Periodontal therapy and treatment of hypertension-alternative to the pharmacological approach. A systematic review and meta-analysis.

AIM: Quantitative comparison of the effects of intensive (IPT) or conventional (CPT) periodontal treatment on arterial blood pressure, endothelial function and inflammatory/metabolic biomarkers. MATERIALS AND METHODS: A systematic search was conducted to identify randomized controlled trials (RCT) of IPT (supra and subgingival instrumentation). Eight RCTs were included in the meta-analysis. Difference in change of systolic blood pressure (SBP) and diastolic blood pressure (DBP) before and after IPT or CPT were the primary outcomes. The secondary outcomes included: endothelial function and selected inflammatory/anti-inflammatory (CRP, IL-6, IL-10, IFN-γ) and metabolic biomarkers (HDL, LDL, TGs). RESULTS: The overall effect estimates (pooled Weighted Mean Difference (WMD)) of the primary outcome for SBP and DBP was -4.3 mmHg [95%CI: -9.10-0.48], p = 0.08 and -3.16 mmHg [95%CI: -6.51-0.19], p = 0.06 respectively. These studies were characterized by high heterogeneity. Therefore, random effects model for meta-analysis was performed. Sub-group analyses confirmed statistically significant reduction in SBP [WMD = -11.41 mmHg (95%CI: -13.66, -9.15) P < 0.00001] and DBP [WMD = -8.43 mmHg (95%CI: -10.96,-5.91)P < 0.00001] after IPT vs CPT among prehypertensive/hypertensive patients, while this was not observed in normotensive individuals. The meta-analyses showed significant reductions in CRP and improvement of endothelial function following IPT at all analysed timepoints. CONCLUSIONS: IPT leads to improvement of the cardiovascular health in hypertensive and prehypertensive individuals.

Weight loss induced increase in fasting ghrelin concentration is a predictor of weight regain: evidence from the Diabetes Remission Clinical Trial.

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomised clinical trial designed to assess the effect of weight-loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (aged 53.6±7.5 years, BMI 34.7±4.4 kg/m2, 59% males). Intervention participants received a 24-month weight-management programme and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, GLP-1, and PYY were measured at baseline, 12 and 24-months in all participants, and at 5-months in a subset of interventions (n=56) and controls (n=22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3±6.0% body-weight at 5-months but regained over time, with weight-losses of 10.0±7.5% at 12-months and 7.6±6.3% at 24-months. Weight-loss in controls was 1.1±3.7% and 2.1±5.0% at 12 and 24-months, respectively. Body-weight increased by 2.3% [95% CI: 0.4,4.1]; p=0.019) between 12 and 24-months for every 1 ng/ml increase in ghrelin between baseline and 12-months, and weight regain between 12 and 24-months was increased by 1.1% (95% CI: 0.2,2.0; p=0.023) body-weight for every 1 ng/ml increase in ghrelin at 12-months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight-loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve WLM. This article is protected by copyright. All rights reserved.

Weight loss-induced increase in fasting ghrelin concentration is a predictor of weight regain: Evidence from the Diabetes Remission Clinical Trial (DiRECT).

AIM: To investigate whether appetite-related hormones were predictors of weight regain in the Diabetes Remission Clinical Trial (DiRECT). MATERIALS AND METHODS: DiRECT is a cluster-randomized clinical trial, designed to assess the effect of weight loss on type 2 diabetes remission. For this post hoc analysis, data were available for 253 (147 interventions, 106 controls) individuals with type 2 diabetes (age 53.6 ± 7.5 years, body mass index 34.7 ± 4.4 kg/m2 , 59% men). Intervention participants received a 24-month weight management programme, and controls remained on usual diabetes care. Fasting plasma concentrations of leptin, ghrelin, glucagon-like peptide-1 and peptide YY were measured at baseline, 12 months and 24 months in all participants, and at 5 months in a subset of participants in the intervention (n = 56) and control groups (n = 22). Potential predictors were examined using multivariable linear regression models. RESULTS: The intervention group lost 14.3 ± 6.0% body weight at 5 months but regained weight over time, with weight losses of 10.0 ± 7.5% at 12 months and 7.6 ± 6.3% at 24 months. Weight loss in controls was 1.1 ± 3.7% and 2.1 ± 5.0% at 12 and 24 months, respectively. Body weight increased by 2.3% (95% confidence interval [CI] 0.4, 4.1; P = 0.019) between 12 and 24 months for every 1-ng/mL increase in ghrelin between baseline and 12 months, and weight regain between 12 and 24 months was increased by 1.1% (95% CI 0.2, 2.0; P = 0.023) body weight for every 1-ng/mL increase in ghrelin at 12 months. CONCLUSION: The rise in ghrelin (but not any other measured hormone) during diet-induced weight loss was a predictor of weight regain during follow-up, and concentrations remained elevated over time, suggesting a small but significant compensatory drive to regain weight. Attenuating the effects of ghrelin may improve weight-loss maintenance.

