Effect of low-volume exercise on hepatic steatosis in adults with obesity plus normal glucose, prediabetes or type 2 diabetes: a randomised controlled trial.

Objectives: This study aimed to evaluate the effects of a novel, low-volume combined high-intensity interval training (HIIT) and progressive resistance training (PRT) in overweight/obese adults. Methods: This randomised control trial compared the effect of regular supervised HIIT combined with PRT (Exercise) with an unsupervised stretching intervention (Control), in previously inactive adults with either normal glucose (NG), pre-diabetes or type 2 diabetes (T2DM) with body mass index of >25 kg/m2. Participants were randomly allocated (1:1) to receive low-volume exercise or control by an online randomisation tool. The primary outcome was the difference in change of hepatic steatosis between Exercise and Control. A prespecified sensitivity analysis was undertaken for weight stable participants (<5% change in bodyweight from baseline). Secondary outcomes were change in hepatic steatosis within the glucose groups, glycaemic control, cardiorespiratory fitness, muscle strength and body composition. Results: Between June 2018 and May 2021, 162 participants were randomly assigned (NG: 76, pre-diabetes: 60, T2DM: 26) and 144 were included in the final analysis. Mean absolute change in hepatic steatosis was -1.4% (4.9) in Exercise (n=73) and -0.1% (7.2) in Control (n=71)(p=0.25). By preplanned sensitivity analysis, the mean change in hepatic steatosis with Exercise (n=70) was -1.5% (5) compared with 0.7% (4.6) with Control (n=61) (p=0.017). Subgroup analysis within the glucose groups showed that exercise reduced hepatic steatosis in those with pre-diabetes but not NG or T2DM (pre-diabetes: -1.2% (4.4) in Exercise and 1.75% (5.7) in Control, p=0.019). Conclusion: These findings show that low-volume HIIT with PRT yields improvements in muscle strength and cardiorespiratory fitness and may have a small effect on hepatic steatosis. Trial registration number: The trial was prospectively registered with the ANZCTR (ACTRN12617000552381).

Examining the upper frequency limit of dynamic cerebral autoregulation: Considerations across the cardiac cycle during eucapnia.

There are differences within the literature regarding the upper frequency cut-off point of the dynamic cerebral autoregulation (CA) high-pass filter. The projection pursuit regression approach has demonstrated that the upper frequency limit is ∼0.07 Hz, whereas another approach [transfer function analysis (TFA) phase approaching zero] indicated a theoretical upper frequency limit for the high-pass filter of 0.24 Hz. We investigated how these limits accurately represent the CA upper frequency limit, in addition to extending earlier findings with respect to biological sexes and across the cardiac cycle. Sixteen participants (nine females and seven males) performed repeated squat-stand manoeuvres at frequencies of 0.05, 0.10, 0.15, 0.20 and 0.25 Hz, with insonation of the middle and posterior cerebral arteries. Linear regression modelling with adjustment for sex and order of squat completion was used to compared TFA gain and phase with 0.25 Hz (above the theoretical limit of CA). The upper frequency limit of CA with TFA gain was within the range of 0.05-0.10 Hz, whereas TFA phase was within the range of 0.20-0.25 Hz, and consistent between vessels, between sexes and across the cardiac cycle. Females displayed greater middle cerebral artery gain compared with males (all P < 0.047), and no phase differences were present (all P > 0.072). Although sex-specific differences were present for specific TFA metrics at a given frequency, the upper frequency limit of autoregulation was similar between cerebral conduit vessels, cardiac cycle phase and biological sex. Future work is warranted to determine whether an upper frequency limit exists with respect to hysteresis analyses.

High-intensity interval training for cardiometabolic health in adults with metabolic syndrome: a systematic review and meta-analysis of randomised controlled trials.

