Objective: The radiologically isolated syndrome (RIS) represents the earliest detectable pre-clinical phase of multiple sclerosis (MS). This study evaluated the impact of therapeutic intervention in preventing first symptom manifestation at this stage in the disease spectrum. Methods: We conducted a multi-center, randomized, double-blinded, placebo-controlled study involving people with RIS. Individuals without clinical symptoms typical of MS but with incidental brain MRI anomalies consistent with CNS demyelination were included. Within 12 MS centers in the U.S., participants were randomly assigned 1:1 to oral dimethyl fumarate (DMF) 240mg twice daily or placebo. The primary endpoint was the time to onset of clinical symptoms attributable to a CNS demyelinating event within a follow-up period of 96 weeks. An intention-to-treat analysis was applied to all participating individuals in the primary and safety investigations. The study is registered at ClinicalTrials.gov, NCT02739542 (ARISE). Results: Participants from 12 centers were recruited from March 9, 2016 to October 31, 2019 with 44 people randomized to dimethyl fumarate and 43 to placebo. Following DMF treatment, the risk of a first clinical demyelinating event during the 96-week study period was highly reduced in the unadjusted Cox proportional-hazards regression model (hazard ratio (HR)=0.18, 95% confidence interval (CI)=0.05-0.63, p=0.007). More moderate adverse reactions were present in the DMF (34 (32%)) than placebo groups (19 (21%)) but severe events were similar (DMF, 3 (5%); placebo, 4 (9%)). Interpretation: This is the first randomized clinical trial demonstrating the benefit of a disease-modifying therapy in preventing a first acute clinical event in people with RIS. This article is protected by copyright. All rights reserved.
Objective To describe the feasibility and outcomes of endovascular repair of distal aortic arch aneurysms using a patient-specific stent graft with a pre-loaded single retrograde left subclavian artery (LSA) branch stent graft.Methods We reviewed the clinical data and outcomes of consecutive patients enrolled in an ongoing prospective, non-randomized physician-sponsored investigational device exemption study to evaluate the outcomes of endovascular aortic arch repair using patient-specific arch branch stent grafts (William Cook Europe, Bjaeverskov, Denmark) between 2019 and 2022. All patients received a design with triple-wide scallop and a single retrograde LSA branch with a pre-loaded catheter.ResultsThere were five male patients with median age of 77 years old (72–80) treated using the single LSA branch stent graft. Technical success was achieved in all patients. Median operating time, fluoroscopy time, and total radiation dose area product were 103 (78–134) minutes, 26 (19–39) minutes, and 123 (71–270) mGy.cm2, respectively. There were no 30-day or in-hospital mortality, neurological or other major adverse events (MAEs). During median follow-up of 21 (20–27) months, all patients were alive with patent LSA branches, except for one who died of COVID-19 complications. There was no branch instability or secondary interventions.Conclusion This early feasibility study demonstrates successful endovascular repair of distal aortic arch aneurysms using a patient-specific stent graft with single retrograde LSA branch without technical failures, mortality or neurological events. Larger clinical experience and longer follow-up are needed to determined effectiveness of this approach in patients who need endovascular repair with proximal extension into Zone 2.
Sudden cardiac death is, by definition, an unexpected, untimely death caused by a cardiac condition in a person with known or unknown heart disease. This major international public health problem accounts for approximately 15-20% of all deaths. Typically more common in older adults with acquired heart disease, SCD also can occur in the young where the cause is more likely to be a genetically transmitted process. As these inherited disease processes can affect multiple family members, it is critical that these deaths are appropriately and thoroughly investigated. Across the United States, SCD cases in those less than 40 years of age will often fall under medical examiner/coroner jurisdiction resulting in scene investigation, review of available medical records and a complete autopsy including toxicological and histological studies. To date, there have not been consistent or uniform guidelines for cardiac examination in these cases. In addition, many medical examiner/coroner offices are understaffed and/or underfunded, both of which may hamper specialized examinations or studies (eg. molecular testing). Use of such guidelines by pathologists in cases of SCD in decedents aged 1 to 39 years of age could result in life-saving medical intervention for other family members. These recommendations also may provide support for underfunded offices to argue for the significance of this specialized testing. As cardiac examinations in the setting of SCD in the young fall under ME/C jurisdiction, this consensus paper has been developed with members of the Society of Cardiovascular Pathology working with cardiovascular pathology-trained, practicing forensic pathologists.
