HIV-1 RNA in extracellular vesicles is associated with neurocognitive outcomes.

Human immunodeficiency virus type-1 (HIV-1) is responsible for significant mortality and morbidity worldwide. Despite complete control of viral replication with antiretrovirals, cells with integrated HIV-1 provirus can produce viral transcripts. In a cross-sectional study of 84 HIV+ individuals of whom 43 were followed longitudinally, we found that HIV-1 RNAs are present in extracellular vesicles (EVs) derived from cerebrospinal fluid and serum of all individuals. We used seven digital droplet polymerase chain reaction assays to evaluate the transcriptional status of the latent reservoir. EV-associated viral RNA was more abundant in the CSF and correlated with neurocognitive dysfunction in both, the cross-sectional and longitudinal studies. Sequencing studies suggested compartmentalization of defective viral transcripts in the serum and CSF. These findings suggest previous studies have underestimated the viral burden and there is a significant relationship between latent viral transcription and CNS complications of long-term disease despite the adequate use of antiretrovirals.

White and Gray Matter Changes are Associated With Neurocognitive Decline in HIV Infection.

OBJECTIVE: To investigate the relationship between neurocognitive deficits and structural changes on brain magnetic resonance imaging in people living with HIV (PLWH) with good virological control on combination antiretroviral therapy, compared with socioeconomically matched control participants recruited from the same communities. METHODS: Brain magnetic resonance imaging scans, and clinical and neuropsychological data were obtained from virologically controlled PLWH (viral load of <50 c/mL and at least 1 year of combination antiretroviral therapy) and socioeconomically matched control participants. Magnetic resonance imaging was carried out on 3 T scanner with 8-channel head coils and segmented using Classification using Derivative-based Features. Multiple regression analysis was performed to examine the association between brain volume and various clinical and neuropsychiatric parameters adjusting for age, race, and sex. To evaluate longitudinal changes in brain volumes, a random coefficient model was used to evaluate the changes over time (age) adjusting for sex and race. RESULTS: The cross-sectional study included 164 PLWH and 51 controls, and the longitudinal study included 68 PLWH and 20 controls with 2 or more visits (mean 2.2 years, range 0.8-5.1 years). Gray matter (GM) atrophy rate was significantly higher in PLWH compared with control participants, and importantly, the GM and global atrophy was associated with the various neuropsychological domain scores. Higher volume of white matter hyperintensities were associated with increased atherosclerotic cardiovascular disease risk score, and decreased executive functioning and memory domain scores in PLWH. INTERPRETATION: These findings suggest ongoing neurological damage even in virologically controlled participants, with significant implications for clinical management of PLWH. ANN NEUROL 2024;95:941-950.

Inability to move one's face dampens facial expression perception.

Humans rely heavily on facial expressions for social communication to convey their thoughts and emotions and to understand them in others. One prominent but controversial view is that humans learn to recognize the significance of facial expressions by mimicking the expressions of others. This view predicts that an inability to make facial expressions (e.g., facial paralysis) would result in reduced perceptual sensitivity to others' facial expressions. To test this hypothesis, we developed a diverse battery of sensitive emotion recognition tasks to characterize expression perception in individuals with Moebius Syndrome (MBS), a congenital neurological disorder that causes facial palsy. Using computer-based detection tasks we systematically assessed expression perception thresholds for static and dynamic face and body expressions. We found that while MBS individuals were able to perform challenging perceptual control tasks and body expression tasks, they were less efficient at extracting emotion from facial expressions, compared to matched controls. Exploratory analyses of fMRI data from a small group of MBS participants suggested potentially reduced engagement of the amygdala in MBS participants during expression processing relative to matched controls. Collectively, these results suggest a role for facial mimicry and consequent facial feedback and motor experience in the perception of others' facial expressions.

Noncoding variants alter GATA2 expression in rhombomere 4 motor neurons and cause dominant hereditary congenital facial paresis.

