Durable biochemical response and safety with oral octreotide capsules in acromegaly.

Objective: The objective of this study is to report results from the open-label extension (OLE) of the OPTIMAL trial of oral octreotide capsules (OOC) in adults with acromegaly, evaluating the long-term durability of therapeutic response. Design: The study design is an OLE of a double-blind placebo-controlled (DPC) trial. Methods: Patients completing the 36-week DPC period on the study drug (OOC or placebo) or meeting predefined withdrawal criteria were eligible for OLE enrollment at 60 mg/day OOC dose, with the option to titrate to 40 or 80 mg/day. The OLE is ongoing; week 48 results are reported. Results: Forty patients were enrolled in the OLE, 20 each having received OOC or placebo, with 14 and 5 patients completing the DPC period as responders, respectively. Ninety percent of patients completing the DPC period on OOC and 70% of those completing on placebo completed 48 weeks of the OLE. Maintenance of response in the OLE (i.e. insulin-like growth factor I (IGF1) ≤ 1.0 × upper limit of normal (ULN)) was achieved by 92.6% of patients who responded to OOC during the DPC period. Mean IGF1 levels were maintained between the end of the DPC period (0.91 × ULN; 95% CI: 0.784, 1.045) and week 48 of the OLE (0.90 × ULN; 95% CI: 0.750, 1.044) for those completing the DPC period on OOC. OOC safety was consistent with previous findings, with no increased adverse events (AEs) associated with the higher dose and improved gastrointestinal tolerability observed over time. Conclusions: Patients with acromegaly maintained long-term biochemical response while receiving OOC, with no new AEs observed with prolonged OOC exposure.

Upregulated miR-200c is associated with downregulation of the functional receptor for severe acute respiratory syndrome coronavirus 2 ACE2 in individuals with obesity.

Obesity is a risk factor for coronavirus disease 2019 (COVID-19) infection, with studies demonstrating the prevalence of individuals with obesity admitted with COVID-19 ranging between 30 and 60%. We determined whether early changes in microRNAs (miRNAs) are associated with dysregulation of angiotensin-converting enzyme 2 (ACE2), the specific functional receptor for severe acute respiratory syndrome coronavirus 2. ACE2 is a membrane-bound enzyme that catalyzes the conversion of angiotensin II to angiotensin 1-7 the latter having cardioprotective and vasorelaxation effects. Quantitative real-time PCR analysis of plasma samples for circulating miRNAs showed upregulation of miR-200c and miR-let-7b in otherwise healthy individuals with obesity. This was associated with significant downregulation of ACE2, a direct target for both miRNAs, in individuals with obesity. Correlation analysis confirmed a significant negative correlation between ACE2 and both the miRNAs. Studies showed that despite being the functional receptor, inhibition/downregulation of ACE2 did not reduce the severity of COVID-19 infection. In contrast, increased angiotensin II following inhibition of ACE2 may increase the severity of the disease. Taken together, our novel results identify that upregulation of miR-200c may increase the susceptibility of individuals with obesity to COVID-19. Considering miRNA are the earliest molecular regulators, the level of circulating miR-200c could be a potential biomarker in the early identification of those at the risk of severe COVID-19.

Severe Tricuspid Valve Endocarditis: A Tale of 2 Circuits.

A 25-year-old woman with severe tricuspid valve endocarditis and septic pulmonary emboli required VA-ECMO for recurrent hypoxemia-induced cardiac arrest. We present the clinical challenges requiring ECMO circuit reconfiguration and a percutaneous approach for vegetation debulking. (Level of Difficulty: Intermediate.).

Age- and sex-specific visceral fat reference cutoffs and their association with cardio-metabolic risk.

BACKGROUND: Although excess visceral fat (VAT) is associated with numerous cardio-metabolic risk factors, measurement of this fat depot has historically been difficult. Recent dual X-ray absorptiometry approaches have provided an accessible estimate of VAT that has shown acceptable validity against gold standard methods. The aims of this study were to (i) evaluate DXA measured VAT as a predictor of elevated blood lipids and blood pressure and (ii) calculate thresholds associated with these cardio-metabolic risk factors. SUBJECTS/METHODS: The sample comprised 1482 adults (56.4% women) aged 18-66 years. Total body scans were performed using a GE Lunar Prodigy, and VAT analyses were enabled through Corescan software (v 16.0). Blood pressure and blood lipids were measured by standard procedures. Regression models assessed how VAT mass was associated with each cardio-metabolic risk factor compared to other body composition measures. Measures of sensitivity and specificity were used to determine age- and sex-specific cut points for VAT mass associated with high cardio-metabolic risk. RESULTS: Similar to waist circumference, VAT mass was a strong predictor of cardio-metabolic risk especially in men over age 40. Four cut-offs for VAT mass were proposed, above which the cardio-metabolic risk increased: 700 g in women <40 yrs; 800 g in women 40+ yrs; 1000g in men <40 yrs; and 1200 g in men 40+ yrs. In general, these cut-offs discriminated well between those with high and low cardio-metabolic risk. CONCLUSIONS: In both sexes, DXA measured VAT was associated with traditional cardio-metabolic risk factors, particularly high blood pressure in those 40+ yrs and low HDL < 40 yrs. These reference values provide a simple, accessible method to assess cardio-metabolic risk in adults.

