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Exploratory laparotomy in neonates is typically performed via a transverse laparotomy incision. However, this incision may be complicated by poor cosmesis and scar contracture. In three patients, primary gastroenterologists identified significant scar contractures that resulted in pain and limitations with physical activity, necessitating surgical referrals. All patients required subsequent surgical revision of their scar, which involved creation of skin flaps, repair of abdominal wall hernias if present, and reapproximation of the subcutaneous tissue. We describe this phenomenon and the resultant need for surgical management to raise awareness of these late complications and suggest subcutaneous tissue reapproximation should be performed when possible during abdominal wall closure. What is Known Exploratory laparotomy in neonates typically occurs via transverse laparotomy, which may be complicated by future concerns for cosmesis and abdominal wall hernias. What is New Scar contracture may also be a significant comorbidity as children grow, due to inadequate reapproximation of the subcutaneous tissue in the initial laparotomy. Patients with scar contractures may require referral for scar revision, which resulted in good functional outcomes in our series.

Exercise intolerance is a major manifestation of post-acute sequelae of severe acute respiratory syndrome coronavirus infection (PASC, or “long-COVID”). Exercise intolerance in PASC is associated with higher arterial blood lactate accumulation and lower fatty acid oxidation rates during graded exercise tests to volitional exertion, suggesting altered metabolism and mitochondrial dysfunction. It remains unclear whether the profound disturbances in metabolism that have been identified in plasma from patients suffering from acute coronavirus disease 2019 (COVID-19) are also present in PASC. To bridge this gap, individuals with a history of previous acute COVID-19 infection that did not require hospitalization were enrolled at National Jewish Health (Denver, CO, USA) and were grouped into those that developed PASC (n = 29) and those that fully recovered (n = 16). Plasma samples from the two groups were analyzed via mass spectrometry-based untargeted metabolomics and compared against plasma metabolic profiles of healthy control individuals (n = 30). Observational demographic and clinical data were retrospectively abstracted from the medical record. Compared to plasma of healthy controls or individuals who recovered from COVID-19, PASC plasma exhibited significantly higher free- and carnitine-conjugated mono-, poly-, and highly unsaturated fatty acids, accompanied by markedly lower levels of mono-, di- and tricarboxylates (pyruvate, lactate, citrate, succinate, and malate), polyamines (spermine) and taurine. Plasma from individuals who fully recovered from COVID-19 exhibited an intermediary metabolic phenotype, with milder disturbances in fatty acid metabolism and higher levels of spermine and taurine. Of note, depletion of tryptophan—a hallmark of disease severity in COVID-19—is not normalized in PASC patients, despite normalization of kynurenine levels—a tryptophan metabolite that predicts mortality in hospitalized COVID-19 patients. In conclusion, PASC plasma metabolites are indicative of altered fatty acid metabolism and dysfunctional mitochondria-dependent lipid catabolism. These metabolic profiles obtained at rest are consistent with previously reported mitochondrial dysfunction during exercise, and may pave the way for therapeutic intervention focused on restoring mitochondrial fat-burning capacity.

Expiratory flow limitation results in dynamic hyperinflation, dyspnoea and premature exercise intolerance. We aimed to measure whether expiratory resistance reduces locomotor power via limiting maximal voluntary motor activity, exacerbating muscle fatigue, or both. Healthy volunteers ( n  = 14; 23 (3) years) performed a series of very heavy‐domain constant power cycling exercise tests with and without an imposed expiratory flow resistance (7 cmH 2 O/L/s). The decline in maximal evocable isokinetic power at intolerance during each experimental condition was apportioned to: (1) the power equivalent from a reduction in maximum voluntary muscle activation (termed ‘activation fatigue’); and (2) the deficit in expected power at a given isokinetic muscle activity (muscle fatigue). Imposed expiratory resistance reduced exercise tolerance (487 (145) vs. 575 (137) s; 95% confidence interval of the difference (CI diff ) 52, 125 s; P = 0.0002). At isotime‐control, imposed expiratory resistance resulted in a greater decline in inspiratory reserve volume (CI diff 0.20, 0.94 L; P = 0.007), and increased dyspnoea (Borg CR‐10; CI diff 0.7, 3.0; P = 0.006) than without. Muscle fatigue was unaffected (CI diff −20, 17 W; P = 0.873), but activation fatigue was greater with expiratory resistance (CI diff 1, 49 W; P = 0.044) and related to the reduction in inspiratory reserve volume ( r 2  = 0.53; P = 0.028). As a result, locomotor power reserve was reduced with expiratory resistance (253 (83) vs. 201 (92) W; CI diff −10, 113; P = 0.09). Imposed expiratory resistive loading initiated a cascade of abnormal lung mechanics and symptoms. These abnormalities conflate to reduce exercise tolerance through limiting maximal voluntary motor activity. What is the central question of this study? Resistance to expiration, such as in asthma and chronic obstructive lung disease, causes abnormal lung function and intolerance to exercise: does abnormal lung mechanics directly affect locomotor fatigue? What is the main finding and its importance? Imposed expiratory resistance initiates a cascade of abnormal lung mechanics and symptoms, which conflate to reduce exercise tolerance through limiting maximal voluntary motor activity.