Objective: To compare the rates of adverse outcomes with postpartum hemorrhage (PPH) before and after implementation of drills or simulation exercises. Study eligibility criteria: We included all English studies that reported on rates of PPH and associated complications during the pre- and post-implementation of interventional exercises. Study apprasial and synthesis methods: Two investigators independently reviewed the abstracts, and full articles for eligibility of all studies. Inconsistencies related to study evaluation or data extraction were resolved by a third author. The co-primary outcomes were the rate of PPH and of any transfusion; the secondary outcomes included admission to the intensive care unit (ICU), transfusion ≥ 4 units of packed red blood cells, hysterectomy, or maternal death. Study effects were combined by Bayesian meta-analysis and reported as risk ratios (RR) and 95% credible intervals (Cr). Results: We reviewed 142 full length articles. Of these, 18 publications, with 355,060 deliveries-150,562 (42%) deliveries during the pre-intervention and 204,498 (57.6%) deliveries in the post-interventional period-were included in the meta-analysis. Using the Newcastle-Ottawa Scale, only three studies were considered good quality, and none of them were done in the US. The rate of PPH prior to intervention was 5.06% and 5.46% afterwards (RR 1.09, 95% CI 0.87-1.36; probability of reduction in the diagnosis being 21%). The likelihood of transfusion decreased from 1.68% in the pre-intervention to 1.27% in the post-intervention period (RR 0.80, 95% Cr 0.57-1.09). The overall probability of reduction in transfusion was 93%, albeit it varied among studies done in non-US countries (96%) versus in the US (23%). Transfusion of 4 units or more of blood occurred in 0.44% of deliveries before intervention and 0.37% afterwards (RR of 0.85, 95% CI 0.50-1.52), with the overall probability of reduction being 72% (76% probability of reduction in studies from non-US countries and 49% reduction with reports from the US). Surgical interventions to manage PPH, which was not reported in any US studies, occurred in 0.14% before intervention and 0.28% afterwards (RR 1.29; 95% CI 0.56-3.06; probability of reduction 27%). Admission to the ICU occurred in 0.10% before intervention and 0.08% subsequently (RR 0.92, 95% CI 0.58-1.43), with the overall probability of reduction being 65% (81% in studies from non-US countries and 27% from the study done in the US). Maternal death occurred in 0.17% in the pre-intervention period and 0.09% during the post-intervention (RR 0.62, 95% CI 0.33-1.05; probability of reduction 93% in studies from non-US countries and 82% in one study from the US). Conclusions: Interventions to reduce the sequelae of PPH are associated with decrease in adverse outcomes. The conclusion, however, ought not to be accepted reflexively for the US population. All of the studies on the topic done in the US are of poor quality and the associated probability of reduction in sequelae are consistently lower than those done in other countries. Synopsis: Since the putative benefits of PPH drills or simulation exercises are based on poor quality pre- and post-intervention trials, policies recommending them ought to be revisited.
Background: Hypoglycemia is a leading cause of preventable hospitalization, and can increase morbidity, mortality, and length of hospital stay. Up to 35% of diabetic patients experience severe hypoglycemia during hospitalization; this concerns veterans, as 25% have been diagnosed with diabetes. Local problem: A medical-surgical unit in a Veterans Affairs facility saw increased hypoglycemic episodes, with 26.8 episodes per 1000 patient days. Staff noted knowledge deficits with how to manage hypoglycemia episodes. Methods: A pre-/post-implementation quality improvement project was conducted over 8 weeks. Interventions: An implementation bundle was used to improve hypoglycemic episodes, including patient and staff education, coordination between meal delivery and insulin coverage, and developing a hypoglycemia protocol. Results: Hypoglycemia rates significantly decreased to 10.27 per 1000 patient days (P = .001), and occasions where insulin was given with food increased significantly to 76.2% (P < .001). Conclusions: A bundled approach was effective in decreasing hypoglycemia episodes and improved consistent management of hypoglycemia.