OBJECTIVE: To assess the effectiveness of high-intensity interval training (HIIT) compared with traditional moderate-intensity continuous training (MICT) and/or non-exercise control (CON) for modification of metabolic syndrome (MetS) components and other cardiometabolic health outcomes in individuals with MetS. DESIGN: Systematic review and meta-analysis DATA SOURCES: Five databases were searched from inception to March 2024. STUDY APPRAISAL AND SYNTHESIS: Meta-analyses of randomised controlled trials (RCTs) comparing HIIT with MICT/CON were performed for components of MetS (waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein cholesterol (HDL-C), triglyceride (TG), and fasting blood glucose (BG)) and clinically relevant cardiometabolic health parameters. Subgroup moderator analyses were conducted based on the intervention duration and HIIT volume. RESULTS: Out of 4819 studies, 23 RCTs involving 1374 participants were included (mean age: 46.2-67.0 years, 55% male). HIIT significantly improved WC (weighted mean difference (WMD) -4.12 cm, 95% CI -4.71 to -3.53), SBP (WMD -6.05 mm Hg, 95% CI -8.11 to -4.00), DBP (WMD -3.68 mm Hg, 95% CI -5.70 to -1.65), HDL-C (WMD 0.12 mmol/L, 95% CI 0.04 to 0.20), TG (WMD -0.34 mmol/L, 95% CI -0.41 to -0.27) and BG (WMD -0.35 mmol/L, 95% CI -0.54 to -0.16) compared with CON (all p<0.01). HIIT approaches demonstrated comparable effects to MICT across all parameters. Subgroup analyses suggested that HIIT protocols with low volume (ie, <15 min of high-intensity exercise per session) were not inferior to higher volume protocols for improving MetS components. CONCLUSION: This review supports HIIT as an efficacious exercise strategy for improving cardiometabolic health in individuals with MetS. Low-volume HIIT appears to be a viable alternative to traditional forms of aerobic exercise.

The global and national energy systems techno-economic (GNESTE) database: Cost and performance data for electricity generation and storage technologies.

Power sector and energy systems models are widely used to explore the impacts of demographic, socio-economic or policy changes on the cost and emissions of electricity generation. Technology cost and performance data are essential inputs to such models. Despite the ubiquity and importance of these parameters, there is no standardised database which collates the variety of values from across the literature, so modellers must collect them independently each time they populate or update model inputs, leading to duplicated efforts and inconsistencies which can profoundly influence model results. Technology cost and performance varies between countries, regions and over time, meaning that data must be country- or region-specific and frequently updated. Values also vary widely between sources, so obtaining a broad consensus view is critical. Here, we present a database which collates historical, current, and future cost and performance data and assumptions for the six most prominent electricity generation technologies; coal, gas, hydroelectric, nuclear, solar photovoltaic (PV) and wind power, which together accounted for over 92 % of installed generation capacity in 2022. In addition, we provide the same data for utility-scale battery energy storage systems (BESS), regarded as critical to the integration of variable renewables such as wind and solar PV. The data are global in scope but with regional and national specificity, covers the years 2015 through to 2050, and span 5518 datapoints from 56 sources. The database enables modellers to select and justify model input data and provides a benchmark for comparing assumptions and projections to other sources across the literature to validate model inputs and outputs. It is designed to be easily updated with new sources of data, ensuring its utility, comprehensiveness, and broad applicability in future.

Circulating CD31+ Angiogenic T cells are reduced in prediabetes and increase with exercise training.