Following an acute infection with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), a substantial percentage of patients report the persistence of debilitating symptoms, often grouped in a syndrome termed ‘long COVID’. We sought to identify potential pathophysiological mechanisms responsible for the persistence, in some long COVID patients, of symptoms related to fatigue/exercise intolerance (excessive or early fatigue, excessive or early dyspnoea, muscle weakness, and myalgias) more than 2 years after the original infection. Twelve patients who reported persistent symptoms (Long COVID group; 57 ± 6 years, mean ± SD), and 14 patients without the symptoms (Control group; 57 ± 8 years) were evaluated. An extensive series of measurements were performed to identify pathophysiological mechanisms potentially responsible for the symptoms. In long COVID patients, all items evaluating quality of life (SF‐36 questionnaire) had lower scores ( P  < 0.01) compared to control. The habitual level of physical activity, muscle size and strength, maximal aerobic power and the ventilatory thresholds, peak cardiac function, the mechanical efficiency of cycling, pulmonary kinetics, microvascular/endothelial function (hyperemic response in the common femoral artery during passive leg movements), skeletal muscle oxidative metabolism (peak fractional O 2 extraction and muscle recovery kinetics by the repeated occlusions test, by near‐infrared spectroscopy) were not different in the two groups. Evidence of ventilatory inefficiency was described in a subgroup of long COVID patients. More than 2 years after the original SARS‐CoV‐2 infection, a discrepancy was observed between the persistence of debilitating symptoms of fatigue/exercise intolerance and the absence of several investigated pathophysiological mechanisms. The discrepancy may be due to factors that remain to be elucidated. What is the central question of this study? Which pathophysiological mechanisms are responsible for the persistence, in some patients, seen more than 2 years after the original SARS‐CoV‐2 infection, of symptoms of fatigue/exercise intolerance? What is the main finding and its importance? A discrepancy was observed between the persistence of symptoms of fatigue/exercise intolerance (excessive or early fatigue, excessive or early dyspnoea on exertion, muscle weakness, and myalgias) and the absence of several investigated pathophysiological mechanisms. Symptoms may be attributable to other factors (i.e., psychological/neurological) that were not investigated.

Individuals with persisting post‐concussion symptoms with physiological subtype (PPCS‐P) demonstrate exercise intolerance due to exacerbation of concussion‐like symptoms during incremental exercise. We tested the hypothesis that individuals with PPCS‐P ( n  = 12) would have a blunted cardiac autonomic response to face cooling compared to healthy controls (CTRL, n  = 12). Participants were supine and performed a 5 min baseline, then experienced a 3 min face cold pressor test followed by 5 min of recovery. A three‐lead electrocardiogram was used to measure heart rate and root mean square of successive differences in R‐R intervals (RMSSD), finger photoplethysmography was used to measure mean arterial pressure (MAP), and laser‐Doppler flowmetry was used to measure finger skin blood flux. The PPCS‐P group had a lower exercise tolerance (9.9 ± 3.2 min, P  < 0.001) and lower peak heart rate (170.0 ± 14.0 beats·min −1 , P  < 0.001) compared to CTRL (19.6 ± 2.5 min; 193.0 ± 5.0 beats·min −1 ). PPCS‐P demonstrated a blunted mean heart rate (CTRL: ∆−4.0 ± 5.0 beats·min −1 , PPCS‐P: ∆2.0 ± 4.0 beats·min −1 ; group effect: P  < 0.001) and mean RMSSD (CTRL: ∆26.6 ± 34.7 ms, PPCS‐P: ∆−1.8 ± 33.9 ms; group effect: P  = 0.026) responses at 2 min of face cooling compared to CTRL. Both groups had a significant increase in MAP during face cooling, where at 2 min, MAP was higher in PPCS‐P (∆+13.2 ± 5.5 mmHg) compared to CTRL (∆+8.7 ± 6.9 mmHg, group effect: P  < 0.001). Furthermore, PPCS‐P had a sustained lower finger skin blood flux (group effect: P  < 0.001) during face cooling (PPCS‐P: ∆−48.2 ± 27.1%, CTRL: ∆−12.8 ± 24.7% at 2 min). These data suggest that individuals with PPCS‐P demonstrate altered cardiac and peripheral autonomic function during face cooling compared to healthy controls. What is the central question of this study? Are there physiological differences in responses to face cooling between individuals who are apparently healthy versus those with persisting post‐concussion symptoms with physiological subtype? What is the main finding and its importance? Compared to controls, individuals with persisting post‐concussion symptoms with physiological subtype exhibited altered autonomic and cardiovascular responses to a face cold pressor test including blunted heart rate variability responses, greater blood pressure responses, and greater finger skin blood flux reductions to face cooling. Persisting post‐concussion symptoms with physiological subtype do not appear to affect cerebral autoregulation. These data suggest that impaired autonomic regulation of the heart and vasculature may mechanistically contribute to persisting post‐concussion symptoms in humans.

