current review is to highlight some of the impactful exercise physiology and metabolism papers published in the journal and to look ahead to what areas exercise physiology publications might address in the next 10 years.

Timing of transcranial direct current stimulation at M1 does not affect motor sequence learning.

Administering anodal transcranial direct current stimulation (tDCS) at the primary motor cortex (M1) at various temporal loci relative to motor training is reported to affect subsequent performance gains. Stimulation administered in conjunction with motor training appears to offer the most robust benefit that emerges during offline epochs. This conclusion is made, however, based on between-experiment comparisons that involved varied methodologies. The present experiment addressed this shortcoming by administering the same 15-minute dose of anodal tDCS at M1 before, during, or after practice of a serial reaction time task (SRTT). It was anticipated that exogenous stimulation during practice with a novel SRTT would facilitate offline gains. Ninety participants were randomly assigned to one of four groups: tDCS before practice, tDCS during practice, tDCS after practice, or no tDCS. Each participant was exposed to 15 min of 2 mA of tDCS and motor training of an eight-element SRTT. The anode was placed at the right M1 with the cathode at the left M1, and the left hand was used to execute the SRTT. Test blocks were administered 1 and 24 h after practice concluded. The results revealed significant offline gain for all conditions at the 1-hour and 24-hour test blocks. Importantly, exposure to anodal tDCS at M1 at any point before, during, or after motor training failed to change the trajectory of skill development as compared to the no-stimulation control condition. These data add to the growing body of evidence questioning the efficacy of a single bout of exogenous stimulation as an adjunct to motor training for fostering skill learning.

Taxonomy development for term standardization in activity resulting from medication review processes: a Delphi study.

BACKGROUND: Medication review (MR) is the systematic assessment of a patient's medications for safety and effectiveness by a healthcare professional. The language used to describe MR activity, such as stopped medicine and increased dose, should be consistent across studies to assist researchers compare how different services operate and identify their mechanism of impact. AIM: To develop an international taxonomy of standardized terms and activity definitions related to medication reviews. METHOD: This was a three-stage Delphi-based consensus study with international medication review experts. A systematic review provided MR activity terms for the survey. Experts rated their consensus on each activity term and its definition on a Likert scale and provided written feedback. The consensus was 75% panel agreement. At each stage, consensus elements were retained, and feedback was used to revise definitions. RESULTS: Seven experts were recruited for the study (response rate 15.2%) from four countries: the United Kingdom (n = 4), New Zealand (n = 1), Australia (n = 1), and Malaysia (n = 1). The following terms achieved consensus: the term Medication as a descriptor for MR terms; discontinue medication, start medication, dose increase, dose decrease, dosage form change, and medication safety and efficacy monitor to describe MR activity; Educate to describe the delivery of healthcare professionals and patients/carers education. CONCLUSION: Standardized medication review activity terms and definitions have been selected for universal adoption in all future MR research to facilitate a meaningful comparison of process evaluations within different settings.

Sex biology in amyotrophic lateral sclerosis.

Although sex differences in amyotrophic lateral sclerosis (ALS) have not been studied systematically, numerous clinical and preclinical studies have shown sex to be influential in disease prognosis. Moreover, with the development of advanced imaging tools, the difference between male and female brain in structure and function and their response to neurodegeneration are more definitive. As discussed in this review, ALS patients exhibit a sex bias pertaining to the features of the disease, and their clinical, pathological, (and pathophysiological) phenotypes. Several epidemiological studies have indicated that this sex disparity stems from various aetiologies, including sex-specific brain structure and neural functioning, genetic predisposition, age, gonadal hormones, susceptibility to traumatic brain injury (TBI)/head trauma and lifestyle factors.

Calcium supplementation for the prevention of pre-eclampsia: Challenging the evidence from meta-analyses.

