Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

The translation initiation factor homolog eif4e1c regulates cardiomyocyte metabolism and proliferation during heart regeneration.

The eIF4E family of translation initiation factors bind 5' methylated caps and act as the limiting step for mRNA translation. The canonical eIF4E1A is required for cell viability, yet other related eIF4E families exist and are utilized in specific contexts or tissues. Here, we describe a family called Eif4e1c, for which we find roles during heart development and regeneration in zebrafish. The Eif4e1c family is present in all aquatic vertebrates but is lost in all terrestrial species. A core group of amino acids shared over 500 million years of evolution forms an interface along the protein surface, suggesting that Eif4e1c functions in a novel pathway. Deletion of eif4e1c in zebrafish caused growth deficits and impaired survival in juveniles. Mutants surviving to adulthood had fewer cardiomyocytes and reduced proliferative responses to cardiac injury. Ribosome profiling of mutant hearts demonstrated changes in translation efficiency of mRNA for genes known to regulate cardiomyocyte proliferation. Although eif4e1c is broadly expressed, its disruption had most notable impact on the heart and at juvenile stages. Our findings reveal context-dependent requirements for translation initiation regulators during heart regeneration.

Critical medical ecology and intersectionality perspectives in schistosomiasis prevention and control in selected communities in Mindanao, the Philippines.

Schistosomiasis japonica remains a public health concern in many areas of the Philippines. Periodic Mass Drug Administration (MDA) to at-risk populations is the main strategy for morbidity control of schistosomiasis. Attaining MDA coverage targets is important for the reduction of morbidity and prevention of complications due to the disease, and towards achieving Universal Health Care. The study employed a qualitative case study design. Key informant interviews and focus group discussions were conducted to provide in-depth and situated descriptions of the contexts surrounding the implementation of MDA in two selected villages in known schistosomiasis-endemic provinces in Mindanao in the Philippines. Data analysis was done using the Critical Ecology for Medical Anthropology (CEMA) model coupled with the intersectionality approach. It was found that within various areas in the CEMA model, enabling as well as constraining factors have been encountered in MDA in the study settings. The interplay of income class, geographical location, gender norms and faith-based beliefs may have led to key populations being missed during the conduct of MDA in the study sites. The constraints faced by the target beneficiaries of MDA, as well as programme implementers, must be addressed to enhance service delivery and to control morbidity due to schistosomiasis. Improving compliance with MDA also requires a holistic, integrated approach to addressing barriers to participation, which are shaped by wider socio-political and power structures.

Impact of the COVID-19 Pandemic on Characteristics of Cutaneous Tumors Treated by Mohs Micrographic Surgery.

The COVID-19 pandemic has impacted the practice of Mohs micrographic surgery (MMS). We sought to determine the characteristics of skin cancers treated by MMS during the pandemic compared with prepandemic controls. A retrospective chart review was conducted. Tumors included were all treated in accordance with best practice guidelines set forth by state- and national-level professional governing bodies. Bivariate and multivariate analyses were performed to compare outcome variables. Changes in tumor characteristics during the pandemic are of clinical significance, potentially affecting extent of reconstructive surgery, cost, operating time, and future tumor characteristics.

Assessment of Risk Factors and Early Presentations of Parkinson Disease in Primary Care in a Diverse UK Population.

IMPORTANCE: Early features of Parkinson disease (PD) have been described through population-based studies that overrepresent White, affluent groups and may not be generalizable. OBJECTIVE: To investigate the association between risk factors and prediagnostic presentations of PD in an ethnically diverse UK population with high socioeconomic deprivation but universal access to health care. DESIGN, SETTING, AND PARTICIPANTS: A nested case-control study was conducted using electronic health care records on 1 016 277 individuals from primary care practices in East London to extract clinical information recorded between 1990 and February 6, 2018. The data were analyzed between September 3, 2020, and September 3, 2021. Individuals with a diagnosis of PD were compared with controls without PD or other major neurological conditions. MAIN OUTCOMES AND MEASURES: A matched analysis (10 controls matched for each patient with PD according to age and sex) and an unmatched analysis (adjusted for age and sex) were undertaken using multivariable logistic regression to determine associations between risk factors and prediagnostic presentations to primary care with subsequent diagnosis of PD. Three time periods (<2, 2-<5, and 5-10 years before diagnosis) were analyzed separately and together. RESULTS: Of 1 016 277 individuals included in the data set, 5699 were excluded and 1055 patients with PD and 1 009 523 controls were included in the analysis. Patients with PD were older than controls (mean [SD], 72.9 [11.3] vs 40.3 [15.2] years), and more were male (632 [59.9%] vs 516 862 [51.2%]). In the matched analysis (1055 individuals with PD and 10 550 controls), associations were found for tremor (odds ratio [OR], 145.96; 95% CI, 90.55-235.28) and memory symptoms (OR, 8.60; 95% CI, 5.91-12.49) less than 2 years before the PD diagnosis. The associations were also found up to 10 years before PD diagnosis for tremor and 5 years for memory symptoms. Among midlife risk factors, hypertension (OR, 1.36; 95% CI, 1.19-1.55) and type 2 diabetes (OR, 1.39; 95% CI, 1.19-1.62) were associated with subsequent diagnosis of PD. Associations with early nonmotor features, including hypotension (OR, 6.84; 95% CI, 3.38-13.85), constipation (OR, 3.29; 95% CI, 2.32-4.66), and depression (OR, 4.69; 95% CI, 2.88-7.63), were also noted. Associations were found for epilepsy (OR, 2.5; 95% CI, 1.63-3.83) and hearing loss (OR, 1.66; 95% CI, 1.06-2.58), which have not previously been well reported. These findings were replicated using data from the UK Biobank. No association with future PD diagnosis was found for ethnicity or deprivation index level. CONCLUSIONS AND RELEVANCE: This study provides data suggesting that a range of comorbidities and symptoms are encountered in primary care settings before PD diagnosis in an ethnically diverse and deprived population. Novel temporal associations were observed for epilepsy and hearing loss with subsequent development of PD. The prominence of memory symptoms suggests an excess of cognitive dysfunction in early PD in this population or difficulty in correctly ascertaining symptoms in traditionally underrepresented groups.