Ageing results in lower exercise tolerance, manifested as decreased critical power (CP). We examined whether the age‐related decrease in CP occurs independently of changes in muscle mass and whether it is related to impaired vascular function. Ten older (63.1 ± 2.5 years) and 10 younger (24.4 ± 4.0 years) physically active volunteers participated. Physical activity was measured with accelerometry. Leg muscle mass was quantified with dual X‐ray absorptiometry. The CP and maximum power during a graded exercise test (PGXT) of single‐leg knee‐extension exercise were determined over the course of four visits. During a fifth visit, vascular function of the leg was assessed with passive leg movement (PLM) hyperaemia and leg blood flow and vascular conductance during knee‐extension exercise at 10 W, 20 W, slightly below CP (90% CP) and PGXT. Despite not differing in leg lean mass (P = 0.901) and physical activity (e.g., steps per day, P = 0.735), older subjects had ∼30% lower mass‐specific CP (old = 3.20 ± 0.94 W kg−1 vs. young = 4.60 ± 0.87 W kg−1; P < 0.001). The PLM‐induced hyperaemia and leg blood flow and/or conductance were blunted in the old at 20 W, 90% CP and PGXT (P < 0.05). When normalized for leg muscle mass, CP was strongly correlated with PLM‐induced hyperaemia (R2 = 0.52; P < 0.001) and vascular conductance during knee‐extension exercise at 20 W (R2 = 0.34; P = 0.014) and 90% CP (R2 = 0.39; P = 0.004). In conclusion, the age‐related decline in CP is not only an issue of muscle quantity, but also of impaired muscle quality that corresponds to impaired vascular function. What is the central question of this study? Does the age‐related decrease in critical power occur independently of changes in muscle mass and is it related to impaired vascular function? What is the main finding and its importance? The age‐related reduction in exercise tolerance, assessed by critical power, occurs independently of loss of muscle mass and is related to vascular function and exercise blood flow. Blood flow during exercise slightly below critical power reaches very high steady‐state levels that do not differ significantly from the maximum blood flow achieved during exercise above critical power.

Management of the athlete with postconcussion syndrome (PCS) is challenging because of the nonspecificity of PCS symptoms. Ongoing symptoms reflect prolonged concussion pathophysiology or conditions such as migraine headaches, depression or anxiety, chronic pain, cervical injury, visual dysfunction, vestibular dysfunction, or some combination of these. In this paper, we focus on the physiological signs of concussion to help narrow the differential diagnosis of PCS in athletes. The physiological effects of exercise on concussion are especially important for athletes. Some athletes with PCS have exercise intolerance that may result from altered control of cerebral blood flow. Systematic evaluation of exercise tolerance combined with a physical examination of the neurologic, visual, cervical, and vestibular systems can in many cases identify one or more treatable postconcussion disorders.

The SLC25A32 dysfunction is associated with neural tube defects (NTDs) and exercise intolerance, but very little is known about disease-specific mechanisms due to a paucity of animal models. Here, we generated homozygous ( Slc25a32 Y174C/Y174C and Slc25a32 K235R/K235R ) and compound heterozygous ( Slc25a32 Y174C/K235R ) knock-in mice by mimicking the missense mutations identified from our patient. A homozygous knock-out ( Slc25a32 −/− ) mouse was also generated. The Slc25a32 K235R/K235R and Slc25a32 Y174C/K235R mice presented with mild motor impairment and recapitulated the biochemical disturbances of the patient. While Slc25a32 −/− mice die in utero with NTDs. None of the Slc25a32 mutations hindered the mitochondrial uptake of folate. Instead, the mitochondrial uptake of flavin adenine dinucleotide (FAD) was specifically blocked by Slc25a32 Y174C/K235R , Slc25a32 K235R/K235R , and Slc25a32 −/− mutations. A positive correlation between SLC25A32 dysfunction and flavoenzyme deficiency was observed. Besides the flavoenzymes involved in fatty acid β-oxidation and amino acid metabolism being impaired, Slc25a32 −/− embryos also had a subunit of glycine cleavage system—dihydrolipoamide dehydrogenase damaged, resulting in glycine accumulation and glycine derived-formate reduction, which further disturbed folate-mediated one-carbon metabolism, leading to 5-methyltetrahydrofolate shortage and other folate intermediates accumulation. Maternal formate supplementation increased the 5-methyltetrahydrofolate levels and ameliorated the NTDs in Slc25a32 −/− embryos. The Slc25a32 K235R/K235R and Slc25a32 Y174C/K235R mice had no glycine accumulation, but had another formate donor—dimethylglycine accumulated and formate deficiency. Meanwhile, they suffered from the absence of all folate intermediates in mitochondria. Formate supplementation increased the folate amounts, but this effect was not restricted to the Slc25a32 mutant mice only. In summary, we established novel animal models, which enabled us to understand the function of SLC25A32 better and to elucidate the role of SLC25A32 dysfunction in human disease development and progression.