Background: The SoliMix study reported improved HbA1c with weight benefit and less hypoglycaemia with iGlarLixi versus BIAsp 30 in adults with suboptimally controlled type 2 diabetes using basal insulin. Here we report pre-specified and post hoc analyses of the SoliMix dataset exploring the impact of baseline participant characteristics on the original SoliMix study outcomes, to enable informed treatment choices for people with different biomedical characteristics. Methods: SoliMix (EudraCT 2017-003370-13) compared once-daily iGlarLixi (a fixed-ratio combination of insulin glargine 100 U/mL and the GLP-1 receptor agonist lixisenatide) with twice-daily BIAsp 30 (30% insulin aspart and 70% insulin aspart protamine). In this analysis, the original primary outcomes of non-inferiority of iGlarLixi versus BIAsp 30 in HbA1c change and superiority in body weight change, together with change in basal insulin dose and hypoglycaemia outcomes, were investigated by baseline age, duration of diabetes, insulin dose, HbA1c, BMI, and renal function. Results: No evidence of difference in comparative treatment effect was detected across baseline age, duration of diabetes, insulin dose, HbA1c, BMI, and renal function subgroups for any endpoint (all heterogeneity p>0.05), except ADA Level 2 hypoglycaemia event rate when stratified by insulin dose (p=0.011), which may be a chance difference given multiple testing and the small numbers of Level 2 events. Conclusions: Treatment effects of iGlarLixi were consistent irrespective of baseline HbA1c, insulin dose, BMI, age, duration of diabetes, and renal function, supporting the use of iGlarLixi as an efficacious and well-tolerated treatment option in people with type 2 diabetes with a wide range of biomedical characteristics. This article is protected by copyright. All rights reserved.
Patients with severe refractory hypoxemic respiratory failure may benefit from extracorporeal membrane oxygenation (ECMO) for salvage therapy. The Coronavirus disease 2019 (COVID-19) pandemic offered three high-volume independent ECMO programs at a large medical center the chance to collaborate to optimize ECMO care at the beginning of the pandemic in Spring 2020. Between March 15, 2020, and May 30, 2020, 3,615 inpatients with COVID-19 were treated at the Texas Medical Center. During this time, 35 COVID-19 patients were cannulated for ECMO, all but one in a veno-venous configuration. At hospital discharge, 23 (66%) of the 35 patients were alive. Twelve patients died of vasodilatory shock (n = 9), intracranial hemorrhage (n = 2), and cannulation-related bleeding and multiorgan dysfunction (n = 1). The average duration of ECMO was 13.6 days in survivors and 25.0 days in nonsurvivors (p < 0.04). At 1 year follow-up, all 23 discharged patients were still alive, making the 1 year survival rate 66% (23/35). At 2 years follow-up, the overall rate of survival was 63% (22/35). Of those patients who survived 2 years, all were at home and alive and well at follow-up.
Background: Atopic dermatitis (AD) is an inflammatory and immune skin disorder. Basic leucine zipper transcription factor ATF-like (BATF) plays a key role in regulating the differentiation and functions of lymphocytes. However, the mechanism underlying the transcriptional regulation of BATF on AD is still not well understood. Methods: BATF knockout (BATF-/-) and C57BL/6(B6) mice were used for the development of spontaneous dermatitis. 17β-Estradiol was injected intraperitoneally to induce AD. The lesioned tail skin of the mice was stained with hematoxylin and eosin to analyze the pathological characteristics. Impaired skin barrier function was assessed by measuring the transepidermal water loss (TEWL). The skin epithelial barrier indicators and cytokine mRNA levels were quantified by real-time quantitative PCR. The total serum immunoglobulin E (IgE) levels were measured by enzyme-linked immunosorbent assay (ELISA). T lymphocytes were analyzed using flow cytometry. Results: Ablation of BATF led to the spontaneous development of AD only in female mice and not in male mice. BATF deletion led to elevated serum levels of IgE and increased infiltration of eosinophils, neutrophils, and lymphocytes and promoted cytokine production including IL-4, IL-22, IL-1β, IFN-γ, and TNF-α in the lesioned tail skin of the mice. The mRNA expression levels of filaggrin and loricrin significantly decreased, while S100A8 and S100A9 increased in female BATF-/- mice. BATF-deficient female mice were found to increase proliferation and IL-5 production by skin-infiltrating CD4+ T cells which implies Th2 activation. Moreover, AD was successfully induced only in the estradiol-treated BATF-deficient male mice and not in WT male mice. Estradiol enhanced the allergic and immunological responses to dermatitis primarily by triggering Th2-type immune responses via enhanced serum IgE and inflammatory cytokine levels in the male BATF-/- mice. Conclusion: The study concluded that BATF potentiates estradiol to induce mouse atopic dermatitis via potentiating inflammatory cytokine releases and Th2-type immune responses and may have important clinical implications for patients with AD.