Upregulation of microRNA-532 enhances cardiomyocyte apoptosis in the diabetic heart.

Type 2 diabetes has a strong association with the development of cardiovascular disease, which is grouped as diabetic heart disease (DHD). DHD is associated with the progressive loss of cardiovascular cells through the alteration of molecular signalling pathways associated with cell death. In this study, we sought to determine whether diabetes induces dysregulation of miR-532 and if this is associated with accentuated apoptosis. RT-PCR analysis showed a significant increase in miR-532 expression in the right atrial appendage tissue of type 2 diabetic patients undergoing coronary artery bypass graft surgery. This was associated with marked downregulation of its anti-apoptotic target protein apoptosis repressor with caspase recruitment domain (ARC) and increased TUNEL positive cardiomyocytes. Further analysis showed a positive correlation between apoptosis and miR-532 levels. Time-course experiments in a mouse model of type 2 diabetes showed that diabetes-induced activation of miR-532 occurs in the later stage of the disease. Importantly, the upregulation of miR-532 preceded the activation of pro-apoptotic caspase-3/7 activity. Finally, inhibition of miR-532 activity in high glucose cultured human cardiomyocytes prevented the downregulation of ARC and attenuated apoptotic cell death. Diabetes induced activation of miR-532 plays a critical role in accelerating cardiomyocytes apoptosis. Therefore, miR-532 may serve as a promising therapeutic agent to overcome the diabetes-induced loss of cardiomyocytes.

Anterior Cingulate Cortex Implants for Alcohol Addiction: A Feasibility Study.

Abnormal neural activity, particularly in the rostrodorsal anterior cingulate cortex (rdACC), appears to be responsible for intense alcohol craving. Neuromodulation of the rdACC using cortical implants may be an option for individuals with treatment-resistant alcohol dependence. This study assessed the effectiveness and feasibility of suppressing alcohol craving using cortical implants of the rdACC using a controlled one-group pre- and post-test study design. Eight intractable alcohol-dependent participants (four males and four females) were implanted with two Lamitrode 44 electrodes over the rdACC bilaterally connected to an internal pulse generator (IPG). The primary endpoint, self-reported alcohol craving reduced by 60.7% (p = 0.004) post- compared to pre-stimulation. Adverse events occurred in four out of the eight participants. Electrophysiology findings showed that among responders, there was a post-stimulation decrease (p = 0.026) in current density at the rdACC for beta 1 band (13-18 Hz). Results suggest that rdACC stimulation using implanted electrodes may potentially be a feasible method for supressing alcohol craving in individuals with severe alcohol use disorder. However, to further establish safety and efficacy, larger controlled clinical trials are needed.

Radial access: So much progress but a way to go.

Transradial access is the key bleeding avoidance strategy in percutaneous coronary intervention. This study showed a marked adoption of transradial access over a 10-year period, however, women had a significantly lower rate compared to men and overall bleeding events did not decrease over time. Strategies to overcome barriers to radial access in women and to maintaining competency in femoral access in all patients are needed.

Acute Weight Loss Restores Dysregulated Circulating MicroRNAs in Individuals Who Are Obese.

CONTEXT: Obesity is a global epidemic and an independent risk factor for several diseases. miRNAs are gaining interest as early molecular regulators of various pathological processes. OBJECTIVE: To examine the miRNA signatures in women who are obese and determine the response of miRNAs to acute weight loss. METHODS: Plasma samples were collected from women who are obese (n = 80) before and after acute weight loss (mean, 7.2%). Plasma samples from age-matched lean volunteers (n = 80) were used as controls. Total RNA was extracted from the plasma samples and subjected to NanoString analysis of 822 miRNAs. The expression level of candidate miRNAs was validated in all participants using quantitative real-time PCR analysis. RESULTS: NanoString analysis identified substantial dysregulation of 21 miRNAs in women who are obese that were associated with impaired glucose tolerance, senescence, cardiac hypertrophy, angiogenesis, inflammation, and cell death. Acute weight loss reversed the expression pattern of 18 of these miRNAs toward those seen in the lean control group. Furthermore, real-time PCR validation of all the samples for 13 miRNAs with at least twofold upregulation or downregulation confirmed substantial dysregulation of all the chosen miRNAs in women who are obese at baseline. After acute weight loss, the levels of seven miRNAs in women who are obese and who are lean were comparable, with no statistically significant evidence for differences between the two groups. CONCLUSIONS: Our study has provided evidence that the circulating miRNAs associated with various disorders are dysregulated in women who are obese. We also found that seven of these miRNAs showed levels comparable to those in lean controls after acute weight loss in women who are obese.

Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa, New Zealand.

Internationally and within Aotearoa, New Zealand, there has been a substantial increase in the demand for gender affirming healthcare over the past decade. It is likely that this level of referrals to health services will continue in the foreseeable future. The Guidelines for Gender Affirming Healthcare for Gender Diverse and Transgender Children, Young People and Adults in Aotearoa, New Zealand were developed following the recognition that the previous good practice guide required updating to be in step with current practice and international standards. This article presents a summary of the guideline focusing on puberty blockers, hormonal therapies, access to surgery and other gender affirming healthcare. We hope these guidelines will support the development and provision of services providing gender affirming healthcare around the country and provide helpful guidance to all health professionals involved in the care of trans people.

Pharmaceutical interventions for weight-loss maintenance: no effect from cabergoline.

BACKGROUND: Weight regain is a major limitation to successful weight maintenance following weight loss. Observational studies suggest that stimulation of dopamine receptors in the central nervous system is associated with weight loss and inhibition of weight gain. Our objective was to test the hypothesis that dopamine agonist treatment would prevent weight regain following acute weight loss in individuals with obesity. METHODS: We conducted a 2-year double blind randomised controlled trial comparing the effect of a dopamine agonist, cabergoline, with placebo on weight regain in obese individuals who had lost at least 5% of their body weight using an 800 kcal/day commercial meal replacement programme. The primary outcome measure was the difference in mean weight between the treatment and control groups over the 2-year period following randomisation. RESULTS: At 24 months, there was no difference in body weight between cabergoline and placebo treatment after adjustment for age, gender and baseline values (0.6 kg (95% CI: -1.5, 2.6), p = 0.58). The mean (±SD) baseline body weight of the randomised participants was 101.8 kg, the mean (±SD) weight loss with the 800 kcal/day diet was 7.1 ± 1.8 kg and the mean (±SD) weight regain at 24 months was 5.1 ± 7.5 kg. There were no significant differences in BMI, percent weight loss, waist circumference, resting energy expenditure, blood pressure or metabolic parameters at 24 months between the two groups. CONCLUSIONS: Treatment with the dopamine agonist cabergoline does not prevent weight regain in obese individuals following weight loss.

A randomised, double-blind, placebo-controlled parallel trial of closed-loop infraslow brain training in food addiction.

The posterior cingulate cortex (PCC) is involved in food craving in obese food addicted individuals. This randomised, double-blind, placebo-controlled parallel study explored the potential therapeutic effects of infraslow neurofeedback (ISF-NF) on food craving targeting the PCC in obese women with symptoms of food addiction. Participants received six sessions of either ISF-NF (n = 11) or placebo (n = 10) over a three-week period. There were no reported adverse effects. Electrophysiologically, there were significant increases in infraslow activity (p = 0.0002) and infraslow/beta nesting (p < 0.001) in the PCC in the ISF-NF group (mean r = 0.004 ± 0.002) compared to placebo (mean r = 0.02 ± 0.002) two days after the last intervention. Also, there was a significant decrease in different dimensions of state food craving compared to baseline and to placebo. Findings suggest that source localized IFS-NF results in electrophysiological changes and may be associated with reduced food craving. This trial is registered at www.anzctr.org.au , identifier, ACTRN12617000601336. This study was funded by the Otago Medical Research Grant: CT375.

The sensitivity and specificity of thyroglobulin concentration using repeated measures of urinary iodine excretion.