5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study.

BACKGROUND: In DiRECT, a randomised controlled effectiveness trial, weight management intervention after 2 years resulted in mean weight loss of 7·6 kg, with 36% of participants in remission of type 2 diabetes. Of 36 in the intervention group who maintained over 10 kg weight loss at 2 years, 29 (81%) were in remission. Continued low-intensity dietary support was then offered up to 5 years from baseline to intervention participants, aiming to maintain weight loss and gain clinical benefits. This extension study was designed to provide observed outcomes at 5 years. METHODS: The DiRECT trial took place in primary care practices in the UK. Participants were individuals aged 20-65 years who had less than 6 years' duration of type 2 diabetes, a BMI greater than 27 kg/m2, and were not on insulin. The intervention consisted of withdrawal of antidiabetic and antihypertensive drugs, total diet replacement (825-853 kcal per day formula diet for 12-20 weeks), stepped food reintroduction (2-8 weeks), and then structured support for weight-loss maintenance. After sharing the 2-year results with all participants, UK National Health Service data were collected annually until year 5 from remaining intervention participants who received low-intensity dietary support, intervention withdrawals, and the original randomly allocated groups. The primary outcome was remission of type 2 diabetes; having established in the DiRECT trial that sustained weight loss was the dominant driver of remission, this was assumed for the Extension study. The trial is registered with the ISRCTN registry, number 03267836. FINDINGS: Between July 25, 2014, and Aug 5, 2016, 149 participants were randomly assigned to the intervention group and 149 were assigned to the control group in the original DiRECT study. After 2 years, all intervention participants still in the trial (101 [68%] of 149) were approached to receive low-intensity support for a further 3 years. 95 (94%) of 101 were able to continue and consented and were allocated to the DiRECT extension group. 54 participants were allocated to the non-extension group, where intervention was withdrawn. At 5 years, DiRECT extension participants (n=85) lost an average of 6·1 kg, with 11 (13%) of 85 in remission. Compared with the non-extension group, DiRECT extension participants had more visits with HbA1c <48 mmol/mol (<6·5%; 36% vs 17%, p=0·0004), without glucose-lowering medication (62% vs 30%, p<0·0001), and in remission (34% vs 12%, p<0·0001). Original control participants (n=149) had mean weight loss 4·6 kg (n=82), and 5 (5%) of 93 were in remission. Compared with control participants, original intervention participants had more visits with weight more than 5% below baseline (61% vs 29%, p<0·0001), HbA1c below 48 mmol/mol (29% vs 15%, p=0·0002), without antidiabetic medication (51% vs 16%, p<0·0001), and in remission (27% vs 4%, p<0·0001). Of those in remission at year 2, 26% remained in remission at 5 years. Serious adverse events in the original intervention group (4·8 events per 100 patient-years) were under half those in the control group (10·2 per 100 patient-years, p=0·0080). INTERPRETATION: The extended DiRECT intervention was associated with greater aggregated and absolute weight loss, and suggested improved health status over 5 years. FUNDING: Diabetes UK.

Measuring congestion with a non-invasive monitoring device in heart failure and haemodialysis: CONGEST-HF.