FOXP3 is the lineage-defining transcription factor for Tregs, a cell type critical to immune tolerance, but the mechanisms that control FOXP3 expression in Tregs remain incompletely defined, particularly as it relates to signals downstream of TCR and CD28 signaling. Herein, we studied the role of IRF4 and BATF3, two transcription factors upregulated upon T cell activation, to the conversion of conventional CD4+ T cells to FOXP3+ T cells (iTregs) in vitro . We found that IRF4 must partner with BATF3 to bind to a regulatory region in the Foxp3 locus where they cooperatively repress FOXP3 expression and iTreg induction. In addition, we found that interactions of these transcription factors are necessary for glycolytic reprogramming of activated T cells that is antagonistic to FOXP3 expression and stability. As a result, Irf4 KO iTregs show increased demethylation of the critical CNS2 region in the Foxp3 locus. Together, our findings provide important insights how BATF3 and IRF4 interactions integrate activating signals to control CD4+ cell fate decisions and govern Foxp3 expression.
Aim: To assess patient-reported outcomes (PROs) in the SoliMix trial, which compared the efficacy and safety of iGlarLixi versus BIAsp 30 in people with type 2 diabetes (T2D). Materials and methods: SoliMix (EudraCT: 2017-003370-13), a 26-week, open-label study, randomized (1:1) 887 adults with T2D and HbA1c ≥7.5%-≤10.0% (≥58-≤86 mmol/mol) on basal insulin plus oral antihyperglycaemic drugs (OADs) to once-daily iGlarLixi or twice-daily premix insulin, BIAsp 30. PROs were assessed using the Treatment-Related Impact Measure Diabetes (TRIM-D) and Global Treatment Effectiveness Evaluation (GTEE) questionnaires. Results: Over 26 weeks, iGlarLixi showed greater improvement from baseline versus BIAsp 30 in total TRIM-D score (least squares mean difference [95% confidence interval]: 5.08 [3.69, 6.47]; effect size: 0.32) and in each TRIM-D domain, with the greatest differences seen in diabetes management (8.47 [6.11, 10.84]) and treatment burden (6.95 [4.83, 9.07]). GTEE scores showed a greater proportion of participants and physicians rated a complete or marked improvement of diabetes control with iGlarLixi (80.5%, 82.8%) versus BIAsp 30 (63.3%, 65.1%) at week 26. Post hoc analyses showed that after adjusting for HbA1c, body weight and hypoglycaemia outcomes, iGlarLixi continued to show greater improvements in TRIM-D total scores versus BIAsp 30. Conclusions: In addition to better glycaemic control, weight benefit and less hypoglycaemia, once-daily iGlarLixi provided improved diabetes management, treatment burden and perceived effectiveness versus twice-daily premix BIAsp 30, further supporting iGlarLixi as an advanced treatment option in people with suboptimally controlled T2D on basal insulin plus OADs.
Aims: To explore details of the incidence and rates of daytime and nocturnal hypoglycaemia, levels of hypoglycaemia, and relationship to glycated haemoglobin (HbA1c), when comparing iGlarLixi versus premixed biphasic insulin aspart 30 (BIAsp 30) in the SoliMix randomized controlled trial. Materials and methods: This exploratory analysis of SoliMix used logistic regression and negative binomial regression analyses to assess between-treatment differences in the incidence and rates of hypoglycaemia by time of day. A negative binomial model was used to derive estimated annualized hypoglycaemia rates as a function of HbA1c. Results: iGlarLixi was associated with lower incidence and rates of American Diabetes Association Level 2 (<54 mg/dL [<3.0 mmol/L]) hypoglycaemia during both night and day versus BIAsp 30. Incidence and rates of Level 1 (<70 to ≥54 mg/dL [<3.9 to ≥3.0 mmol/L]) hypoglycaemia were also mostly shown to be reduced with iGlarLixi versus BIAsp 30. Severe (Level 3) events were too few for analysis (n = 3). iGlarLixi was associated with lower modelled event rates of Level 2 and Level 1 hypoglycaemia over a wide range of HbA1c levels versus BIAsp 30. Conclusions: These results show that the lower HbA1c levels and weight benefit seen with iGlarLixi versus premixed BIAsp 30 in people with type 2 diabetes advancing their basal insulin therapy in the SoliMix trial are also accompanied by a lower risk of hypoglycaemia at any time of day and across a broad range of HbA1c levels.