AIMS: To investigate circulating angiogenic cells in adults with prediabetes and the effect of a structured exercise program. METHODS: A cohort of adults with overweight/obesity and either normal glucose (NG) or prediabetes were randomised to receive exercise (Exercise) (as twice weekly supervised combined high intensity aerobic exercise and progressive resistance training, and once weekly home-based aerobic exercise) or an unsupervised stretching intervention (Control) for 12 weeks. Circulating angiogenic T cells, muscle strength, and cardiovascular disease risk factors, including blood lipids, arterial stiffness, central haemodynamic responses, and cardiorespiratory fitness (VO2peak) in those with prediabetes (n = 35, 16 Control, 19 Exercise) and NG (n = 37, 17 Control, 20 Exercise) were analysed at baseline and after the 12-week intervention. RESULTS: At baseline, compared with NG those with prediabetes demonstrated reduced VO2peak, angiogenic CD31+CD8+ T cells and VEGFR2+CD4+ T cells, and increased systolic blood pressure. CD31+ T cells were negatively correlated with cardiovascular disease (CVD) risk. Compared with Control, exercise training increased muscle strength, VO2peak, and CD31+CD4+ and CD31+CD8+ T cells in NG and prediabetes. CONCLUSIONS: Circulating angiogenic CD31+ T cells are decreased in people with prediabetes and are enhanced with exercise training. Exercise increases CD31+ T cells, and through this mechanism it is proposed that it may reduce CVD risk. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry number: ACTRN12617000552381.

Technology-Based Interventions, with a Stepped Care Approach, for Reducing Sexual Risk Behaviors and Increasing PrEP Initiation Among Transgender and Gender Expansive Youth and Young Adults.

TechStep was a technology-based trial, with a stepped care approach, to reduce sexual risks and increase PrEP uptake among transgender and gender expansive youth and young adults (15-24 years old). From October 2019 to September 2021, 254 participants were randomized into: 1) Text (n = 82), or 2) Webapp (n = 87), or 3) Control (n = 85). At the 3-month follow-up assessment, those randomized to Text and Webapp and did not demonstrate improvement on primary outcomes were re-randomized to receive virtual eCoaching (Text + or Webapp +), or to remain in their initial condition without eCoaching. Results showed no effect on condomless encounters at 6-month, the primary endpoint, when comparing the Webapp + (0.33 decrease; 95%CI: -0.01, 0.67, p-value = 0.057) or the Text + (0.27 decrease; 95%CI: -0.13, 0.68, p-value = 0.181) conditions to the Control condition. However, in secondary analyses, condomless encounters were significantly reduced for Text compared to Control. The rate of PrEP uptake was low for all study arms.Trial registration: Clinical Trials # NCT04000724 (registered June 26, 2019).

Active Learning for Rapid Targeted Synthesis of Compositionally Complex Alloys.

The next generation of advanced materials is tending toward increasingly complex compositions. Synthesizing precise composition is time-consuming and becomes exponentially demanding with increasing compositional complexity. An experienced human operator does significantly better than a novice but still struggles to consistently achieve precision when synthesis parameters are coupled. The time to optimize synthesis becomes a barrier to exploring scientifically and technologically exciting compositionally complex materials. This investigation demonstrates an active learning (AL) approach for optimizing physical vapor deposition synthesis of thin-film alloys with up to five principal elements. We compared AL-based on Gaussian process (GP) and random forest (RF) models. The best performing models were able to discover synthesis parameters for a target quinary alloy in 14 iterations. We also demonstrate the capability of these models to be used in transfer learning tasks. RF and GP models trained on lower dimensional systems (i.e., ternary, quarternary) show an immediate improvement in prediction accuracy compared to models trained only on quinary samples. Furthermore, samples that only share a few elements in common with the target composition can be used for model pre-training. We believe that such AL approaches can be widely adapted to significantly accelerate the exploration of compositionally complex materials.

Extracellular domain, hinge, and transmembrane determinants affecting surface CD4 expression of a novel anti-HIV chimeric antigen receptor (CAR) construct.

Chimeric antigen receptor (CAR)-T cells have demonstrated clinical potential, but current receptors still need improvements to be successful against chronic HIV infection. In this study, we address some requirements of CAR motifs for strong surface expression of a novel anti-HIV CAR by evaluating important elements in the extracellular, hinge, and transmembrane (TM) domains. When combining a truncated CD4 extracellular domain and CD8α hinge/TM, the novel CAR did not express extracellularly but was detectable intracellularly. By shortening the CD8α hinge, CD4-CAR surface expression was partially recovered and addition of the LYC motif at the end of the CD8α TM fully recovered both intracellular and extracellular CAR expression. Mutation of LYC to TTA or TTC showed severe abrogation of CAR expression by flow cytometry and confocal microscopy. Additionally, we determined that CD4-CAR surface expression could be maximized by the removal of FQKAS motif at the junction of the extracellular domain and the hinge region. CD4-CAR surface expression also resulted in cytotoxic CAR T cell killing of HIV Env+ target cells. In this study, we identified elements that are crucial for optimal CAR surface expression, highlighting the need for structural analysis studies to establish fundamental guidelines of CAR designs.