Hereditary congenital facial paresis type 1 (HCFP1) is an autosomal dominant disorder of absent or limited facial movement that maps to chromosome 3q21-q22 and is hypothesized to result from facial branchial motor neuron (FBMN) maldevelopment. In the present study, we report that HCFP1 results from heterozygous duplications within a neuron-specific GATA2 regulatory region that includes two enhancers and one silencer, and from noncoding single-nucleotide variants (SNVs) within the silencer. Some SNVs impair binding of NR2F1 to the silencer in vitro and in vivo and attenuate in vivo enhancer reporter expression in FBMNs. Gata2 and its effector Gata3 are essential for inner-ear efferent neuron (IEE) but not FBMN development. A humanized HCFP1 mouse model extends Gata2 expression, favors the formation of IEEs over FBMNs and is rescued by conditional loss of Gata3. These findings highlight the importance of temporal gene regulation in development and of noncoding variation in rare mendelian disease.

Neurocognitive Dysfunction With Neuronal Injury in People With HIV on Long-Duration Antiretroviral Therapy.

BACKGROUND AND OBJECTIVES: Neurologic outcomes in people with HIV (PWH) on long-duration antiretroviral therapy (ART) are not fully understood, and the underlying pathophysiology is unclear. To address this, we established a cohort of such individuals and compared them with HIV-negative controls using a novel matching technique. Both groups underwent extensive cognitive testing, evaluation for psychiatric measures, and MRI and CSF analyses. METHODS: Participants underwent comprehensive neuropsychological testing and completed standardized questionnaires measuring depressive symptoms, perceptions of own functioning, and activities of daily living as part of an observational study. Brain MRI and lumbar puncture were optional. Coarsened Exact Matching was used to reduce between-group differences in age and sex, and weighted linear/logistic regression models were used to assess the effect of HIV on outcomes. RESULTS: Data were analyzed from 155 PWH on ART for at least 15 years and 100 HIV-negative controls. Compared with controls, PWH scored lower in the domains of attention/working memory (PWH least square mean [LSM] = 50.4 vs controls LSM = 53.1, p = 0.008) and motor function (44.6 vs 47.7, p = 0.009) and a test of information processing speed (symbol search 30.3 vs 32.2, p = 0.003). They were more likely to self-report a higher number of cognitive difficulties in everyday life (p = 0.011). PWH also reported more depressive symptoms, general anxiety, and use of psychiatric medications (all with p < 0.05). PWH had reduced proportions of subcortical gray matter on MRI (ß = -0.001, p < 0.001), and CSF showed elevated levels of neurofilament light chain (664 vs 529 pg/mL, p = 0.01) and tumor necrosis factor α (0.229 vs 0.156 ng/mL, p = 0.0008). DISCUSSION: PWH, despite effective ART for over a decade, displayed neurocognitive deficits and mood abnormalities. MRI and CSF analyses revealed reduced brain volume and signs of ongoing neuronal injury and neuroinflammation. As the already large proportion of virologically controlled PWH continues to grow, longitudinal studies should be conducted to elucidate the implications of cognitive, psychiatric, MRI, and CSF abnormalities in this group.

Retinal Thinning in People With Well-Controlled HIV Infection.

BACKGROUND: Retinal measurements correlate with disease progression in patients with multiple sclerosis; however, whether they associate with neurologic disease in people with controlled HIV is unknown. Using spectral domain optical coherence tomography, we evaluated retinal differences between people with HIV and HIV-negative controls and investigated clinical correlates of retinal thinning. METHODS: People with HIV on antiretroviral therapy for at least 1 year and HIV-negative controls recruited from the same communities underwent spectral domain optical coherence tomography, ophthalmic examination, brain MRI, and neuropsychological testing. Retinal nerve fiber layer (RNFL) and ganglion cell inner plexiform layer (GC-IPL) thicknesses were compared between groups using analysis of covariance with relevant clinical variables as covariates. Linear regression was used to explore associations of HIV history variables, cognitive domain scores, and MRI volume measurements within the HIV group. RESULTS: The HIV group (n = 69), with long-duration HIV infection (median time from diagnosis 19 years) and outstanding viral control have thinner retinal layers than HIV-negative controls (n = 28), after adjusting for covariates (GC-IPL: P = 0.002; RNFL: P = 0.024). The effect of HIV on GC-IPL thickness was stronger in women than in men (Women: P = 0.011; Men: P = 0.126). GC-IPL thickness is associated with information processing speed in the HIV group (P = 0.007, semipartial r = 0.309). No associations were found with retinal thinning and MRI volumes or HIV factors. CONCLUSIONS: People with HIV on antiretroviral therapy have thinning of the RNFL and GC-IPL of the retina, and women particularly are affected to a greater degree. This retinal thinning was associated with worse performance on tests of information processing speed.