PURPOSE: Iodine deficiency affects 30% of populations worldwide. The amount of thyroglobulin (Tg) in blood increases in iodine deficiency and also in iodine excess. Tg is considered as a sensitive index of iodine status in groups of children and adults, but its usefulness for individuals is unknown. The aim of this study was to determine the diagnostic performance of Tg as an index of iodine status in individual adults. METHODS: Adults aged 18-40 years (n = 151) provided five spot urine samples for the measurement of urinary iodine concentration expressed as µg/L (UIC), µg/g of creatinine (I:Cre), and µg/day (estimated UIE); the mean of the five samples was used as the reference standard. Participants also provided a blood sample for the determination of Tg, thyroid-stimulating hormone (TSH), and free thyroxine (FT4). RESULTS: The median of UIC, I:Cre, estimated UIE, and Tg was 72 (range 16-350) µg/L, 90 (range 33-371) µg/g, 129 (range 41-646) µg/day, and 16.4 (range 0.8-178.9) µg/L, respectively. Using Tg cut-offs of >10, >11, >13, and >15 µg/L, the sensitivity and specificity for UIC, I:Cre, and estimated UIE ranged from 52 to 79% and 20-48%, respectively, below the acceptable value of ≥80%. Furthermore, receiver-operating characteristic (ROC) curves for Tg using the three measurements of urinary iodine were situated close to the chance line and the area under the curve ranged from 0.49 to 0.52. CONCLUSIONS: The results from this cross-sectional study indicate that Tg has low sensitivity and specificity to repeated measures of urinary iodine excretion. Further studies are still needed to investigate the usefulness of Tg as a biomarker of individual iodine status.

High definition transcranial pink noise stimulation of anterior cingulate cortex on food craving: An explorative study.

Dysfunctional neural activity in the cortical reward system network has been implicated in food addiction. This is the first study exploring the potential therapeutic effects of high definition transcranial pink noise stimulation (HD-tPNS) targeted at the anterior cingulate cortex (ACC) on craving and brain activity in women with obesity who showed features of food addiction (Yale Food Addiction Scale score of ≥3). Sixteen eligible females participated in a randomized, double-blind, parallel group study. Participants received six 20-minute sessions of either 1 mA (n = 8) or sham (n = 8) stimulation with HD-tPNS over two weeks. Anode was placed above the ACC (Fz) with 4 cathodes (F7, T3, F8, and T4). Food craving was assessed using the Food Cravings Questionnaire State (FCQ-S) and brain activity was measured using electroencephalogram (EEG). Assessments were at baseline, and two days, four weeks, and six weeks after stimulation. A 22% decrease (mean decrease of -1.11, 95% CI -2.09, -0.14) was observed on the 5-point 'intense desire to eat' subscale two days after stimulation in the HD-tPNS group compared to sham. Furthermore, whole brain analysis showed a significant decrease in beta 1 activity in the ACC in the stimulation group compared to sham (threshold 0.38, p = 0.04). These preliminary findings suggest HD-tPNS of the ACC transiently inhibits the desire to eat and, thus, warrants further examination as a potential tool in combating food craving.

Resting heart rate variability and exercise capacity in Type 1 diabetes.

People with type 1 diabetes (T1D) have lower exercise capacity (V̇O2max) than their age-matched nondiabetic counterparts (CON), which might be related to cardiac autonomic dysfunction. We examined whether Heart Rate Variability (HRV; indicator of cardiac autonomic modulation) was associated with exercise capacity in those with and without T1D. Twenty-three participants with uncomplicated T1D and 17 matched CON were recruited. Heart rate (HR; ECG), blood pressure (BP; finger photo-plethysmography), and respiratory rate (respiratory belt) were measured during baseline, paced-breathing and clinical autonomic reflex tests (CARTs); deep breathing, lying-to-stand, and Valsalva maneuver. Baseline and paced-breathing ECG were analyzed for HRV (frequency-domain). Exercise capacity was determined during an incremental cycle ergometer test while V̇O2, 12-lead ECG, and BP were measured. In uncomplicated T1D, resting HR was elevated and resting HRV metrics were reduced, indicative of altered cardiac parasympathetic modulation; this was generally undetected by the CARTs. However, BP and plasma catecholamines were not different between groups. In T1D, V̇O2max tended to be lower (P = 0.07) and HR reserve was lower (P < 0.01). Resting Total Power (TP) had stronger positive associations with V̇O2max (R2 ≥ 0.3) than all other traditional indicators such as age, resting HR, and self-reported exercise (R2 = 0.042-0.3) in both T1D and CON Alterations in cardiac autonomic modulation are an early manifestation of uncomplicated T1D. Total Power was associated with reduced exercise capacity regardless of group, and these associations were generally stronger than traditional indicators.

Down-regulation of miR-15a/b accelerates fibrotic remodelling in the Type 2 diabetic human and mouse heart.

