Functional Limitations and Exercise Intolerance in Patients With Post-COVID Condition: A Randomized Crossover Clinical Trial.

Importance: Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration. Objective: To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC. Design, Setting, and Participants: In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited. Interventions: After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise. Main Outcomes and Measures: The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC. Results: Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing. Conclusions and Relevance: In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC. Trial Registration: ClinicalTrials.gov Identifier: NCT05445830.

Plasma levels of tissue inhibitor of metalloproteinase-1 in patients with type 1 diabetes mellitus associate with early diabetic neuropathy and nephropathy.

BACKGROUND: Tissue inhibitor of metalloproteinase-1 (TIMP-1) has been suggested as a marker for abnormal regulation of tissue remodelling in type 1 diabetes. Metalloproteinase-9 (MMP-9) has been associated with matrix turnover, and Neutrophil gelatinase associated lipocalin (NGAL) is a marker of tubular injury in diabetic nephropathy. The aim was to analyse these biomarkers to unmask early diabetic complications. METHODS: Thirty-three type 1 diabetes patients, aged 20-35 years, and disease duration 20 ± 5.3 years were included. Along with clinical examination, neurophysiological measurements, routine biochemistry, plasma concentrations of TIMP-1, MMP-9 and NGAL were determined with immunoenzymatic techniques. RESULTS: TIMP-1 correlated with abnormal unilateral and bilateral vibratory sense foot perception (r = -0.49 and r = -0.51, respectively), foot neuropathy impairment assessment score (NIA; r = -0.55), neuropathy symptom assessment score (r = 0.42), microalbuminuria (r = 0.50) and eGFR (r = -0.45). MMP-9 correlated with impaired foot NIA (r = 0.51). Multiple regression analysis showed an association for TIMP-1 (p = 0.004) with impaired neurophysiological examinations and renal dysfunction along with NGAL (p = 0.016 and p = 0.015 respectively). CONCLUSIONS: This study suggests that plasma levels of TIMP-1, MMP-9 and NGAL may serve as useful biomarkers in unravelling subclinical neuropathy and nephropathy in type 1 diabetes.

On the physiology of cognitive decline in type 1 diabetes.

OBJECTIVES: Type 1 diabetes mellitus (T1DM) may be associated with cognitive impairment and notably a decline in psychomotor speed, information processing speed and attention. The mechanism for this decline is uncertain. Previous studies by our group and others have demonstrated a decline in EEG-power and event-related potential amplitude in T1DM. The objectives of the present study were to explore whether 1) the association between event-related potential (N100) amplitude and psychomotor speed is different between T1DM and healthy subjects, and 2) the decline in N100 amplitude depends on duration of diabetes. METHODS: Patients with T1DM (N = 204) and healthy control subjects (N = 358) were included in a cross-sectional study. Event-related brain potentials were recorded with auditory reaction tasks. Psychomotor speed was evaluated with the Grooved Pegboard test in a subset of the patients (N = 70) and the healthy control subjects (N = 89). RESULTS: Patients with T1DM had a decrease in the N100 amplitude that correlated with a decline in psychomotor speed, longer duration of diabetes and increasing age. In healthy controls, the N100 amplitude did not decrease with age and the association between psychomotor speed and N100 amplitude was absent. CONCLUSION: The association between psychomotor speed and N100 amplitude is likely to be a specific trait for T1DM since it was not found in healthy controls and was dependent on diabetes duration. Our findings indicate that the pathogenesis of cognitive decline in T1DM may involve a disease-related factor with a long-term influence on the N100 amplitude.

Early electrophysiological abnormalities and clinical neuropathy: a prospective study in patients with type 1 diabetes.

OBJECTIVE: The aim of this study was to elucidate whether subclinical nerve dysfunction as reflected by neurophysiological testing predicts the development of clinical neuropathy in patients with type 1 diabetes. RESEARCH DESIGN AND METHODS: Fifty-nine patients were studied twice with neurophysiological measurements at baseline and at follow-up. At baseline, patients were 15.5±3.22 years (range 7-22 years) of age, and duration of diabetes was 6.8±3.3 years. At follow-up, patients were 20-35 years of age, and disease duration was 20±5.3 years (range 10-31 years). RESULTS: At baseline, patients showed modestly reduced nerve conduction velocities and amplitudes compared with healthy subjects, but all were free of clinical neuropathy. At follow-up, clinical neuropathy was present in nine (15%) patients. These patients had a more pronounced reduction in peroneal motor nerve conduction velocity (MCV), median MCV, and sural sensory nerve action potential at baseline (P<0.010-0.003). In simple logistic regression analyses, the predictor with the strongest association with clinical neuropathy was baseline HbA1c (R2=48%, odds ratio 7.9, P<0.002) followed by peroneal MCV at baseline (R2=38%, odds ratio 0.6, P<0.006). With the use of a stepwise forward analysis that included all predictors, first baseline HbA1c and then only peroneal MCV at baseline entered significantly (R2=61%). Neuropathy impairment assessment showed a stronger correlation with baseline HbA1c (ρ=0.40, P<0.002) than with follow-up HbA1c (ρ=0.034, P<0.007). CONCLUSIONS: Early defects in nerve conduction velocity predict the development of diabetic neuropathy. However, the strongest predictor was HbA1c during the first years of the disease.