The NIMH intramural healthy volunteer dataset: A comprehensive MEG, MRI, and behavioral resource.

The NIMH Healthy Research Volunteer Dataset is a collection of phenotypic data characterizing healthy research volunteers using clinical assessments such as assays of blood and urine, mental health assessments, diagnostic and dimensional measures of mental health, cognitive and neuropsychological functioning, structural and functional magnetic resonance imaging (MRI), along with diffusion tensor imaging (DTI), and a comprehensive magnetoencephalography battery (MEG). In addition, blood samples of healthy volunteers are banked for future analyses. All data collected in this protocol are broadly shared in the OpenNeuro repository, in the Brain Imaging Data Structure (BIDS) format. In addition, task paradigms and basic pre-processing scripts are shared on GitHub. There are currently few open access MEG datasets, and multimodal neuroimaging datasets are even more rare. Due to its depth of characterization of a healthy population in terms of brain health, this dataset may contribute to a wide array of secondary investigations of non-clinical and clinical research questions.

Proteomic response of the marine ammonia-oxidising archaeon Nitrosopumilus maritimus to iron limitation reveals strategies to compensate for nutrient scarcity.

Dissolved iron (Fe) is vanishingly low in the oceans, with ecological success conferred to microorganisms that can restructure their biochemistry to maintain high growth rates during Fe scarcity. Chemolithoautotrophic ammonia-oxidising archaea (AOA) are highly abundant in the oceans, constituting ~30% of cells below the photic zone. Here we examine the proteomic response of the AOA isolate Nitrosopumilus maritimus to growth-limiting Fe concentrations. Under Fe limitation, we observed a significant reduction in the intensity of Fe-dense ferredoxins associated with respiratory complex I whilst complex III and IV proteins with more central roles in the electron transport chain remain unchanged. We concomitantly observed an increase in the intensity of Fe-free functional alternatives such as flavodoxin and plastocyanin, thioredoxin and alkyl hydroperoxide which are known to mediate electron transport and reactive oxygen species detoxification, respectively. Under Fe limitation, we found a marked increase in the intensity of the ABC phosphonate transport system (Phn), highlighting an intriguing link between Fe and P cycling in N. maritimus. We hypothesise that an elevated uptake of exogenous phosphonates under Fe limitation may either supplement N. maritimus' endogenous methylphosphonate biosynthesis pathway - which requires Fe - or enhance the production of phosphonate-containing exopolysaccharides known to efficiently bind environmental Fe.

Medical Symptom Validity Test (MSVT) profiles in individuals being evaluated for Alzheimer's disease.

Objective:Our purpose was to determine whether Medical Symptom Validity Test (MSVT) profiles could differentiate performance invalidity from true impairment in patients with varying levels of memory impairment and functional ability being evaluated for Alzheimer's disease (AD). Method: Seventy-three older adults (13 healthy controls, 25 mild cognitive impairment [MCI], 16 mild AD, 19 moderate AD) were evaluated with a neuropsychological battery including the MSVT and activities of daily living (ADL) measures. Using MSVT classification guidelines, examinees' MSVT profiles were categorized as: 1) valid, 2) invalid, 3) weak memory, or 4) genuine memory impairment (GMIP). Results: Eighty-four percent of moderate AD examinees produced a GMIP. Among MCI and mild AD examinees, who had only modestly affected ADLs, a substantial proportion manifested a GMIP (40% and 62.5%, respectively). An invalid profile was uncommon across patient groups (12.5% in mild AD, 5.3% in moderate AD, and 0% in MCI). Conclusions: The MSVT functions reasonably well in a dementia sample to determine if an examinee has an invalid profile, although for mild AD examinees, the false positive rate is slightly above the recommended 10% cut-off. However, even individuals with MCI, mild AD and relative preservation of ADLs may manifest a GMIP, demonstrating that such profile is found across patients with lower and higher degrees of functional impairment. Given this finding, the usefulness of the GMIP in differentiating performance invalidity from true impairment in patients being evaluated for AD appears limited.

Quality Improvement of Primary Care Provider Communication on Hospital Discharge.