Does exercise modality and posture influence cerebrovascular and cardiovascular systems similarly?

Cerebral hemodynamics have been quantified during exercise via transcranial Doppler ultrasound, as it has high-sensitivity to movement artifacts and displays temporal superiority. Currently, limited research exists regarding how different exercise modalities and postural changes impact the cerebrovasculature across the cardiac cycle. Ten participants (4 females and 6 males) ages 20-29 completed three exercise tests (treadmill, supine, and upright cycling) to volitional fatigue. Physiological data collected included middle cerebral artery velocity (MCAv), blood pressure (BP), heart rate, and respiratory parameters. Normalized data were analyzed for variance and effect sizes were calculated to examine differences between physiological measures across the three exercise modalities. Systolic MCAv was greater during treadmill compared to supine and upright cycling (p < 0.001, (large) effect size), and greater during upright versus supine cycling (p < 0.017, (large)). Diastolic MCAv was lower during treadmill versus cycling exercise only at 60% maximal effort (p < 0.005, (moderate)) and no differences were observed between upright and supine cycling. No main effect was found for mean and diastolic BP (p > 0.05, (negligible)). Systolic BP was lower during treadmill versus supine cycling at 40% and 60% intensity (p < 0.05, (moderate-large)) and greater during supine versus upright at only 60% intensity (p < 0.003, (moderate)). The above differences were not explained by partial pressure of end-tidal carbon dioxide levels (main effect: p = 0.432). The current study demonstrates the cerebrovascular and cardiovascular systems respond heterogeneously to different exercise modalities and aspects of the cardiac cycle. As physiological data were largely similar between tests, differences associated with posture and modality are likely contributors.

Feasibility of superimposed supine cycling and lower body negative pressure as an effective means of prolonging exercise tolerance in individuals experiencing persisting post-concussive symptoms: Preliminary results.

To examine the feasibility, utility and safety of superimposed lower body negative pressure (LBNP) and tilt during supine cycling in individuals suffering from persisting post-concussive symptoms (PPCS). Eleven individuals aged 17-31 (6 females/5 males) participated in two randomized separate visits, 1 week apart. A ramp-incremental test was performed during both visits until volitional failure. Visits included no pressure (control) or LBNP at -40 Torr (experimental) with head-up tilt at 15 degrees (females) or 30 degrees (males). Transcranial Doppler ultrasound was utilized to quantify middle cerebral artery velocity (MCAv), while symptom reports were filled out before and 0, 10, and 60 min post-exertion. Ratings of exertion and overall condition followed similar trends for participants across both tests. The relative increase in MCAv was blunted during the experimental condition (8%) compared to control (24%), while a greater heart rate (17 beats/min) was achieved during the LBNP condition (P = 0.047). Symptom severity at the 0 and 10 min post-exertion time points displayed negligible-to-small effect sizes between conditions (Wilcoxon's r < 0.11). Symptom reporting was lower at the 60 min post-exertion time point with these displaying a moderate effect size (Wilcoxon's r = 0.31). The combination of LBNP and tilt during supine cycling did not change the participants' subjective interpretation of the exertional test but attenuated the hyperpnia-induced vasodilatory MCAv response, while also enabling participants to achieve a higher heart rate during exercise and reduced symptoms 1 h later. As this protocol is safe and feasible, further research is warranted in this area for developing PPCS treatment options. HIGHLIGHTS: What is the central question of this study? What are the feasibility, safety and utility of combining head-up tilt with lower body negative pressure during supine cycling for blunting the increase in cerebral blood velocity seen during moderate-intensity exercise in individuals experiencing persisting post-concussion symptoms? What is the main finding and its importance? Although no differences were found in symptoms between conditions within the first 10 min following exertion, symptom severity scores showed a clinically meaningful reduction 60 min following the experimental condition compared to the non-experimental control condition.