Cirrhosis is complicated by a high rate of nosocomial infections (NI), which result in poor outcomes, and are challenging to predict using clinical variables alone. Determine predictors of NI using admission serum metabolomics and gut microbiota in inpatients with cirrhosis. In this multi‐center inpatient cirrhosis study, serum was collected on admission for LC/MS metabolomics and a subset provided stool for 16SrRNA analysis. Hospital course, including NI development and death were analyzed. Metabolomic analysis using ANCOVA (demographics, admission MELD, WBC, rifaximin, and infection status‐adjusted) and random forest analyses for NI development were performed. Additional value of serum metabolites over clinical variables towards NI was evaluated using logistic regression. Stool microbiota and metabolomic correlations were compared in patients with/without NI development. 602 patients (231 admission infection) were included. 101 (17%) developed NI, which resulted in worse inpatient outcomes including ICU transfer, organ failures and death. 127 patients also gave stool, of which 20 developed NI. The most common NIs were SBP followed by UTI, C.difficile and pneumonia. 247 metabolites were significantly altered on ANCOVA. Higher MELD (OR 1.05,p<0.0001), admission infection (3.54,p<0.0001) and admission WBC (1.05,p=0.04) predicted NI (AUC 0.74), which increased to 0.77(p=0.05) with lower 1‐linolenoyl‐GPC and 1‐stearoyl‐GPC and higher N‐acetyltryptophan and N‐acetyl isoputreanine. Commensal microbiota were lower and pathobionts higher in those who developed NI. Microbial‐metabolite correlation networks were complex and dense in NI patients, especially focused on Ruminococcaceae and Pseudomonadaceae. NIs are common and associated with poor outcomes in cirrhosis. Admission gut microbiota in NI patients showed higher pathobionts and lower commensal microbiota. Microbial‐metabolomic correlations were more complex, dense, and homogeneous among those who developed NI, indicating greater linkage strength. Serum metabolites and gut microbiota on admission are associated with NI development in cirrhosis.
An 85-year-old female with severe aortic valve stenosis presented with heart failure complicated with cardiogenic shock and was found to have a right coronary cusp sinus of Valsalva aneurysm. We report the first case of successful exclusion of a sinus of Valsalva aneurysm during transcatheter aortic valve replacement using a balloon-expandable valve. (Level of Difficulty: Intermediate.) (J Am Coll Cardiol Case Rep 2022;4:787-789) © 2022 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). CASE PRESENTATION Sinus of Valsalva aneurysm (SVA) is defined as an asymmetric dilation of the aortic root area between the aortic valve annulus and the sinotubular ridge. Successful exclusion of SVA has been described during self-expandable transcatheter valve replacement (TAVR) in aortic stenosis. 1,2 We report the first case of a successful occlusion of a SVA during TAVR with severe aortic stenosis using a balloon-expandable valve. An 85-year-old female with hypertension, hypercholesterolemia, stroke, coronary artery disease, chronic kidney disease, atrial fibrillation, and asthma was admitted to the hospital with refractory heart failure and cardiogenic shock. On arrival she was afebrile, her blood pressure was 95/60 mm Hg, her heart rate was 109 beats/m, her respiratory rate was 20 rpm, and her oxygen saturation was 88% at room air. She was in moderate distress, with elevated jugular venous pulse, a harsh 3/6 systolic murmur irradiated to carotids, and crackles in 2/3 of both lungs. The patient had severe aortic stenosis (mean aortic gradient: 42 mm Hg; aortic valve area: 0.6 cm 2 ; annular area: 360 mm 2), with a left ventricular ejection fraction of 45%. After the patient was stabilized with noninvasive ventilation, diuretics, and intravenous dobutamine, the heart team was consulted for aortic valve replacement. Transthoracic echocardiography revealed a partially calcified SVA limited to the right coronary cusp, which was confirmed using computed tomography angiography (Figure 1A). A virtual 23-mm
