Progressive Familial Intrahepatic Cholestasis-2 Mimicking Non-accidental Injury.

Progressive familial intrahepatic cholestasis (PFIC) is a heterogeneous group of disorders characterized by defective secretion of bile acids or transport defects resulting in progressive cholestasis. These disorders usually present during infancy or childhood and are associated with progressive liver disease. PFIC is estimated to affect 1 in 50,000-100,000 births, with PFIC-2 representing half of PFIC cases. PFIC-2 presents with hepatosplenomegaly, jaundice, pruritus, fat-soluble vitamin deficiencies, and growth failure. Laboratory findings include low/normal gamma glutamyl transpeptidase levels and elevated bilirubin, transaminases, and alpha-fetoprotein levels. In this report, we present a case of PFIC-2 presenting with severe coagulopathy, bruising, subcutaneous hematomas, and acute-onset anemia.

Users' views on the use of a smartwatch app to collect daily symptom data in individuals with multiple long-term conditions (Multimorbidity): A qualitative study.

Introduction: Long-term conditions are a major burden on health systems. One way to facilitate more research and better clinical care among patients with long-term conditions is to collect accurate data on their daily symptoms (patient-generated health data) using wearable technologies. Whilst evidence is growing for the use of wearable technologies in single conditions, there is less evidence of the utility of frequent symptom tracking in those who have more than one condition. Aims: To explore patient views of the acceptability of collecting daily patient-generated health data for three months using a smartwatch app. Methods: Watch Your Steps was a longitudinal study which recruited 53 patients to track over 20 symptoms per day for a 90-day period using a study app on smartwatches. Semi-structured interviews were conducted with a sub-sample of 20 participants to explore their experience of engaging with the app. Results: In a population of older people with multimorbidity, patients were willing and able to engage with a patient-generated health data app on a smartwatch. It was suggested that to maintain engagement over a longer period, more 'real-time' feedback from the app should be available. Participants did not seem to consider the management of more than one condition to be a factor in either engagement or use of the app, but the presence of severe or chronic pain was at times a barrier. Conclusion: This study has provided preliminary evidence that multimorbidity was not a major barrier to engagement with patient-generated health data via a smartwatch symptom tracking app.

A prospective study of risk factors associated with seroprevalence of SARS-CoV-2 antibodies in healthcare workers at a large UK teaching hospital.

OBJECTIVES: To describe the risk factors for SARS-CoV-2 infection in UK healthcare workers (HCWs). METHODS: We conducted a prospective sero-epidemiological study of HCWs at a major UK teaching hospital using a SARS-CoV-2 immunoassay. Risk factors for seropositivity were analysed using multivariate logistic regression. RESULTS: 410/5,698 (7·2%) staff tested positive for SARS-CoV-2 antibodies. Seroprevalence was higher in those working in designated COVID-19 areas compared with other areas (9·47% versus 6·16%) Healthcare assistants (aOR 2·06 [95%CI 1·14-3·71]; p=0·016) and domestic and portering staff (aOR 3·45 [95% CI 1·07-11·42]; p=0·039) had significantly higher seroprevalence than other staff groups after adjusting for age, sex, ethnicity and COVID-19 working location. Staff working in acute medicine and medical sub-specialities were also at higher risk (aOR 2·07 [95% CI 1·31-3·25]; p<0·002). Staff from Black, Asian and minority ethnic (BAME) backgrounds had an aOR of 1·65 (95% CI 1·32 - 2·07; p<0·001) compared to white staff; this increased risk was independent of COVID-19 area working. The only symptoms significantly associated with seropositivity in a multivariable model were loss of sense of taste or smell, fever, and myalgia; 31% of staff testing positive reported no prior symptoms. CONCLUSIONS: Risk of SARS-CoV-2 infection amongst HCWs is highly heterogeneous and influenced by COVID-19 working location, role, age and ethnicity. Increased risk amongst BAME staff cannot be accounted for solely by occupational factors.

A novel cause of emergent hyperammonemia: Cryptococcal fungemia and meningitis.

Among etiologies of hyperammonemic emergencies, infection must be considered in certain clinical contexts, particularly among immunocompromised individuals. Although Cryptococcus neoformans is known to be urease-producing, to our knowledge it has not previously been described as a cause of hyperammonemia in patients. We report an immunocompromised man with acute on chronic kidney disease with hyperammonemic crisis due to Cryptococcal meningitis and fungemia. It is important to be aware of C. neoformans as a possible cause of hyperammonemia.