Time to Elicit Physiological and Exertional Vigorous Responses from Daily Living Activities: Setting Foundations of an Empirical Definition of VILPA.

PURPOSE: Vigorous intermittent lifestyle physical activity (VILPA) are bursts of incidental vigorous activity that occur during day-to-day activities outside of the exercise-domain. VILPA has shown promise in lowering risk of mortality and chronic disease. However, there is an absence of an empirically derived definition. Using physiological and effort-based metrics commonly used to define vigorous intensity, we investigated the minimum time needed to elicit physiological and perceived exertion responses to standardised activities of daily living. METHODS: Seventy adults (Age = 58.0 ± 9.6y; 35 female) completed 9 VILPA activities of daily living in a randomised order, that included: fast walking, fast incline walking, stair climbing, stationary cycling, and carrying external weight equal to 5% and 10% of body weight. Metabolic rate (by continuous indirect calorimetry), heart rate (telemetry) and perceived effort (Borg Scale) were measured during exercise. Time to reach VILPA was assessed using %VO 2 max, %HRmax, and rating of perceived exertion thresholds. RESULTS: The mean time to elicit VILPA ranged from 65-95 seconds (mean ± sd = 76.7 ± 3.8 seconds) for %VO 2 max, 68 to 105 seconds (mean ± sd = 82.8 ± 6.8 seconds) for %HRmax, and 20 to 60 seconds (mean ± sd = 44.6 ± 6.7 seconds) for rating of perceived exertion. For each of the three indices, there was no difference in the time to elicit VILPA responses by sex or age (p > 0.08), and times were also consistent between activities of daily living tasks. For example, for females and males, the average time to elicit vigorous responses while walking on a flat surface was 85.8 (±16.9) and 80 (±13.9) seconds, respectively, and for stair climbing while carrying 10% of body weight the duration was 78.4 (±17.6) and 76.9 (±17.7) seconds. CONCLUSIONS: When participants undertook activities of daily living, VILPA elicited a physiological response at an average of 77-83 seconds for %VO 2 max and %HRmax, and 45 seconds for perceived exertion. The absence of a difference in the time to reach VILPA between sex and age suggests that a consistent behavioural VILPA translation can be used in interventions and population-based studies designed to assess the health effects of incidental physical activity.

Promoting vigorous intermittent lifestyle physical activity (vilpa) in middle-aged adults: an evaluation of the movsnax mobile app.

BACKGROUND: Most adults fail to meet the moderate to vigorous physical activity-based recommendations needed to maintain or improve health. Vigorous Intermittent Lifestyle Physical Activity (VILPA) refers to short (1-2 min) high-intensity activities that are integrated into activities of daily living. VILPA has shown strong potential to improve health and addresses commonly reported barriers to physical activity. However, it is unknown how VILPA can best be promoted among the adult population. This study aimed to evaluate the usability, user engagement, and satisfaction of a mobile application (MovSnax) designed to promote VILPA. METHODS: A concurrent mixed methods design was used. It comprised four parts. Part A was a survey with n = 8 mHealth and physical activity experts who had used the app over 7-10 days. Part B was think-aloud interviews with n = 5 end-users aged 40-65 years old. Part C was a survey with a new group of 40-65-year-old end-users (n = 35) who had used the MovSnax app over 7-10 days. Part D was semi-structured interviews with n = 18 participants who took part in Part C. Directed content analysis was used to analyze the results from Parts A, B, and D, and descriptive statistics were used to analyze findings from Part C. RESULTS: Participants reported positive views on the MovSnax app for promoting VILPA but also identified usability issues such as unclear purpose, difficulties in manual data entry, and limited customization options. Across the different data collections, they consistently emphasized the need for more motivational features, clearer feedback, and gamification elements to enhance engagement. Quantitative assessment showed satisfactory scores on objective measures but lower ratings on subjective aspects, possibly due to unfamiliarity with the VILPA concept and/or technical barriers. CONCLUSIONS: The MovSnax app, tested in the present study, is the world's first digital tool aimed specifically at increasing VILPA. The findings of the present study underscore the need for further app refinement, focusing on clarifying its purpose and instructions, boosting user engagement through personalization and added motivational elements, enhancing accuracy in detecting VILPA bouts, implementing clearer feedback mechanisms, expanding customization choices (such as font size and comparative data), and ensuring transparent and meaningful activity tracking.