CD8+ T cells are central mediators of immune responses against infections and cancer. Here we identified Dapl1 as a crucial regulator of CD8+ T cell responses to cancer and infections. Dapl1 deficiency promotes the expansion of tumour-infiltrating effector memory-like CD8+ T cells and prevents their functional exhaustion, coupled with increased antitumour immunity and improved efficacy of adoptive T cell therapy. Dapl1 controls activation of NFATc2, a transcription factor required for the effector function of CD8+ T cells. Although NFATc2 mediates induction of the immune checkpoint receptor Tim3, competent NFATc2 activation prevents functional exhaustion of CD8+ T cells. Interestingly, exhausted CD8+ T cells display attenuated NFATc2 activation due to Tim3-mediated feedback inhibition; Dapl1 deletion rescues NFATc2 activation and thereby prevents dysfunction of exhausted CD8+ T cells in chronic infection and cancer. These findings establish Dapl1 as a crucial regulator of CD8+ T cell immunity and a potential target for cancer immunotherapy. Zhu et al. identify Dapl1 as a negative regulator of CD8+ T cell responses by modulating NFATc2 activation and T cell exhaustion, leading to dysregulated control of chronic infection and cancer.
Multimodal polygraphy including cardiorespiratory monitoring is a valuable tool for epilepsy and sudden unexpected death in epilepsy (SUDEP) research. Broader applications in research into stress, anxiety, mood and other domains exist. Polygraphy techniques used during video electroencephalogram (EEG) recordings provide information on cardiac and respiratory changes in the peri-ictal period. In addition, such monitoring in brain mapping during chronic intracranial EEG evaluations has helped the understanding of pathomechanisms that lead to seizure induced cardiorespiratory dysfunction. Our aim here is to provide protocols and information on devices that may be used in the Epilepsy Monitoring Unit, in addition to proposed standard of care data acquisition. These devices include oronasal thermistors, oronasal pressure transducers, capnography, transcutaneous CO2 sensors and continuous noninvasive blood pressure monitoring. Standard protocols for cardiorespiratory monitoring simultaneously with video EEG recording, may be useful in the study of cardiorespiratory phenomena in persons with epilepsy.
In patients with inherited bleeding disorders, thrombus development poses a challenge in balancing the management of thrombosis and bleeding. Pediatric antithrombotic therapy guidelines do not address the treatment of a thrombus in the setting of a bleeding disorder. We present a case series of four children with inherited bleeding disorders presenting with cerebral sinus venous thrombosis and bleeding, in order to summarize the different therapeutic approaches and outcomes of these patients.
Multimodal polygraphy including cardiorespiratory monitoring in the Epilepsy Monitoring is becoming increasingly important. In addition to simultaneous recording of video and EEG, the combination of these techniques not only improves seizure detection, it enhances patient safety and provides information on autonomic clinical symptoms, which may be contributory to localization of seizure foci. However, there are currently no consensus guidelines, nor adequate information on devices available for multimodal polygraphy for cardiorespiratory monitoring in the Epilepsy Monitoring Unit. Our purpose here is to provide protocols and information on devices for such monitoring. Suggested parameters include respiratory inductance plethysmography (thoraco-abdominal belts for respiratory rate), pulse oximetry and four-lead electrocardiography. Detailed knowledge of devices, their operability and acquisition optimization enables accurate interpretation of signal and differentiation of abnormalities from artifacts. Multimodal polygraphy brings new opportunities for identification of peri-ictal cardiorespiratory abnormalities, and may identify high SUDEP risk individuals.