Engagement with consumer smartwatches for tracking symptoms of individuals living with multiple long-term conditions (multimorbidity): A longitudinal observational study.

INTRODUCTION: People living with multiple long-term conditions (multimorbidity) (MLTC-M) experience an accumulating combination of different symptoms. It has been suggested that these symptoms can be tracked longitudinally using consumer technology, such as smartphones and wearable devices. AIM: The aim of this study was to investigate longitudinal user engagement with a smartwatch application, collecting survey questions and active tasks over 90 days, in people living with MLTC-M. METHODS: 'Watch Your Steps' was a prospective observational study, administering multiple questions and active tasks over 90 days. Adults with more than one clinician-diagnosed long-term conditions were loaned Fossil® Sport smartwatches, pre-loaded with the study app. Around 20 questions were prompted per day.Daily completion rates were calculated to describe engagement patterns over time, and to explore how these varied by patient characteristics and question type. RESULTS: Fifty three people with MLTC-M took part in the study. Around half were male ( = 26; 49%) and the majority had a white ethnic background (n = 45; 85%). About a third of participants engaged with the smartwatch app nearly every day. The overall completion rate of symptom questions was 45% inter-quartile range (IQR 23-67%) across all study participants. Older patients and those with greater MLTC-M were more engaged, although engagement was not significantly different between genders. CONCLUSION: It was feasible for people living with MLTC-M to report multiple symptoms per day over 3 months. User engagement appeared as good as other mobile health studies that recruited people with single health conditions, despite the higher daily data entry burden.

Transforming the clinical outcome in CRIM-negative infantile Pompe disease identified via newborn screening: the benefits of early treatment with enzyme replacement therapy and immune tolerance induction.

PURPOSE: To assess the magnitude of benefit to early treatment initiation, enabled by newborn screening or prenatal diagnosis, in patients with cross-reactive immunological material (CRIM)-negative infantile Pompe disease (IPD), treated with enzyme replacement therapy (ERT) and prophylactic immune tolerance induction (ITI) with rituximab, methotrexate, and intravenous immunoglobulin (IVIG). METHODS: A total of 41 CRIM-negative IPD patients were evaluated. Among patients who were treated with ERT + ITI (n = 30), those who were invasive ventilator-free at baseline and had ≥6 months of follow-up were stratified based on age at treatment initiation: (1) early (≤4 weeks), (2) intermediate (>4 and ≤15 weeks), and (3) late (>15 weeks). A historical cohort of 11 CRIM-negative patients with IPD treated with ERT monotherapy served as an additional comparator group. RESULTS: Twenty patients were included; five, seven, and eight in early, intermediate, and late treatment groups, respectively. Genotypes were similar across the three groups. Early-treated patients showed significant improvements in left ventricular mass index, motor and pulmonary outcomes, as well as biomarkers creatine kinase and urinary glucose tetrasaccharide, compared with those treated later. CONCLUSION: Our preliminary data suggest that early treatment with ERT + ITI can transform the long-term CRIM-negative IPD phenotype, which represents the most severe end of the Pompe disease spectrum.

Life-threatening presentations of propionic acidemia due to the Amish PCCB founder variant.

Although individuals of Amish descent with propionic acidemia (PA) are generally thought to have a milder disease phenotype, we now have a better understanding of the natural history of PA in this population. Here we describe two Amish patients with emergent presentations of PA, one with metabolic decompensation and another with cardiogenic shock. PA can present with life-threatening metabolic decompensation or an adult-onset severe cardiomyopathy. We discuss critical clinical implications of this observation.

Impaired visuomotor adaptation in adults with ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a prevalent psychiatric disorder in children that often continues into adulthood. It has been suggested that motor impairments in ADHD are associated with underlying cerebellar pathology. If such is the case, individuals with ADHD should be impaired on motor tasks requiring healthy cerebellar function. To test this, we compared performance of individuals with ADHD and ADHD-like symptoms with non-ADHD controls on a visuomotor adaptation task known to be impaired following cerebellar lesions. Participants adapted reaching movements to a visual representation that was rotated by 30°. Individuals with ADHD and those with ADHD-like symptoms took longer to correct the angle of movement once the rotation was applied relative to controls. However, post-adaptation residual effect did not differ for individuals with ADHD and ADHD-like symptoms compared to the control group. These results are consistent with the hypothesis that mild cerebellar deficits are evident in the motor performance of adults with ADHD.