BACKGROUND AND OBJECTIVES: Effective communication between inpatient and primary care providers (PCPs) is important for safe transition of care for hospitalized patients. In 2017, communication with PCPs was prioritized for the pediatric hospital medicine division. Our primary aim was to improve documented attempted communication with PCPs within 72 hours of discharge from 41% to at least 60% by January 1, 2018, and maintain this performance through 2019. METHODS: This study included all inpatient encounters discharged by a pediatric hospital medicine provider from March 2017 to April 2020. An electronic health record phrase debuted March 2017. Successful documentation was defined as any attempt to contact the PCP, regardless of whether actual communication occurred. Group and individual audit and feedback occurred in July 2017 to April 2020. Provider communication was financially incentivized in July 2018 to June 2019. An annotated P-chart for the proportion of encounters with documented PCP communication occurring within 72 hours was established. Special-cause variation was determined by using Shewhart rules. RESULTS: The mean proportion of encounters with documented PCP communication increased from 41% at baseline (March 2017 through July 2017) to 60% in August 2017 and 66% in December 2017. After the financial incentive was removed in July 2019, documentation decreased to 54%. Phone calls with clinic staff were the most common communication method (40% to 71%). Direct conversations with the PCP occurred rarely (0% to 3%). CONCLUSIONS: Even when coupled with audit and feedback with EHR interventions, our work suggests that shifting to external financial motivation may hinder sustainability of behavior change to improve attempted documented PCP communication.

Prospective Evaluation of an Abbreviated Test Battery to Screen for Neurocognitive Impairment in HIV-Positive Military Members.

Human immunodeficiency virus (HIV)-associated neurocognitive disorder (HAND) affects around 20-50% of people living with HIV (PLWH). Although batteries of tests are used to identify neurocognitive impairment (NCI), they are long and difficult to perform during a routine clinic visit, thus impairing the ability to diagnose HAND. Therefore, a brief yet sensitive screening tool to identify NCI is necessary. This study prospectively evaluated an abbreviated screening battery with reported 86.5%/87.1% sensitivity/specificity, identified from a planned post-hoc analysis in a prior neurocognitive study among military PLWH. Adult HIV-positive military beneficiaries in the U.S. Military HIV Natural History Study, who agreed to undergo a comprehensive seven-domain neuropsychological battery (16 tests), and who completed an additional 20-min abbreviated battery (AB), comprised of four tests, prior to the full battery (FB) were included in this analysis. A group of 169 individuals completed both tests, of which 25.4% had a positive AB and 17.8% had NCI on FB (global deficit score ≥ 0.5). With the FB as the reference standard, the specificity for the AB was 79.9% (73.2-86.5), however the sensitivity was 50.0% (32.1-67.9). In those with NCI by FB but not AB, the most common impaired domains were executive function (73.3%) and memory (73.3%), both being domains not fully tested by the AB. An abbreviated HAND screening battery of four tests requiring approximately 20 min provided a relatively high level of specificity but lacked sensitivity for detection of NCI. Inclusion of additional domains or alternative scoring approaches may improve sensitivity but require further study. Continued efforts are needed to develop an effective brief screening test for HAND.

Severity modeling of propionic acidemia using clinical and laboratory biomarkers.

PURPOSE: To conduct a proof-of-principle study to identify subtypes of propionic acidemia (PA) and associated biomarkers. METHODS: Data from a clinically diverse PA patient population ( https://clinicaltrials.gov/ct2/show/NCT02890342 ) were used to train and test machine learning models, identify PA-relevant biomarkers, and perform validation analysis using data from liver-transplanted participants. k-Means clustering was used to test for the existence of PA subtypes. Expert knowledge was used to define PA subtypes (mild and severe). Given expert classification, supervised machine learning (support vector machine with a polynomial kernel, svmPoly) performed dimensional reduction to define relevant features of each PA subtype. RESULTS: Forty participants enrolled in the study; five underwent liver transplant. Analysis with k-means clustering indicated that several PA subtypes may exist on the biochemical continuum. The conventional PA biomarkers, plasma total 2-methylctirate and propionylcarnitine, were not statistically significantly different between nontransplanted and transplanted participants motivating us to search for other biomarkers. Unbiased dimensional reduction using svmPoly revealed that plasma transthyretin, alanine:serine ratio, GDF15, FGF21, and in vivo 1-13C-propionate oxidation, play roles in defining PA subtypes. CONCLUSION: Support vector machine prioritized biomarkers that helped classify propionic acidemia patients according to severity subtypes, with important ramifications for future clinical trials and management of PA.