AIMS: We examined the effectiveness of a novel cardiopulmonary management wearable sensor (worn for less than 5 mins) at measuring congestion and correlated the device findings with established clinical measures of congestion. METHODS AND RESULTS: We enrolled three cohorts of patients: (1) patients with heart failure (HF) receiving intravenous diuretics in hospital; (2) patients established on haemodialysis, and (3) HF patients undergoing right heart catheterization (RHC). The primary outcomes in the respective cohorts were a Spearman correlation between (1) change in weight and change in thoracic impedance (TI) (from enrolment, 24 h after admission to discharge) in patients hospitalized for HF; (2) lung ultrasound B-lines and volume removed during dialysis with device measured TI, and (3) pulmonary capillary wedge pressure (PCWP) and sub-acoustic diastolic, third heart sound (S3) in the patients undergoing RHC. A total of 66 patients were enrolled. In HF patients (n = 25), change in weight was correlated with both change in device TI (Spearman correlation [rsp] = -0.64, p = 0.002) and change in device S3 (rsp = -0.53, p = 0.014). In the haemodialysis cohort (n = 21), B-lines and TI were strongly correlated before (rsp = -0.71, p < 0.001) and after (rsp = -0.77, p < 0.001) dialysis. Volume of fluid removed by dialysis was correlated with change in device TI (rsp = 0.49, p = 0.024). In the RHC cohort (n = 20), PCWP measured at one time point and device S3 were not significantly correlated (rsp = 0.230, p = 0.204). There were no device-related adverse events. CONCLUSIONS: A non-invasive device was able to detect changes in congestion in patients with HF receiving decongestion therapy and patients having fluid removed at haemodialysis. The cardiopulmonary management device, which measures multiple parameters, is a potentially useful tool to monitor patients with HF to prevent hospitalizations.

Pulmonary Hypertension: Intensification and Personalization of Combination Rx (PHoenix): A phase IV randomized trial for the evaluation of dose-response and clinical efficacy of riociguat and selexipag using implanted technologies.

Approved therapies for the treatment of patients with pulmonary arterial hypertension (PAH) mediate pulmonary vascular vasodilatation by targeting distinct biological pathways. International guidelines recommend that patients with an inadequate response to dual therapy with a phosphodiesterase type-5 inhibitor (PDE5i) and endothelin receptor antagonist (ERA), are recommended to either intensify oral therapy by adding a selective prostacyclin receptor (IP) agonist (selexipag), or switching from PDE5i to a soluble guanylate-cyclase stimulator (sGCS; riociguat). The clinical equipoise between these therapeutic choices provides the opportunity for evaluation of individualized therapeutic effects. Traditionally, invasive/hospital-based investigations are required to comprehensively assess disease severity and demonstrate treatment benefits. Regulatory-approved, minimally invasive monitors enable equivalent measurements to be obtained while patients are at home. In this 2 × 2 randomized crossover trial, patients with PAH established on guideline-recommended dual therapy and implanted with CardioMEMS™ (a wireless pulmonary artery sensor) and ConfirmRx™ (an insertable cardiac rhythm monitor), will receive ERA + sGCS, or PDEi + ERA + IP agonist. The study will evaluate clinical efficacy via established clinical investigations and remote monitoring technologies, with remote data relayed through regulatory-approved online clinical portals. The primary aim will be the change in right ventricular systolic volume measured by magnetic resonance imaging (MRI) from baseline to maximal tolerated dose with each therapy. Using data from MRI and other outcomes, including hemodynamics, physical activity, physiological measurements, quality of life, and side effect reporting, we will determine whether remote technology facilitates early evaluation of clinical efficacy, and investigate intra-patient efficacy of the two treatment approaches.

Vascular mechanisms of post-COVID-19 conditions: Rho-kinase is a novel target for therapy.

BACKGROUND: In post-coronavirus disease-19 (post-COVID-19) conditions (long COVID), systemic vascular dysfunction is implicated, but the mechanisms are uncertain, and the treatment is imprecise. METHODS AND RESULTS: Patients convalescing after hospitalization for COVID-19 and risk factor matched controls underwent multisystem phenotyping using blood biomarkers, cardiorenal and pulmonary imaging, and gluteal subcutaneous biopsy (NCT04403607). Small resistance arteries were isolated and examined using wire myography, histopathology, immunohistochemistry, and spatial transcriptomics. Endothelium-independent (sodium nitroprusside) and -dependent (acetylcholine) vasorelaxation and vasoconstriction to the thromboxane A2 receptor agonist, U46619, and endothelin-1 (ET-1) in the presence or absence of a RhoA/Rho-kinase inhibitor (fasudil), were investigated. Thirty-seven patients, including 27 (mean age 57 years, 48% women, 41% cardiovascular disease) 3 months post-COVID-19 and 10 controls (mean age 57 years, 20% women, 30% cardiovascular disease), were included. Compared with control responses, U46619-induced constriction was increased (P = 0.002) and endothelium-independent vasorelaxation was reduced in arteries from COVID-19 patients (P < 0.001). This difference was abolished by fasudil. Histopathology revealed greater collagen abundance in COVID-19 arteries {Masson's trichrome (MT) 69.7% [95% confidence interval (CI): 67.8-71.7]; picrosirius red 68.6% [95% CI: 64.4-72.8]} vs. controls [MT 64.9% (95% CI: 59.4-70.3) (P = 0.028); picrosirius red 60.1% (95% CI: 55.4-64.8), (P = 0.029)]. Greater phosphorylated myosin light chain antibody-positive staining in vascular smooth muscle cells was observed in COVID-19 arteries (40.1%; 95% CI: 30.9-49.3) vs. controls (10.0%; 95% CI: 4.4-15.6) (P < 0.001). In proof-of-concept studies, gene pathways associated with extracellular matrix alteration, proteoglycan synthesis, and viral mRNA replication appeared to be upregulated. CONCLUSION: Patients with post-COVID-19 conditions have enhanced vascular fibrosis and myosin light change phosphorylation. Rho-kinase activation represents a novel therapeutic target for clinical trials.