Is it all Lynch syndrome?: An assessment of family history in individuals with mismatch repair-deficient tumors.

PURPOSE: Mismatch repair-deficient (MMRD) colorectal cancer (CRC) and endometrial cancer (EC) may be suggestive of Lynch syndrome (LS). LS can be confirmed only by positive germ-line testing. It is unclear if individuals with MMRD tumors but no identifiable cause (MMRD+/germ-line-) have LS. Because LS is hereditary, individuals with LS are expected to have family histories of LS-related tumors. Our study compared the family histories of MMRD+/germ-line- CRC and/or EC patients with LS CRC and/or EC patients. METHODS: A total of 253 individuals with an MMRD CRC or EC from one institution were included for analysis in one of four groups: LS; MMRD+/germ-line-; MMRD tumor with variant of uncertain significance (MMRD+/VUS); and sporadic MSI-H (MMRD tumor with MLH1 promoter hypermethylation or BRAF mutation). Family histories were analyzed utilizing MMRpro and PREMM1,2,6. Kruskal-Wallis tests were used to compare family history scores. RESULTS: MMRD+/germ-line- individuals had significantly lower median family history scores (MMRpro = 8.1, PREMM1,2,6 = 7.3) than did LS individuals (MMRpro = 89.8, PREMM1,2,6 = 26.1, P < 0.0001). CONCLUSION: MMRD+/germ-line- individuals have less suggestive family histories of LS than individuals with LS. These results imply that MMRD+/germ-line- individuals may not all have LS. This finding highlights the need to determine other causes of MMRD tumors so that these patients and their families can be accurately counseled regarding screening and management.Genet Med 17 6, 476-484.

Consequences of universal MSI/IHC in screening ENDOMETRIAL cancer patients for Lynch syndrome.

OBJECTIVE: Determine factors impacting the uptake of genetic counseling and results of genetic testing following universal tumor testing for Lynch syndrome in patients with endometrial cancer. METHODS: The study population consisted of two unselected cohorts of endometrial cancer patients, 408 identified retrospectively and 206 identified prospectively. Immunohistochemistry for mismatch repair protein expression and/or microsatellite instability analysis was performed on these tumors. MLH1 methylation analysis was performed on tumors with loss of MLH1 protein. Tumor studies were considered suggestive of Lynch Syndrome if they showed immunohistochemical loss of MSH2, MSH6 or PMS2, loss of MLH1 without MLH1 promoter methylation, and/or microsatellite instability. Participants with suggestive tumor studies were contacted and offered genetic counseling and testing. RESULTS: In the retrospective cohort, 11% had tumor studies suggestive of Lynch syndrome, and 42% was seen for genetic counseling. A germline mutation was detected in 40%, and one had a variant of uncertain significance. In the prospective cohort, 8.7% of patients had tumor testing suggestive of Lynch syndrome; 72% were seen for genetic counseling. Germline mutations were found in 40%, and one had a variant of uncertain significance. Common challenges included timing of re-contact, age, perceived lack of relevance, inability to travel and limited insurance coverage. CONCLUSIONS: There are several barriers to genetic counseling and testing follow-up after universal tumor testing, and uninformative genetic test results present a management challenge. It is important to consider these limitations when implementing an approach to screening endometrial cancer patients for Lynch syndrome.

Outcomes of screening endometrial cancer patients for Lynch syndrome by patient-administered checklist.

OBJECTIVE: The aims of this study were to implement a patient-administered checklist designed to identify endometrial cancer patients at elevated risk for Lynch syndrome; measure subsequent genetic counseling and testing; and identify differences between those who attended genetic counseling and those who did not. METHODS: We developed a 4-item yes/no checklist of personal and family history risk factors for Lynch syndrome-associated endometrial cancer and recommended referral for genetic counseling for patients meeting any of the criteria. Retrospective chart review was performed to determine subsequent genetic counseling and testing outcomes over a 15 month period. RESULTS: 6/387 (1.6%) of endometrial cancer patients tested positive for a Lynch syndrome mutation. 4/24 (17%) of endometrial cancer patients who met referral criteria and attended genetic counseling tested positive. 38/70 (55%) of patients who met referral criteria were not seen for genetic counseling. Patients who were diagnosed with endometrial cancer at younger ages, who had primary surgery at our institution, or who met more than one referral criteria were more likely to be seen for genetic counseling. CONCLUSIONS: Endometrial cancer patients who met referral criteria and attended genetic counseling comprised a population enriched for Lynch syndrome. This approach allowed Lynch syndrome evaluation resources to be targeted to a population of patients that is high risk and interested in the information. The referral rate of at-risk patients needs to be improved, and allocating resources towards this goal could increase the identification of Lynch syndrome while avoiding some of the pitfalls of universal screening.