Aim: Myocardial fibrosis is a well-established cause of increased myocardial stiffness and subsequent diastolic dysfunction in the diabetic heart. The molecular regulators that drive the process of fibrotic events in the diabetic heart are still unknown. We determined the role of the microRNA (miR)-15 family in fibrotic remodelling of the diabetic heart.Methods and results: Right atrial appendage (RAA) and left ventricular (LV) biopsy tissues collected from diabetic and non-diabetic (ND) patients undergoing coronary artery bypass graft surgery showed significant down-regulation of miR-15a and -15b. This was associated with marked up-regulation of pro-fibrotic transforming growth factor-ß receptor-1 (TGFßR1) and connective tissue growth factor (CTGF), direct targets for miR-15a/b and pro-senescence p53 protein. Interestingly, down-regulation of miR-15a/b preceded the development of diastolic dysfunction and fibrosis in Type 2 diabetic mouse heart. Therapeutic restoration of miR-15a and -15b in HL-1 cardiomyocytes reduced the activation of pro-fibrotic TGFßR1 and CTGF, and the pro-senescence p53 protein expression, confirming a causal regulation of these fibrotic and senescence mediators by miR-15a/b. Moreover, conditioned medium (CM) collected from cardiomyocytes treated with miR-15a/b markedly diminished the differentiation of diabetic human cardiac fibroblasts.Conclusion: Our results provide first evidence that early down-regulation of miR-15a/b activates fibrotic signalling in diabetic heart, and hence could be a potential target for the treatment/prevention of diabetes-induced fibrotic remodelling of the heart.

Down-regulation of proangiogenic microRNA-126 and microRNA-132 are early modulators of diabetic cardiac microangiopathy.

AIM: Microangiopathy due to endothelial dysfunction is a major contributing factor to the development of diabetes-induced cardiovascular disease (CVD). Dysregulation of endothelial-specific microRNAs (miRs) is correlated with impaired angiogenesis and cell survival. We investigated the profile of two angiomiRs, miR-126, and miR-132, in the plasma of type 2 diabetic individuals without any known history of CVD as well as in the cardiac tissues collected from diabetics undergoing cardiac surgery. METHODS AND RESULTS: The presence of diabetes alone significantly decreased both angiomiRs in the plasma and the myocardium. The down-regulation of angiomiRs was also associated with reduced capillaries and arterioles and increased endothelial cell apoptosis, the hallmark of microangiopathy. Importantly, a time course study in a type 2 diabetic mouse model confirmed that the down-regulation of angiomiRs preceded endothelial apoptosis as well as alterations in the density of the microvasculature. Finally, therapeutic overexpression of both angiomiRs in diabetic aortic rings and human umbilical vein endothelial cells exposed to high glucose (HG) abrogated the deleterious effects of diabetes and HG on cell survival and proliferation and restored their angiogenic potential. CONCLUSIONS: These novel findings demonstrate that the down-regulation of angiomiRs is a major underlying mechanism for the development of microangiopathy in diabetic hearts. Therefore, therapeutic restoration of angiomiRs could become a potential approach to combat the cardiovascular complications of diabetes.

Anterior Cingulate Implant for Obsessive-Compulsive Disorder.

BACKGROUND: Obsessive-compulsive disorder (OCD) is a brain disorder with a lifetime prevalence of 2.3%, causing severe functional impairment as a result of anxiety and distress, persistent and repetitive, unwanted, intrusive thoughts (obsessions), and repetitive ritualized behavior (compulsions). Approximately 40%-60% of patients with OCD fail to satisfactorily respond to standard treatments. Intractable OCD has been treated by anterior capsulotomy and cingulotomy, but more recently, neurostimulation approaches have become more popular because of their reversibility. OBJECTIVE: Implants for OCD are commonly being used, targeting the anterior limb of the internal capsula or the nucleus accumbens, but an implant on the anterior cingulate cortex has never been reported. METHODS: We describe a patient who was primarily treated for alcohol addiction, first with transcranial magnetic stimulation, then by implantation of 2 electrodes overlying the rostrodorsal part of the anterior cingulate cortex bilaterally. RESULTS: Her alcohol addiction developed as she was relief drinking to self-treat her OCD, anxiety, and depression. After the surgical implant, she underwent placebo stimulation followed by real stimulation of the dorsal anterior cingulate cortex, which dramatically improved her OCD symptoms (decrease of 65.5% on the Yale-Brown Obsessive Compulsive Drinking Scale) as well as her alcohol craving (decrease of 87.5%) after 36 weeks of treatment. Although there were improvements in all the scores, there was only a modest reduction in the patient's weekly alcohol consumption (from 50 units to 32 units). CONCLUSIONS: Based on these preliminary positive results we propose to further study the possible beneficial effect of anterior cingulate cortex stimulation for intractable OCD.