[11C]metomidate PET-CT versus adrenal vein sampling for diagnosing surgically curable primary aldosteronism: a prospective, within-patient trial.

Primary aldosteronism (PA) due to a unilateral aldosterone-producing adenoma is a common cause of hypertension. This can be cured, or greatly improved, by adrenal surgery. However, the invasive nature of the standard pre-surgical investigation contributes to fewer than 1% of patients with PA being offered the chance of a cure. The primary objective of our prospective study of 143 patients with PA ( NCT02945904 ) was to compare the accuracy of a non-invasive test, [11C]metomidate positron emission tomography computed tomography (MTO) scanning, with adrenal vein sampling (AVS) in predicting the biochemical remission of PA and the resolution of hypertension after surgery. A total of 128 patients reached 6- to 9-month follow-up, with 78 (61%) treated surgically and 50 (39%) managed medically. Of the 78 patients receiving surgery, 77 achieved one or more PA surgical outcome criterion for success. The accuracies of MTO at predicting biochemical and clinical success following adrenalectomy were, respectively, 72.7 and 65.4%. For AVS, the accuracies were 63.6 and 61.5%. MTO was not significantly superior, but the differences of 9.1% (95% confidence interval = -6.5 to 24.1%) and 3.8% (95% confidence interval = -11.9 to 9.4) lay within the pre-specified -17% margin for non-inferiority (P = 0.00055 and P = 0.0077, respectively). Of 24 serious adverse events, none was considered related to either investigation and 22 were fully resolved. MTO enables non-invasive diagnosis of unilateral PA.

Adjudicated myocarditis and multisystem illness trajectory in healthcare workers post-COVID-19.

BACKGROUND: We investigated the associations of healthcare worker status with multisystem illness trajectory in hospitalised post-COVID-19 individuals. METHODS AND RESULTS: One hundred and sixty-eight patients were evaluated 28-60 days after the last episode of hospital care. Thirty-six (21%) were healthcare workers. Compared with non-healthcare workers, healthcare workers were of similar age (51.3 (8.7) years vs 55.0 (12.4) years; p=0.09) more often women (26 (72%) vs 48 (38%); p<0.01) and had lower 10-year cardiovascular risk (%) (8.1 (7.9) vs 15.0 (11.5); p<0.01) and Coronavirus Clinical Characterisation Consortium in-hospital mortality risk (7.3 (10.2) vs 12.7 (9.8); p<0.01). Healthcare worker status associated with less acute inflammation (peak C reactive protein 48 mg/L (IQR: 14-165) vs 112 mg/L (52-181)), milder illness reflected by WHO clinical severity score distribution (p=0.04) and shorter duration of admission (4 days (IQR: 2-6) vs 6 days (3-12)).In adjusted multivariate logistic regression analysis, healthcare worker status associated with a binary classification (probable/very likely vs not present/unlikely) of adjudicated myocarditis (OR: 2.99; 95% CI (1.01 to 8.89) by 28-60 days postdischarge).After a mean (SD, range) duration of follow-up after hospital discharge of 450 (88) days (range 290, 627 days), fewer healthcare workers died or were rehospitalised (1 (3%) vs 22 (17%); p=0.038) and secondary care referrals for post-COVID-19 syndrome were common (42%) and similar to non-healthcare workers (38%; p=0.934). CONCLUSION: Healthcare worker status was independently associated with the likelihood of adjudicated myocarditis, despite better antecedent health. Two in five healthcare workers had a secondary care referral for post-COVID-19 syndrome. TRIAL REGISTRATION NUMBER: NCT04403607.