Access to subspecialty care for patients with mobility impairment: a survey.

BACKGROUND: Adults who use wheelchairs have difficulty accessing physicians and receive less preventive care than their able-bodied counterparts. OBJECTIVE: To learn about the accessibility of medical and surgical subspecialist practices for patients with mobility impairment. DESIGN: A telephone survey was used to try to make an appointment for a fictional patient who was obese and hemiparetic, used a wheelchair, and could not self-transfer from chair to examination table. SETTING: 256 endocrinology, gynecology, orthopedic surgery, rheumatology, urology, ophthalmology, otolaryngology, and psychiatry practices in 4 U.S. cities. PATIENTS: None. MEASUREMENTS: Accessibility of the practice, reasons for lack of accessibility, and planned method of transfer of the patient to an examination table. RESULTS: Of 256 practices, 56 (22%) reported that they could not accommodate the patient, 9 (4%) reported that the building was inaccessible, 47 (18%) reported inability to transfer a patient from a wheelchair to an examination table, and 22 (9%) reported use of height-adjustable tables or a lift for transfer. Gynecology was the subspecialty with the highest rate of inaccessible practices (44%). LIMITATION: Small numbers of practices in 8 subspecialties in 4 cities and use of a fictional patient with obesity and hemiparesis limit generalizability. CONCLUSION: Many subspecialists could not accommodate a patient with mobility impairment because they could not transfer the patient to an examination table. Better awareness among providers about the requirements of the Americans with Disabilities Act and the standards of care for patients in wheelchairs is needed. PRIMARY FUNDING SOURCE: None.

HCN1 and HCN2 in Rat DRG neurons: levels in nociceptors and non-nociceptors, NT3-dependence and influence of CFA-induced skin inflammation on HCN2 and NT3 expression.

I(h), which influences neuronal excitability, has recently been measured in vivo in sensory neuron subtypes in dorsal root ganglia (DRGs). However, expression levels of HCN (hyperpolarization-activated cyclic nucleotide-gated) channel proteins that underlie I(h) were unknown. We therefore examined immunostaining of the most abundant isoforms in DRGs, HCN1 and HCN2 in these neuron subtypes. This immunostaining was cytoplasmic and membrane-associated (ring). Ring-staining for both isoforms was in neurofilament-rich A-fiber neurons, but not in small neurofilament-poor C-fiber neurons, although some C-neurons showed cytoplasmic HCN2 staining. We recorded intracellularly from DRG neurons in vivo, determined their sensory properties (nociceptive or low-threshold-mechanoreceptive, LTM) and conduction velocities (CVs). We then injected fluorescent dye enabling subsequent immunostaining. For each dye-injected neuron, ring- and cytoplasmic-immunointensities were determined relative to maximum ring-immunointensity. Both HCN1- and HCN2-ring-immunointensities were positively correlated with CV in both nociceptors and LTMs; they were high in Aß-nociceptors and Aα/ß-LTMs. High HCN1 and HCN2 levels in Aα/ß-neurons may, via I(h), influence normal non-painful (e.g. touch and proprioceptive) sensations as well as nociception and pain. HCN2-, not HCN1-, ring-intensities were higher in muscle spindle afferents (MSAs) than in all other neurons. The previously reported very high I(h) in MSAs may relate to their very high HCN2. In normal C-nociceptors, low HCN1 and HCN2 were consistent with their low/undetectable I(h.) In some C-LTMs HCN2-intensities were higher than in C-nociceptors. Together, HCN1 and HCN2 expressions reflect previously reported I(h) magnitudes and properties in neuronal subgroups, suggesting these isoforms underlie I(h) in DRG neurons. Expression of both isoforms was NT3-dependent in cultured DRG neurons. HCN2-immunostaining in small neurons increased 1 day after cutaneous inflammation (CFA-induced) and recovered by 4 days. This could contribute to acute inflammatory pain. HCN2-immunostaining in large neurons decreased 4 days after CFA, when NT3 was decreased in the DRG. Thus HCN2-expression control differs between large and small neurons.