The influence of elevated SiO2 (aq) on intracellular silica uptake and microbial metabolism.

Microbes are known to accumulate intracellular SiO2 (aq) up to 100s of mmol/l from modern seawater (SiO2 (aq) <100 µmol/l), despite having no known nutrient requirement for Si. Before the evolution of siliceous skeletons, marine silica concentrations were likely an order of magnitude higher than the modern ocean, raising the possibility that intracellular SiO2 (aq) accumulation interfered with normal cellular function in non-silicifying algae. Yet, because few culturing studies have isolated the effects of SiO2 (aq) at high concentration, the potential impact of elevated marine silica on early microbial evolution is unknown. Here, we test the influence of elevated SiO2 (aq) on eukaryotic algae, as well as a prokaryote species. Our results demonstrate that under SiO2 (aq) concentrations relevant to ancient seawater, intracellular Si accumulates to concentrations comparable to those found in siliceous algae such as diatoms. In addition, all eukaryotic algae showed a statistically significant response to the high-Si treatment, including reduced average cell sizes and/or a reduction in the maximum growth rate. In contrast, there was no consistent response to the high-Si treatment by the prokaryote species. Our results highlight the possibility that elevated marine SiO2 (aq) may have been an environmental stressor during early eukaryotic evolution.

1-13C-propionate breath testing as a surrogate endpoint to assess efficacy of liver-directed therapies in methylmalonic acidemia (MMA).

PURPOSE: To develop a safe and noninvasive in vivo assay of hepatic propionate oxidative capacity. METHODS: A modified 1-13C-propionate breath test was administered to 57 methylmalonic acidemia (MMA) subjects, including 19 transplant recipients, and 16 healthy volunteers. Isotopomer enrichment (13CO2/12CO2) was measured in exhaled breath after an enteral bolus of sodium-1-13C-propionate, and normalized for CO2 production. 1-13C-propionate oxidation was then correlated with clinical, laboratory, and imaging parameters collected via a dedicated natural history protocol. RESULTS: Lower propionate oxidation was observed in patients with the severe mut0 and cblB subtypes of MMA, but was near normal in those with the cblA and mut- forms of the disorder. Liver transplant recipients demonstrated complete restoration of 1-13C-propionate oxidation to control levels. 1-13C-propionate oxidation correlated with cognitive test result, growth indices, bone mineral density, renal function, and serum biomarkers. Test repeatability was robust in controls and in MMA subjects (mean coefficient of variation 6.9% and 12.8%, respectively), despite widely variable serum methylmalonic acid concentrations in the patients. CONCLUSION: Propionate oxidative capacity, as measured with 1-13C-propionate breath testing, predicts disease severity and clinical outcomes, and could be used to assess the therapeutic effects of liver-targeted genomic therapies for MMA and related disorders of propionate metabolism. TRIAL REGISTRATION: This clinical study is registered in www.clinicaltrials.gov with the ID: NCT00078078. Study URL: http://clinicaltrials.gov/ct2/show/NCT00078078.

Association of White Matter Hyperintensities With HIV Status and Vascular Risk Factors.

OBJECTIVE: To test the hypothesis that brain white matter hyperintensities (WMH) are more common in people living with HIV (PLWH), even in the setting of well-controlled infection, and to identify clinical measures that correlate with these abnormalities. METHODS: Research brain MRI scans, acquired within longitudinal studies evaluating neurocognitive outcomes, were reviewed to determine WMH load using the Fazekas visual rating scale in PLWH with well-controlled infection (antiretroviral therapy for at least 1 year and plasma viral load <200 copies/mL) and in sociodemographically matched controls without HIV (CWOH). The primary outcome measure of this cross-sectional analysis was increased WMH load, determined by total Fazekas score ≥2. Multiple logistic regression analysis was performed to evaluate the effect of HIV serostatus on WMH load and to identify MRI, CSF, and clinical variables that associate with WMH in the PLWH group. RESULTS: The study included 203 PLWH and 58 CWOH who completed a brain MRI scan between April 2014 and March 2019. The multiple logistic regression analysis, with age and history of tobacco use as covariates, showed that the adjusted odds ratio of the PLWH group for increased WMH load is 3.7 (95% confidence interval 1.8-7.5; p = 0.0004). For the PLWH group, increased WMH load was associated with older age, male sex, tobacco use, hypertension, and hepatitis C virus coinfection, and also with the presence of measurable tumor necrosis factor α in CSF. CONCLUSION: Our results suggest that HIV serostatus affects the extent of brain WMH. This effect is mainly associated with aging and modifiable comorbidities.