A multisystem, cardio-renal investigation of post-COVID-19 illness.

The pathophysiology and trajectory of post-Coronavirus Disease 2019 (COVID-19) syndrome is uncertain. To clarify multisystem involvement, we undertook a prospective cohort study including patients who had been hospitalized with COVID-19 (ClinicalTrials.gov ID NCT04403607 ). Serial blood biomarkers, digital electrocardiography and patient-reported outcome measures were obtained in-hospital and at 28-60 days post-discharge when multisystem imaging using chest computed tomography with pulmonary and coronary angiography and cardio-renal magnetic resonance imaging was also obtained. Longer-term clinical outcomes were assessed using electronic health records. Compared to controls (n = 29), at 28-60 days post-discharge, people with COVID-19 (n = 159; mean age, 55 years; 43% female) had persisting evidence of cardio-renal involvement and hemostasis pathway activation. The adjudicated likelihood of myocarditis was 'very likely' in 21 (13%) patients, 'probable' in 65 (41%) patients, 'unlikely' in 56 (35%) patients and 'not present' in 17 (11%) patients. At 28-60 days post-discharge, COVID-19 was associated with worse health-related quality of life (EQ-5D-5L score 0.77 (0.23) versus 0.87 (0.20)), anxiety and depression (PHQ-4 total score 3.59 (3.71) versus 1.28 (2.67)) and aerobic exercise capacity reflected by predicted maximal oxygen utilization (20.0 (7.6) versus 29.5 (8.0) ml/kg/min) (all P < 0.01). During follow-up (mean, 450 days), 24 (15%) patients and two (7%) controls died or were rehospitalized, and 108 (68%) patients and seven (26%) controls received outpatient secondary care (P = 0.017). The illness trajectory of patients after hospitalization with COVID-19 includes persisting multisystem abnormalities and health impairments that could lead to substantial demand on healthcare services in the future.

Changes over a decade in psychotropic prescribing for people with intellectual disabilities: prospective cohort study.

OBJECTIVES: To investigate psychotropic prescribing in the intellectual disabilities population over 10 years, and associated mental ill health diagnoses. DESIGN: Comparison of cross-sectional data in 2002-2004 (T1) and 2014 (T2). Longitudinal cohort study with detailed health assessments at T1 and record linkage to T2 prescribing data. SETTING: General community. PARTICIPANTS: 1190 adults with intellectual disabilities in T1 compared with 3906 adults with intellectual disabilities in T2. 545/1190 adults with intellectual disabilities in T1 were alive and their records linked to T2 prescribing data. MAIN OUTCOME MEASURES: Encashed regular and as-required psychotropic prescriptions. RESULTS: 50.7% (603/1190) of adults in T1 and 48.2% (1881/3906) in T2 were prescribed at least one psychotropic; antipsychotics: 24.5% (292/1190) in T1 and 16.7% (653/3906) in T2; antidepressants: 11.2% (133/1190) in T1 and 19.1% (746/3906) in T2. 21.2% (62/292) prescribed antipsychotics in T1 had psychosis or bipolar disorder, 33.2% (97/292) had no mental ill health or problem behaviours, 20.6% (60/292) had problem behaviours but no psychosis or bipolar disorder. Psychotropics increased from 47.0% (256/545) in T1 to 57.8% (315/545) in T2 (p<0.001): antipsychotics did not change (OR 1.18; 95% CI 0.87 to 1.60; p=0.280), there was an increase for antidepressants (OR 2.80; 95% CI 1.96 to 4.00; p<0.001), hypnotics/anxiolytics (OR 2.19; 95% CI 1.34 to 3.61; p=0.002), and antiepileptics (OR 1.40; 95% CI 1.06 to 1.84; p=0.017). Antipsychotic prescribing increased for people with problem behaviours in T1 (OR 6.45; 95% CI 4.41 to 9.45; p<0.001), more so than for people with other mental ill health in T1 (OR 4.11; 95% CI 2.76 to 6.11; p<0.001). CONCLUSIONS: Despite concerns about antipsychotic prescribing and guidelines recommending their withdrawal, it appears that while fewer antipsychotic prescriptions were initiated by T2 than in T1, people were not withdrawn from them once commenced. People with problem behaviours had increased prescribing. There was also a striking increase in antidepressant prescriptions. Adults with intellectual disabilities need frequent and careful medication reviews.