OBJECTIVE: To investigate the validity of the conclusion from Cochrane reviews and meta-analyses that treatment with calcium supplementation during pregnancy reduces the risk for pre-eclampsia by 55%, which has been influential in international guidelines and future research. DESIGN: Sensitivity analysis of data from Cochrane reviews of trials evaluating high-dose calcium supplementation (of at least 1 g/day) for reduction of pre-eclampsia risk. SETTING: Systematic review and meta-analysis. POPULATION: The Cochrane reviews and meta-analyses included 13 trials enrolling a total of 15 730 women. Random-effects meta-analysis of these studies resulted in a mean risk ratio (RR, calcium/placebo) of 0.45 (95% confidence interval [CI] 0.31-0.65; p < 0.0001). METHODS: We carried out a sensitivity analysis of evidence from the relevant Cochrane review, to examine the impact of study size. MAIN OUTCOME MEASURES: pre-eclampsia. RESULTS: In the three largest studies, accounting for 13 815 (88%) of total recruitment, mean RR was 0.92 (95% CI 0.80-1.06) and there was no evidence of heterogeneity between studies (I2 = 0). With inclusion of the smaller studies, mean RR decreased to 0.45 and I2 increased to 70%. CONCLUSIONS: In assessment of the effect of calcium supplementation on pre-eclampsia risk, the naive focus on the mean of the random-effects meta-analysis in the presence of substantial heterogeneity is highly misleading.

Memory consolidation of sequence learning and dynamic adaptation during wakefulness.

Motor learning involves acquiring new movement sequences and adapting motor commands to novel conditions. Labile motor memories, acquired through sequence learning and dynamic adaptation, undergo a consolidation process during wakefulness after initial training. This process stabilizes the new memories, leading to long-term memory formation. However, it remains unclear if the consolidation processes underlying sequence learning and dynamic adaptation are independent and if distinct neural regions underpin memory consolidation associated with sequence learning and dynamic adaptation. Here, we first demonstrated that the initially labile memories formed during sequence learning and dynamic adaptation were stabilized against interference through time-dependent consolidation processes occurring during wakefulness. Furthermore, we found that sequence learning memory was not disrupted when immediately followed by dynamic adaptation and vice versa, indicating distinct mechanisms for sequence learning and dynamic adaptation consolidation. Finally, by applying patterned transcranial magnetic stimulation to selectively disrupt the activity in the primary motor (M1) or sensory (S1) cortices immediately after sequence learning or dynamic adaptation, we found that sequence learning consolidation depended on M1 but not S1, while dynamic adaptation consolidation relied on S1 but not M1. For the first time in a single experimental framework, this study revealed distinct neural underpinnings for sequence learning and dynamic adaptation consolidation during wakefulness, with significant implications for motor skill enhancement and rehabilitation.

Patellar tendon shortening surgery restores the knee extensor mechanism in flexed knee gait in children with cerebral palsy.

BACKGROUND: This study evaluated a patellar tendon shortening (PTS) surgical procedure that uses an overlapping repair combined with an additional Tycron non-absorbable suture to support the shortening in children with Cerebral Palsy (CP). This study aimed to outline this surgical technique and to evaluate its effectiveness in restoring the knee extensor mechanism. METHODS: The sagittal plane lower limb kinematics, peak knee extensor moment, gait deviation index (GDI), localised movement deviation profile (MDP), temporospatial parameters, passive knee extension ROM, quadriceps lag, and knee extensor strength were calculated pre- and postoperatively. To determine significant differences a robust linear regression model with high breakdown point and high efficiency was fitted to the data. RESULTS: In this retrospective cohort study, a total of 41 patients with CP who were treated with unilateral or bilateral PTS in isolation or as part of single event multilevel surgery (SEMLS), with a mean age of 11.1 years were included. The knee extension angle improved at initial contact (p < 0.0001), and during stance phase (p < 0.0001). The peak internal knee extensor moment decreased during early (p = 0.0014) and late stance phase (p < 0.0001). The quadriceps lag decreased (p < 0.0001) and knee extensor strength increased (p < 0.0001). The GDI improved (p < 0.0001), as well as the localised MDP for sagittal angles (p < 0.0001) and moments (p = 0.0001). Walking speed (p = 1.0) remained unchanged, but the cadence decreased (p = 0.024) and step length increased (p = 0.0001). CONCLUSIONS: The knee extension angle and moment during stance phase improved significantly. The children with CP in this study showed improvements in knee extensor strength and quadriceps lag. Thereby it can be concluded that the PTS procedure was able to restore the knee extensor mechanism effectively.

Pregnancy-An Ideal Period to Identify Women at Risk for Chronic Hypertension.