Decreased cortical connectivity and information flow in type 1 diabetes.

OBJECTIVE: To investigate the effect of type 1 diabetes on EEG connectivity and information flow and study the relationship between these parameters and electrophysiological, neuropsychological and clinical variables. METHODS: Connectivity was assessed using several measures (phase coherence, phase lag index, synchronization likelihood and phase slope index) on 119 patients and 61 healthy controls over several frequency bands (between 0.5 and 45 Hz). Data was further correlated to EEG power, event related potentials, neuropsychological function and demographic variables. RESULTS: Multivariate test on the connectivity data showed a difference between patients and controls both with mastoid reference (p<0.01) and current source density estimates (p<0.04). Connectivity and information flow correlated with EEG power but not with event related potentials or neuropsychological function. CONCLUSIONS: Connectivity and information flow are decreased in diabetes. These variables assess other functions of the brain than captured by the present cognitive tests. Several tests need to be performed in order to monitor the effect of diabetes on brain function. SIGNIFICANCE: The decrease in connectivity and cortical information flow are EEG abnormalities that add to the previously described EEG and ERP abnormalities described for type 1 diabetes.

Effect of valproate, lamotrigine and levetiracetam on excitability and firing properties of CA1 neurons in rat brain slices.

The purpose of this study was to analyze the rapid effects of the antiepileptic drugs valproate, lamotrigine, and levetiracetam on excitability and firing properties of hippocampal neurons. The drug effects on resting potential, action potential, and repetitive firing properties were studied in whole-cell current-clamp recordings of CA1 neurons in rat brain slices. Lamotrigine changed action potential rising slope by -24 ± 38 V/s (mean ± SD), peak amplitude by -6.8 ± 5.0 mV, and maximum firing frequency by -60 ± 13%. Lamotrigine thereto increased the voltage threshold by 4.3 ± 4.2 mV and augmented the action potential attenuation during repetitive firing. All effects were significant (P < 0.01 to P < 0.0002) compared to control cells. Valproate and levetiracetam showed no significant effects on these parameters. None of the tested drugs had a significant effect on the resting potential. The lamotrigine effects are consistent with sodium channel blocking which may explain or contribute to the antiepileptic mode of action. Valproate and levetiracetam did not show these effects and the mechanism of their antiepileptic action need to be different. These findings (valproate) differ in some respects from findings reported in cultured or dissociated neurons. In a slice where the neurons have largely preserved connections, drug effects are likely to be more similar to the therapeutic action in the brain.

Continuous EEG monitoring in a paediatric intensive care unit.

Monitoring with continuous EEG (cEEG) has become a valuable tool in the adult neurointensive care unit. The benefits of cEEG or amplitude-integrated EEG in neonatal intensive care have also been described. The aim of the present study was to describe and evaluate the use of cEEG in a paediatric intensive care unit. The study is a description of children and adolescents with acute neurological disorders monitored by cEEG in a paediatric intensive care unit for more than 12h. The indication for cEEG and the outcome are reported for 54 patients during a 4-year period. Twelve patients were monitored for high intracranial pressure, eight of whom died. Fourteen were monitored due to suspected, but not detected, epilepsy, their underlying diagnoses being variable. Refractory status epilepticus was the reason for cEEG in 24 cases. All of these patients survived the acute phase of status epilepticus. Four patients had seizure activity on cEEG due to global anoxia; these were not classified as status epilepticus. In conclusion, in the paediatric intensive care unit the most important indication for cEEG monitoring is in patients with suspected refractory status epilepticus where it adds to the diagnosis and choice of treatment. Continuous EEG should therefore be part of the paediatric intensive care unit technical support to select and monitor, among children with critical neurological disorders, those with refractory status epilepticus.

Early diabetic complications in a population of young patients with type 1 diabetes mellitus despite intensive treatment.