Background aims: Frailty and sarcopenia are common complications of advanced liver disease. Due to associated morbidity/mortality, there have been targeted efforts to prevent and/or improve both by enrolling these patients in focused exercise programs. This review systematically analyzes the data of randomized clinical trials (RCT) on anthropometric, physical fitness, quality of life, and safety outcomes of exercise interventions in patients with advanced liver disease. Methods: Two authors independently searched trials on PubMed and EMBASE from inception up to 11/18/2021. A third independent arbitrator adjudicated all disagreements. We qualitatively summarized these outcomes: 1) muscular fitness (maximal inspiratory/expiratory pressures, muscle size, muscle strength, and bioimpedance testing); 2) cardiorespiratory fitness (cardiopulmonary exercise testing, 6-minute walk distance), 3) quality of life, and 4) others (safety or frailty indices). Results: There were eleven RCTs (4 home-based interventions) with 358 participants. Interventions ranged from 8-14 weeks and included cycling, walking, resistance exercises, balance and coordination training, and respiratory exercises. All described outcomes compared pre- to post-intervention measurements. Nine studies showed statistically significant improvements in at least one physical fitness variable. Ten studies showed statistically significant improvements in at least one muscular fitness variable. Six studies showed statistically significant improvements in at least one quality of life variable. Attrition rates ranged from 5-36% and adherence rates ranged very widely from 14-100%. Only one study reported frailty indices. Notably, no complications of portal hypertension were seen in intervention groups in the nine studies that reported this data. Conclusions: A review of eleven randomized clinical trials with 358 participants with advanced liver disease demonstrates that exercise interventions can have favorable outcomes on muscular/cardiorespiratory fitness, and quality of life. While attrition and adherence varied, these interventions appear to be safe in patients with cirrhosis and are well tolerated.
Background and Purpose. The optic nerve is surrounded by the extension of meningeal coverings of the brain. When the pressure in the cerebrospinal fluid increases, it causes a distention of the optic nerve sheath diameter (ONSD), which allows the use of this measurement by ultrasonography (US) as a noninvasive surrogate of elevated intracranial pressure. However, ONSD measurements in the literature have exhibited significant heterogeneity, suggesting a need for consensus on ONSD image acquisition and measurement. We aim to establish a consensus for an ONSD US Quality Criteria Checklist (ONSD US QCC). Methods A scoping systematic review of published ultrasound ONSD imaging and measurement criteria was performed to guide the development of a preliminary ONSD US QCC that will undergo a modified Delphi study to reach expert consensus on ONSD quality criteria. The protocol of this modified Delphi study is presented in this manuscript. Results A total of 357 ultrasound studies were included in the review. Quality criteria were evaluated under five categories: probe selection, safety, positioning, image acquisition, and measurement. Conclusions This review and Delphi protocol aim to establish ONSD US QCC. A broad consensus from this process may reduce the variability of ONSD measurements in future studies, which would ultimately translate into improved ONSD clinical applications. This protocol was reviewed and endorsed by the German Society of Ultrasound in Medicine.
Background The single patient (n-of-1) trial can be used to resolve therapeutic uncertainty for the individual patient. Treatment alternatives are systematically tested against each other, generating patient-specific data used to inform an individualized treatment plan. We hypothesize that clinical decisions informed by n-of-1 trials improve patient outcomes compared to usual care. Our objective was to provide an overview of the clinical trial evidence on the effect of n-of-1 trials on clinical outcomes. Methods A systematic search of medical databases, trial registries, and gray literature was performed to identify trials assessing clinical outcomes in a group of patients undergoing an n-of-1 trial compared to those receiving usual care for any clinical condition. We abstracted elements related to study design and results and assessed risk of bias for both the overall randomized trials and the n-of-1 trials. The review was registered on PROSPERO. (CRD: 42020166490). Findings Twelve randomized trials of the n-of-1 approach were identified in conditions spanning chronic pain, osteoarthritis, chronic irreversible airflow limitation, attention-deficit hyperactivity disorder, hyperlipidemia, atrial fibrillation, statin intolerance, and hypertension. One trial showed a statistically significant benefit in the primary outcome. Only one reached the pre-specified sample size target. Secondary outcomes showed modest benefits, including decreasing medication use, fewer atrial fibrillation episodes, and improved patient satisfaction. Interpretation Very few trials have been undertaken to assess the effectiveness of n-of-1 trials in improving clinical outcomes, and most trials were underpowered for the primary outcome. Barriers to enrollment and retention in these trials should be explored, as well-powered randomized trials are needed to clarify the clinical impact of n-of-1 trials and assess their utility in clinical practice.
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