Developing and assessing a new web-based tapping test for measuring distal movement in Parkinson's disease: a Distal Finger Tapping test.

Disability in Parkinson's disease (PD) is measured by standardised scales including the MDS-UPDRS, which are subject to high inter and intra-rater variability and fail to capture subtle motor impairment. The BRadykinesia Akinesia INcoordination (BRAIN) test is a validated keyboard tapping test, evaluating proximal upper-limb motor impairment. Here, a new Distal Finger Tapping (DFT) test was developed to assess distal upper-limb function. Kinetic parameters of the test include kinesia score (KS20, key taps over 20 s), akinesia time (AT20, mean dwell-time on each key) and incoordination score (IS20, variance of travelling time between key taps). To develop and evaluate a new keyboard-tapping test for objective and remote distal motor function in PD patients. The DFT and BRAIN tests were assessed in 55 PD patients and 65 controls. Test scores were compared between groups and correlated with the MDS-UPDRS-III finger tapping sub-scores. Nine additional PD patients were recruited for monitoring motor fluctuations. All three parameters discriminated effectively between PD patients and controls, with KS20 performing best, yielding 79% sensitivity for 85% specificity; area under the receiver operating characteristic curve (AUC) = 0.90. A combination of DFT and BRAIN tests improved discrimination (AUC = 0.95). Among three parameters, KS20 showed a moderate correlation with the MDS-UPDRS finger-tapping sub-score (Pearson's r = - 0.40, p = 0.002). Further, the DFT test detected subtle changes in motor fluctuation states which were not reflected clearly by the MDS-UPDRS-III finger tapping sub-scores. The DFT test is an online tool for assessing distal movements in PD, with future scope for longitudinal monitoring of motor complications.

Magnetic Resonance Imaging in Stable Mild Cognitive Impairment, Prodromal Alzheimer's Disease, and Prodromal Dementia with Lewy Bodies.

INTRODUCTION: Fifteen percent of people with mild cognitive impairment (MCI) will progress to dementia within 2 years. There is increasing focus on the evaluation of biomarkers which point towards the underlying pathology. This enables better prediction of clinical outcomes. Early diagnosis of the dementia subtype is crucial for appropriate management and accurate prognosis. The aim of this study was to compare MRI measures in stable mild cognitive impairment patients (stable-MCI), prodromal Alzheimer's disease (pro-AD), and prodromal dementia with Lewy bodies (pro-DLB). METHODS: Out of 1,814 patients assessed in Essex memory clinic between 2002 and 2017, 424 had MCI at baseline with follow-up data. All patients underwent comprehensive clinical and cognitive assessment at each assessment. MRI scans were acquired at patients' baseline assessment, corresponding to the time of initial MCI clinical diagnosis. Patients were grouped according to their diagnosis at the end of follow-up. All baseline scans were visually rated according to established rating scales for medial temporal atrophy (MTA), global cortical atrophy (GCA), and white matter lesions (WMLs). RESULTS: MRI scans were available for 28 pro-DLB patients and were matched against 27 pro-AD and 28 stable-MCI patients for age, sex, and education. The mean follow-up duration was 34 months for the pro-AD group, 27 months for the pro-DLB group, and 21 months for the stable-MCI group. MTA scores were significantly greater in pro-AD patients compared to pro-DLB (p = 0.047) and stable-MCI patients (p = 0.012). There was no difference on GCA or WMLs between pro-AD, pro-DLB, and stable-MCI. CONCLUSIONS: This study indicates that a simple visual rating of MTA at the stage of MCI already differs at a group level between patients that progress to AD, DLB, or continue to be stable-MCI. This could aid clinicians to differentiate between MCI patients who are likely to develop AD, versus those who might progress to DLB or remain stable.