Quality of life of HIV-negative, previously healthy individuals following cryptococcal meningoencephalitis.

The morbidity and mortality of cryptococcal meningoencephalitis (CM) in previously healthy, HIV-negative individuals is increasingly recognized. We administered a healthcare associated quality of life (QOL) survey to the largest longitudinally followed cohort of these patients in the United States. We identified moderate or severe self-reported impairment in at least one QOL domain in 61% of subjects at least one year following diagnosis. Self-reported cognitive impairment was noted in 52% and sleep disturbance was noted in 55%. This is the first comprehensive study of cross-sectional long-term QOL in previously healthy patients following cryptococcal infection.

Marine ammonia-oxidising archaea and bacteria occupy distinct iron and copper niches.

Ammonia oxidation by archaea and bacteria (AOA and AOB), is the first step of nitrification in the oceans. As AOA have an ammonium affinity 200-fold higher than AOB isolates, the chemical niche allowing AOB to persist in the oligotrophic ocean remains unclear. Here we show that marine isolates, Nitrosopumilus maritimus strain SCM1 (AOA) and Nitrosococcus oceani strain C-107 (AOB) have contrasting physiologies in response to the trace metals iron (Fe) and copper (Cu), holding potential implications for their niche separation in the oceans. A greater affinity for unchelated Fe may allow AOB to inhabit shallower, euphotic waters where ammonium supply is high, but competition for Fe is rife. In contrast to AOB, AOA isolates have a greater affinity and toxicity threshold for unchelated Cu providing additional explanation to the greater success of AOA in the marine environment where Cu availability can be highly variable. Using comparative genomics, we predict that the proteomic and metal transport basis giving rise to contrasting physiologies in isolates is widespread across phylogenetically diverse marine AOA and AOB that are not yet available in pure culture. Our results develop the testable hypothesis that ammonia oxidation may be limited by Cu in large tracts of the open ocean and suggest a relatively earlier emergence of AOB than AOA when considered in the context of evolving trace metal availabilities over geologic time.

Characterization of Post-exertional Malaise in Patients With Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Background: Myalgic encephalomyelitis/chronic fatigue syndrome is characterized by persistent and disabling fatigue, exercise intolerance, cognitive difficulty, and musculoskeletal/joint pain. Post-exertional malaise is a worsening of these symptoms after a physical or mental exertion and is considered a central feature of the illness. Scant observations in the available literature provide qualitative assessments of post-exertional malaise in patients with myalgic encephalomyelitis/chronic fatigue syndrome. To enhance our understanding, a series of outpatient focus groups were convened. Methods: Nine focus groups totaling 43 patients who reported being diagnosed with myalgic encephalomyelitis/chronic fatigue syndrome were held between November 2016 and August 2019. Focus groups queried post-exertional malaise in daily life and participants' retrospective memory of post-exertional malaise that followed an exercise provocation with a cardiopulmonary exercise test. Data analysis followed the grounded theory method to systematically code and categorize the data to find meaningful patterns. A qualitative software package was used to move text into categories during data coding. Results: A wide range of symptoms were attributed to exertion both in daily lives and following cardiopulmonary exercise testing. While three core symptoms emerged (exhaustion, cognitive difficulties, and neuromuscular complaints), participants' descriptions were notable for their unique individual variations. Of 18 participants who responded to questions centered around symptoms following a cardiopulmonary exercise test, 17 reported that symptoms started within 24 h and peaked in severity within 72 h following the cardiopulmonary exercise test. Patients described post-exertional malaise as interfering with their ability to lead a "normal" life. Conclusion: The experience of post-exertional malaise in myalgic encephalomyelitis/chronic fatigue syndrome varies greatly between individuals and leads to a diminished quality of life. myalgic encephalomyelitis/chronic fatigue syndrome patients describe post-exertional malaise as all-encompassing with symptoms affecting every part of the body, difficult to predict or manage, and requiring complete bedrest to fully or partially recover. Given the extensive variability in patients, further research identifying subtypes of post-exertional malaise could lead to better targeted therapeutic options.