Filling the gaps on root hair development under salt stress and phosphate starvation using current evidence coupled with a meta-analysis approach.

Population expansion is a global issue, especially for food production. Meanwhile, global climate change is damaging our soils, making it difficult for crops to thrive and lowering both production and quality. Poor nutrition and salinity stress affect plant growth and development. Although the impact of individual plant stresses has been studied for decades, the real stress scenario is more complex due to the exposure to multiple stresses at the same time. Here we investigate using existing evidence and a meta-analysis approach to determine molecular linkages between two contemporaneous abiotic stimuli, phosphate (Pi) deficiency and salinity, on a single plant cell model, the root hairs (RHs), which is the first plant cell exposed to them. Understanding how these two stresses work molecularly in RHs may help us build super-adaptable crops and sustainable agriculture in the face of global climate change.

Effect of 5:2 Regimens: Energy-Restricted Diet or Low-Volume High-Intensity Interval Training Combined With Resistance Exercise on Glycemic Control and Cardiometabolic Health in Adults With Overweight/Obesity and Type 2 Diabetes: A Three-Arm Randomized Controlled Trial.

OBJECTIVE: We aimed to examine the effects of a 5:2 diet (2 days per week of energy restriction by formula diet) or an exercise (2 days per week of high-intensity interval training and resistance training) intervention compared with routine lifestyle education (control) on glycemic control and cardiometabolic health among adults with overweight/obesity and type 2 diabetes. RESEARCH DESIGN AND METHODS: This two-center, open-label, three-arm, parallel-group, randomized controlled trial recruited 326 participants with overweight/obesity and type 2 diabetes and randomized them into 12 weeks of diet intervention (n = 109), exercise intervention (n = 108), or lifestyle education (control) (n = 109). The primary outcome was the change of glycemic control measured as glycated hemoglobin (HbA1c) between the diet or exercise intervention groups and the control group after the 12-week intervention. RESULTS: The diet intervention significantly reduced HbA1c level (%) after the 12-week intervention (-0.72, 95% CI -0.95 to -0.48) compared with the control group (-0.37, 95% CI -0.60 to -0.15) (diet vs. control -0.34, 95% CI -0.58 to -0.11, P = 0.007). The reduction in HbA1c level in the exercise intervention group (-0.46, 95% CI -0.70 to -0.23) did not significantly differ from the control group (exercise vs. control -0.09, 95% CI -0.32 to 0.15, P = 0.47). The exercise intervention group was superior in maintaining lean body mass. Both diet and exercise interventions induced improvements in adiposity and hepatic steatosis. CONCLUSIONS: These findings suggest that the medically supervised 5:2 energy-restricted diet could provide an alternative strategy for improving glycemic control and that the exercise regimen could improve body composition, although it inadequately improved glycemic control.

Chimeric antigen receptors: "CARs" in the fast lane for rheumatology.