Background After COVID-19 infection, 10–20% of patients suffer from varying symptoms lasting more than 12 weeks (Long COVID, LC). Exercise intolerance and fatigue are common in LC. The aim was to measure the maximal exercise capacity of the LC patients with these symptoms and to analyze whether this capacity was related to heart rate (HR) responses at rest and during exercise and recovery, to find out possible sympathetic overactivity, dysautonomia or chronotropic incompetence. Methods Cardiopulmonary exercise test was conducted on 101 LC patients, who were admitted to exercise testing. The majority of them (86%) had been treated at home during their acute COVID-19 infection. Peak oxygen uptake (VO2peak), maximal power during the last 4 min of exercise (Wlast4), HRs, and other exercise test variables were compared between those with or without subjective exercise intolerance, fatigue, or both. Results The measurements were performed in mean 12.7 months (SD 5.75) after COVID-19 infection in patients with exercise intolerance (group EI, 19 patients), fatigue (group F, 31 patients), their combination (group EI + F, 37 patients), or neither (group N, 14 patients). Exercise capacity was, in the mean, normal in all symptom groups and did not significantly differ among them. HRs were higher in group EI + F than in group N at maximum exercise (169/min vs. 158/min, p  = 0.034) and 10 min after exercise (104/min vs. 87/min, p  = 0.028). Independent of symptoms, 12 patients filled the criteria of dysautonomia associated with slightly decreased Wlast4 (73% vs. 91% of sex, age, height, and weight-based reference values p  = 0.017) and 13 filled the criteria of chronotropic incompetence with the lowest Wlast4 (63% vs. 93%, p  < 0.001), VO2peak (70% vs. 94%, p  < 0.001), the lowest increase of systolic blood pressure (50 mmHg vs. 67 mmHg, p  = 0.001), and the greatest prevalence of slight ECG-findings ( p  = 0.017) compared to patients without these features. The highest prevalence of chronotropic incompetence was seen in the group N ( p  = 0.022). Conclusions This study on LC patients with different symptoms showed that cardiopulmonary exercise capacity was in mean normal, with increased sympathetic activity in most patients. However, we identified subgroups with dysautonomia or chronotropic incompetence with a lowered exercise capacity as measured by Wlast4 or VO2peak. Subjective exercise intolerance and fatigue poorly foresaw the level of exercise capacity. The results could be used to plan the rehabilitation from LC and for selection of the patients suitable for it.

The pathogenesis of exercise intolerance and persistent fatigue which can follow an infection with the SARS‐CoV‐2 virus (“long COVID”) is not fully understood. Cases were recruited from a long COVID clinic (N = 32; 44 ± 12 years; 10 (31%) men), and age‐/sex‐matched healthy controls (HC) (N = 19; 40 ± 13 years; 6 (32%) men) from University College London staff and students. We assessed exercise performance, lung and cardiac function, vascular health, skeletal muscle oxidative capacity, and autonomic nervous system (ANS) function. Key outcome measures for each physiological system were compared between groups using potential outcome means (95% confidence intervals) adjusted for potential confounders. Long COVID participant outcomes were compared to normative values. When compared to HC, cases exhibited reduced oxygen uptake efficiency slope (1847 (1679, 2016) vs. 2176 (1978, 2373) mL/min, p = 0.002) and anaerobic threshold (13.2 (12.2, 14.3) vs. 15.6 (14.4, 17.2) mL/kg/min, p < 0.001), and lower oxidative capacity, measured using near infrared spectroscopy (τ: 38.7 (31.9, 45.6) vs. 24.6 (19.1, 30.1) s, p = 0.001). In cases, ANS measures fell below normal limits in 39%. Long COVID is associated with reduced measures of exercise performance and skeletal muscle oxidative capacity in the absence of evidence of microvascular dysfunction, suggesting mitochondrial pathology. There was evidence of attendant ANS dysregulation in a significant proportion. These multisystem factors might contribute to impaired exercise tolerance in long COVID sufferers.