The Impact of External Loads Carried by Police Officers on Vertical Jump Performance.

The purpose of this study was to examine the impact that external loads have on vertical jump height and peak anaerobic power output (PAPw) of police officers during a vertical jump (VJ) test. Retrospective data of 47 (mean age 38.79 ± 7.97 years) police officers from a US Law Enforcement Agency (LEA) were used for analysis. VJ heights and body mass were used in the Sayers Peak Power Equation to calculate PAPw. Power-to-weight (P:W) ratios were then calculated by dividing PAPw by the officer's body mass. VJ height significantly (p < .001) decreased with load (unloaded = 49.49 ± 8.46 cm: loaded = 43.62 ± 7.68 cm). A Pearson's correlation showed a significant (p < .01) low-moderate (r = .387) relationship between absolute load (9.57 ± .94 kg) and change in PAPw, and a significant (p < .01) strong (r = .794) correlation between relative load and changes in P:W. This study supports previous research that suggests that occupational load carriage has a negative impact on VJ performance in police officers and may influence job performance, and that training programs may mitigate these negative effects.

Ethnic Variation in the Manifestation of Parkinson's Disease: A Narrative Review.

The global prevalence of Parkinson's disease is increasing, yet the characteristics, risk factors and genetics of PD in Black, Asian and Hispanic populations is little understood. In this paper we review the published literature on clinical variation in the symptoms and signs of Parkinson's disease in different ethnic groups and responses to treatment. We included any study that sampled patients with Parkinson's disease from distinct ethnic backgrounds. We conclude that whilst there is little published evidence for ethnic variation in the clinical features of Parkinson's disease, there are substantial limitations and gaps in the current literature, which mean that the evidence does necessarily not fit with clinical observation. Possible explanations for expected differences in manifestation include genetic determinants, the co-existence of cerebrovascular disease and/or Alzheimer's disease pathology, healthcare inequalities and socio-cultural factors.

The Impact of Load Carriage on Measures of Power and Agility in Tactical Occupations: A Critical Review.

The current literature suggests that load carriage can impact on a tactical officer's mobility, and that survival in the field may rely on the officer's mobility. The ability for humans to generate power and agility is critical for performance of the high-intensity movements required in the field of duty. The aims of this review were to critically examine the literature investigating the impacts of load carriage on measures of power and agility and to synthesize the findings. The authors completed a search of the literature using key search terms in four databases. After relevant studies were located using strict inclusion and exclusion criteria, the studies were critically appraised using the Downs and Black Checklist and relevant data were extracted and tabled. Fourteen studies were deemed relevant for this review, ranging in percentage quality scores from 42.85% to 71.43%. Outcome measures used in these studies to indicate levels of power and agility included short-distance sprints, vertical jumps, and agility runs, among others. Performance of both power and agility was shown to decrease when tactical load was added to the participants. This suggests that the increase in weight carried by tactical officers may put this population at risk of injury or fatality in the line of duty.

Transcription-factor-dependent enhancer transcription defines a gene regulatory network for cardiac rhythm.

The noncoding genome is pervasively transcribed. Noncoding RNAs (ncRNAs) generated from enhancers have been proposed as a general facet of enhancer function and some have been shown to be required for enhancer activity. Here we examine the transcription-factor-(TF)-dependence of ncRNA expression to define enhancers and enhancer-associated ncRNAs that are involved in a TF-dependent regulatory network. TBX5, a cardiac TF, regulates a network of cardiac channel genes to maintain cardiac rhythm. We deep sequenced wildtype and Tbx5-mutant mouse atria, identifying ~2600 novel Tbx5-dependent ncRNAs. Tbx5-dependent ncRNAs were enriched for tissue-specific marks of active enhancers genome-wide. Tbx5-dependent ncRNAs emanated from regions that are enriched for TBX5-binding and that demonstrated Tbx5-dependent enhancer activity. Tbx5-dependent ncRNA transcription provided a quantitative metric of Tbx5-dependent enhancer activity, correlating with target gene expression. We identified RACER, a novel Tbx5-dependent long noncoding RNA (lncRNA) required for the expression of the calcium-handling gene Ryr2. We illustrate that TF-dependent enhancer transcription can illuminate components of TF-dependent gene regulatory networks.

Magnification for the dermatologic surgeon.

Ergonomic practice increases the productivity, quality, and longevity of the dermatologic surgeon. When used properly, magnification devices can be ergonomic and beneficial additions to the dermatologic surgeon's practice. Herein, we review the available magnification options for the dermatologic surgeon and evaluate the options based on cost, design, and functional advantages and disadvantages. Magnification for the dermatologic surgeon may be a useful tool for a healthier, more efficient, and higher-quality practice.