PURPOSE OF REVIEW: Recent advances in hematology-oncology have pioneered cell-mediated elimination of pathologic B-cell populations employing chimeric antigen receptor (CAR) T cells. In this review, we discuss recent adoption of CAR-T treatment for severe refractory autoimmune disease. We highlight unique aspects of the autoimmune model and review current clinical data regarding treatment of rheumatologic disease. RECENT FINDINGS: To date, several CAR-Ts are FDA approved for Multiple Myeloma and B-cell malignancies and have demonstrated extraordinary clinical responses in refractory disease. Realizing the central role of B-cells in certain autoimmune diseases, CAR-T is now being explored for achieving drug-free remission induction, and potentially cure, of several rheumatologic diseases. The largest experience to date in the field of autoimmunity, building off the University Hospital Erlangen groups' earlier success treating a single patient with CD19-CAR in severe refractory SLE, Mackensen et al. enrolled five patients in a compassionate use program. Following autologous CD19-CAR T infusion, they demonstrated drug-free clinical and laboratory remission for at least 12 months in all five patients, with reconstitution of B cells expressing a naïve phenotype. SUMMARY: CAR-T treatment has shown striking drug-free responses in severe lupus and other autoimmune diseases, creating a need for further exploration and development.

Vertebrate-conserved Schnurri zinc fingers restrain Drosophila vein patterning.

The Drosophila Smad-interacting co-factor, Schnurri (Shn) confers transcriptional repression in response to Decapentaplegic (Dpp) signaling. Shn zinc fingers 6-8 mediate this Smad interaction but are lacking in vertebrate Shn homologs. In contrast, the vertebrate-conserved zinc finger 1,2 and 4,5 pairs have been reported to engage in Smad-mediated transcriptional activation in fly and vertebrate systems, and to contribute to Dpp-dependent tissue repair in the fly retina. We report that mutation of zinc coordination residues within vertebrate-conserved Shn zinc finger pairs 1,2 and 4,5 results in ectopic venation that is sensitive to Dpp signaling.

Characterization of Fatigue in Primary Mitochondrial Myopathies: Findings From a Qualitative Interview Study.

Background and Objectives: Primary mitochondrial myopathies are genetic disorders that primarily affect peripheral skeletal muscles. Patients with primary mitochondrial myopathies often experience muscle weakness, fatigue, and other significant impacts on health-related quality of life. The aim of this noninterventional qualitative study was to collect the most bothersome fatigue-related symptoms and impacts reported by patients with primary mitochondrial myopathies and determine whether the questions included in an existing patient-reported outcome measure, the Modified Fatigue Impact Scale, are relevant and interpretable for this population. Methods: The interviews contained a concept elicitation exercise to understand the most bothersome primary mitochondrial myopathies symptoms and impacts and a cognitive debriefing section to review the questions included in the Modified Fatigue Impact Scale for relevance and interpretability. Transcripts were coded using ATLAS.ti software. Results: Interviews were conducted with 16 patients who were aged 16 years and older with a genetically confirmed and clinical diagnosis of symptomatic primary mitochondrial myopathies. Concept elicitation interviews established that while patients with mitochondrial myopathies reported a wide variety of symptoms and impacts, one of the most impactful symptoms discussed was fatigue. Cognitive debriefing interview results confirmed that the Modified Fatigue Impact Scale items were relevant, were interpretable, and largely captured patients' experience with fatigue. Discussion: Fatigue was one of the most widely discussed experiences discussed by participants and was considered the most important symptom/impact to treat by most of the participants. The Modified Fatigue Impact Scale could be used in future clinical trials to measure treatment benefit in fatigue-related impacts.

Non-steroidal anti-inflammatory drug induced intestinal stricturing: diaphragm disease.

Diaphragm disease (DD) is a rare small bowel enteropathy associated with non-steroidal anti-inflammatory drug use. Since the first description there have only been approximately 100 cases of DD reported in the literature. Stricturing webs or 'diaphragms' form in the bowel, causing non-specific abdominal symptoms that can ultimately lead to bleeding and obstruction. Diagnosis is notoriously challenging as there is no single gold standard investigation. We present two cases of DD both of which were ultimately diagnosed by surgical resection. We also propose a novel flow algorithm that can be utilized for working up patients with suspected DD.