BACKGROUND: Cardiovascular disease is the leading cause of mortality in women. Pregnancy is an ideal period to implement cardiovascular prevention strategies as women seek medical help. We aimed to develop a predictive model to identify women at increased risk for chronic hypertension (CH) based on information collected in the index pregnancy. METHODS: Cohort of 26 511 women seen in 2 consecutive pregnancies. Included were women without CH, with information on maternal characteristics and blood pressure at 11 to 13 weeks' gestation, and the development of preeclampsia or gestational hypertension (GH) in the index pregnancy. Logistic regression models were fitted for the prediction of the development of future CH by the 20th week of the subsequent pregnancy. The performance of screening and risk calibration of the model were assessed. RESULTS: In this study 1560 (5.9%) women developed preeclampsia or GH (index pregnancy), and 215 (0.8%) developed future CH, with a median of 3.0 years later. Predictors of development of future CH were maternal age, weight, and blood pressure; Black and South Asian ethnicity; family history of preeclampsia; parity; and development of preeclampsia or GH. Preeclampsia or GH detected 52.1% (45.2%-58.9%) of future CH. At a screen-positive rate of 10%, a model including maternal characteristics, early pregnancy blood pressure, and development of preeclampsia or GH detected 73.5% (67.1-79.3) of future CH. CONCLUSIONS: Early pregnancy maternal characteristics, blood pressure, and development of preeclampsia or GH identify three-fourths of women at risk for future CH. Our results offer an important preventative strategy for identifying women at increased risk of future CH, which is applicable worldwide.

Amylin receptor agonism enhances the effects of liraglutide in protecting against the acute metabolic side effects of olanzapine.

Olanzapine is a second-generation antipsychotic (AP) used in the management of schizophrenia. Although effective at reducing psychoses, APs cause rapid hyperglycemia, insulin resistance, and dyslipidemia, an effect mediated in part by glucagon. We tested if amylin, a hormone that reduces glucagon, or the amylin receptor agonist pramlintide would protect against acute olanzapine-induced impairments in glucose and lipid homeostasis alone or in combination with other glucose-lowering agents such as liraglutide. We demonstrated that pramlintide lowered olanzapine-induced increases in glucagon:insulin ratio with a trend to protect against excursions in blood glucose. There was an additive effect of pramlintide and liraglutide in protecting against olanzapine-induced hyperglycemia, which was mirrored by reductions in glucagon and attenuated markers of dyslipidemia. Our findings provide evidence that pramlintide, although moderately protective against some aspects of olanzapine-induced metabolic dysfunction, can be used to enhance the protective effects of other interventions against acute olanzapine-induced metabolic dysfunction.

Haptoglobin genotype is a risk factor for coronary artery disease in prediabetes: A case-control study.

Objective: Coronary artery disease (CAD) prediction remains inconsistent with many unappreciated risk factors. Haptoglobin genotype determines the haptoglobin protein's effectiveness to bind free hemoglobin and prevent oxidative stress, a contributor to atherosclerosis. The haptoglobin 2-2 genotype increases the prevalence of cardiovascular disease (CVD) approximately five times compared to the 1-1 genotype in individuals with diabetes. The risk is unknown in prediabetes. The purpose of this study was to determine an association between haptoglobin genotype and CAD in prediabetes. Methods: The researchers used case-control convenience sampling from two cardiovascular disease prevention clinics in Memphis, TN, and Spokane, WA, from January 1, 2016 to March 31, 2020. Participants were ages 35-70, had prediabetes, and free of chronic inflammatory or infectious diseases. Cases had a history of subclinical or clinical CAD, while controls did not have a history of CAD. Differences between cases and controls and among haptoglobin genotypes were analyzed using t-tests and ANOVA for continuous variables and chi-square or Fisher's exact tests for categorical variables. Associations among Hp genotypes and CAD were estimated using logistic regression. Results: The sample (N = 178; 72 cases and 106 controls) was 96 % white and 64 % male. Cases had lower total cholesterol (p = 0.0001) and high-sensitivity C-reactive protein (p = 0.021). Except for CAD, haptoglobin genotype was independent of any demographic or clinical variable. Haptoglobin 2-2 genotype had 4.0 times higher odds of CAD than haptoglobin 1-1 (p = 0.01). Conclusion: Haptoglobin 2-2 genotype had approximately four times higher odds of having CAD compared to the haptoglobin 1-1 genotype. Cases had more desirable clinical profiles, likely attributable to more aggressive treatment of traditional risk factors than controls. Haptoglobin genotype is a potentially important CAD risk factor in prediabetes (88 million Americans). Further studies are needed for interventions to reduce the oxidative stress associated with the Hp 2-2 genotype and glycosylated hemoglobin and for CAD reduction.