AIM: To describe the prevalence of early complications in an unselected population of patients with type 1 diabetes mellitus (DM1) diagnosed in childhood with intensive insulin treatment from diagnosis. METHODS: Eighty children and adolescents with DM1, age 7-22 years and DM1 duration >3 years, were studied. Neuropathy was defined as abnormal nerve conduction finding in > or = 2 of 4 nerves (sural and peroneal nerves), nephropathy as albumin excretion rate > or = 20 microg/min and retinopathy as all grades of retinal changes in fundus photographs. RESULTS: The prevalence of neuropathy was 59%, of retinopathy 27% and of nephropathy 5% after 13 years DM1 duration. Mean (SD) long-term HbA1c was 8.4 (0.9)% (DCCT-corrected value). CONCLUSION: Even in a population with intensive insulin treatment from the beginning and fairly good metabolic control, the prevalence of subclinical neuropathy was high, while other diabetic complications were lower than usually reported.

Impaired microvascular function related to poor metabolic control in young patients with diabetes.

The purpose of the present study was to identify whether young patients with type 1 diabetes using modern multiple insulin injection therapy (MIT) have signs of microvascular dysfunction and to elucidate possible correlations with various disease parameters. Skin blood flow on the dorsum of the foot was measured with laser Doppler perfusion imaging in 37 patients (age 10-21 years, disease duration 6.0-16 years) and 10 healthy controls. Measurements were performed at rest, after change in posture (the leg was lowered below heart level) and during postocclusive hyperaemia. Following a change in posture blood flow increased instead of decreased in a majority of the study subjects. Patients with acute HbA1c >7.5% (n = 22) had an increase in skin blood flow at rest and a significantly reduced blood flow when the leg was lowered below heart level as compared with patients with HbA1c <7.5% (0.26 V versus 0.17 V, P<0.01 and 0.12 V versus 0.23 V, P<0.05, respectively) and healthy controls. Following occlusion of the macrocirculation for 3 min a small non-significant decrease in the hyperaemic response was seen in the patients. The postocclusive hyperaemic response and the venoarteriolar reflex were not correlated to duration of disease, long-term metabolic control or electrophysiological signs of peripheral nerve dysfunction. It is concluded that signs of microvascular dysfunction related to poor metabolic control are present in young patients with MIT treatment and rather well-controlled diabetes. Low resting blood flow levels are suggested to contribute to the absence of postural vasoconstrictor response.

Time course and variability of power in different frequency bands of EEG during resting conditions.

The aim of the present study was to evaluate the variability of EEG power spectrum data, considering the time course of the EEG spectrum in resting conditions, and the relationship between the spectral parameters and the length of the analyzed segments. Recordings were performed in 57 normal subjects, with a protocol consisting of regular cycles with open eyes (5 s) followed by closed eyes (55 s) repeated during 10 min. Towards the end of the recording there was a decrease in the alpha and beta power and an increase in the delta and theta power. The coefficient of variation (CV) for the power of 4 s epochs was in the range 0.49-0.67 (delta), 0.53-0.58 (theta), 0.58-0.76 (alpha), 0.37-0.49 (beta) and 0.09-0.12 for the alpha peak frequency. CV decreased with the increase of the sample size, being inversely proportional to the square root of the sample size. Increasing the recording length from 40 to 400 s increased CV by 36% (alpha), 41% (beta), 29% (delta) and 35% (theta), while the standard error of the mean decreased by 55-60%. It is concluded that the power estimates of the EEG activity are heavily dependent on the length of the analyzed segments, and the way they are selected. This observation is particularly relevant for clinical and drug studies where short recordings are often used, thus significantly biasing the estimation of the EEG parameters. The present data provide an estimate on the minimal length of EEG required for a given level of variability.

Loss of temporal lobe beta power in young adults with type 1 diabetes mellitus.

Cognitive defects have been reported in type 1 diabetes mellitus with possible correlation to recurrent episodes of hypoglycemia. The purpose of the present study was to identify signs of brain dysfunction with quantitative EEG in adults with insulin-dependent (type 1) diabetes. Patients (n = 49) with type 1 diabetes and controls (n = 51) were recruited. All patients had good glycemic control, no diabetic polyneuropathy and a minor history of severe hypoglycaemia. EEG was recorded for 15 min following a standardized protocol, power spectra were obtained from 236-584 s of artefact-free EEG from each subject and EEG was repeated in diabetic patients after 3 and 9 months. The most pronounced finding was a loss of fast oscillations (alpha, beta and gamma activity) in both posterior temporal regions, with p< 0.001 for beta and p< 0.05 or 0.01 for alpha and gamma activity in the diabetes patients. A decrease in beta activity was also present bilaterally in the anterior temporal and occipital regions (p< 0.05 or 0.01). The alpha peak frequency was lower in patients than in controls, with reductions bilaterally in the temporo-central regions (p< 0.01). These changes were not found to correlate to a previous history of hypoglycaemia. The alpha and beta power showed a high test-retest reliability at both 3 and 9 months (0.88-0.92). The focal decrease in temporal lobe fast activity suggests that these brain regions are preferentially affected by type 1 diabetes. This abnormality may be related to the mechanism underlying the cognitive dysfunction described in diabetes.