Polycystic kidney disease complicates renal pathology in a family with Fabry disease.

Fabry disease is a rare lysosomal storage disorder that primarily affects the heart and kidneys, often presenting with reduced renal function. Polycystic kidney disease is a renal condition in which cysts are found, which have a different presentation than the cysts associated with Fabry disease. We report a 60-year-old male patient who was diagnosed with Fabry disease with the classic c.730G > A (p.Asp244Asn) variant of the GLA gene at 34 years of age. Fabry symptoms in this patient include hypohidrosis, hearing loss, corneal whorling, and edema. He also presented with polycystic kidney disease with multiple simple and mildly complex cysts on abdominal ultrasound. Family history of note included Fabry disease in his mother and maternal uncle as well as polycystic kidneys in his mother. Molecular analysis for polycystic kidney disease revealed a variant of uncertain significance (VUS) in the PKD1 gene. Although the in silico studies of this VUS have inconclusive results, the patient fills clinical criteria of autosomal dominant polycystic kidney disease, therefore, Fabry disease and polycystic kidney disease are considered two co-existing manifestations in this family. This case demonstrates the possibility of two renal comorbidities in the same individual and the risk of one diagnosis being overlooked by the other.

Severe manifestations and treatment of COVID-19 in a transplanted patient with Fabry disease.

Fabry disease is an X linked disease caused by pathogenic variants in the GLA gene. The cardiovascular and renal systems are most affected in Fabry patients and may require heart or kidney transplants in the late stages of the disease depending on severity of manifestations. Enzyme replacement therapy (ERT) has proven to delay progression of Fabry disease considerably, especially when started early in life. Current research has shown that individuals who have received cardiac or renal transplants or are currently on dialysis have the greatest probability of developing severe manifestations of COVID-19. It has also been shown that people who contract COVID-19 experience a rapid increase in cytokine levels which can lead to a prothrombotic state and have a greater risk in the presence of comorbidities. A history of cardiac or renal transplants as well as the naturally elevated cytokine levels in Fabry disease make it likely that COVID-19 could have a greater impact on the health of these patients. We report the case of a 67-year-old male with diabetes mellitus, history of kidney transplant, and Fabry disease treated late in progression of the disease first with agalsidase beta ERT, then oral migalastat who developed severe manifestations of COVID-19. The autopsy findings showed acute and organizing hyaline membrane disease consistent with COVID-19 pneumonia and secondary invasive bronchopulmonary aspergillosis with cavitary lesion formation. The sections of the heart showed scattered subendocardial fibrosis, and the transplanted kidneys showed thyroidization and interstitial nephritis potentially secondary to COVID-19, in addition to his long-standing renal disease. This case report serves to chronicle complications in a complex patient with late stage Fabry disease and multiple COVID-19 related complications who succumbed from respiratory failure despite the advanced management for the COVID-19 infection.

Variable clinical features of patients with Fabry disease and outcome of enzyme replacement therapy.

Fabry disease (FD) is an X-linked lysosomal storage disorder caused by a deficiency in the enzyme α-galactosidase A due to mutations in the GLA gene. This leads to an accumulation of globotriaosylceramide (GL-3) in many tissues, which results in progressive damage to the kidneys, heart, and nervous system. We present the molecular and clinical characteristics and long-term outcomes of FD patients from a multidisciplinary clinic at the University of California, Irvine treated with agalsidase beta enzyme replacement therapy (ERT) for 2-20 years. This cohort comprised 24 adults (11 males, 13 females) and two male children (median age 45; range 10-68 years). Of the 26 patients in this cohort, 20 were on ERT (12 males, 8 females). We describe one novel variant not previously reported in the literature in a patient with features of 'classic' FD. The vast majority of patients in this cohort presented with symptoms of 'classic' FD including peripheral neuropathic pain, some form of cardiac involvement, angiokeratomas, corneal verticillata, hypohidrosis, tinnitus, and gastrointestinal symptoms, primarily abdominal pain. The majority of males had clinically evident renal involvement. An annual eGFR reduction of -1.88 mL/min/1.73 m2/yr during the course of ERT was seen in this cohort. The most common renal presentation was proteinuria, and one individual required a renal transplant. Other common findings were pulmonary involvement, lymphedema, hearing loss, and significantly, three patients had strokes. Notably, there was a high prevalence of endocrine dysfunction and low bone mineral density, including several with osteoporosis. While enzyme replacement therapy (ERT) cleared plasma GL-3 in this cohort, there was limited improvement in renal function or health-related quality of life based on the patient-reported SF-36 Health Survey. Physical functioning significantly declined over the course of ERT treatment, which may be, in part, due to the late initiation of ERT in several patients. Further delineation of the phenotypic and genotypic spectrum in patients with FD and the long-term outcome of ERT will help improve management and treatment options for this disease.

NUBPL mitochondrial disease: new patients and review of the genetic and clinical spectrum.

BACKGROUND: The nucleotide binding protein-like (NUBPL) gene was first reported as a cause of mitochondrial complex I deficiency (MIM 613621, 618242) in 2010. To date, only eight patients have been reported with this mitochondrial disorder. Five other patients were recently reported to have NUBPL disease but their clinical picture was different from the first eight patients. Here, we report clinical and genetic findings in five additional patients (four families). METHODS: Whole exome sequencing was used to identify patients with compound heterozygous NUBPL variants. Functional studies included RNA-Seq transcript analyses, missense variant biochemical analyses in a yeast model (Yarrowia lipolytica) and mitochondrial respiration experiments on patient fibroblasts. RESULTS: The previously reported c.815-27T>C branch-site mutation was found in all four families. In prior patients, c.166G>A [p.G56R] was always found in cis with c.815-27T>C, but only two of four families had both variants. The second variant found in trans with c.815-27T>C in each family was: c.311T>C [p.L104P] in three patients, c.693+1G>A in one patient and c.545T>C [p.V182A] in one patient. Complex I function in the yeast model was impacted by p.L104P but not p.V182A. Clinical features include onset of neurological symptoms at 3-18 months, global developmental delay, cerebellar dysfunction (including ataxia, dysarthria, nystagmus and tremor) and spasticity. Brain MRI showed cerebellar atrophy. Mitochondrial function studies on patient fibroblasts showed significantly reduced spare respiratory capacity. CONCLUSION: We report on five new patients with NUBPL disease, adding to the number and phenotypic variability of patients diagnosed worldwide, and review prior reported patients with pathogenic NUBPL variants.

Temporomandibular disorder content in the curricula of physical therapist professional programs in the United States.

Objective: To describe the status of entry-level physical therapist (PT) education related to the diagnosis and management of temporomandibular disorders (TMD) in accredited, entry-level United States PT programs. Methods: An electronic survey explored specific TMD diagnostic and management curricular content, including the use of evidence-based diagnostic criteria, opportunities for students to interact with individuals with TMD, and faculty qualifications. Results: Eighty-four programs completed the survey. TMD content is covered in the entry-level PT curriculum of almost all (98.8%) responding programs. Content specifically related to TMD averaged 12 h across program respondents (range 1.5-50 h). The majority (68%) of respondents utilized established evidence-based diagnostic criteria. Discussion: Consistent entry-level education guidelines related to TMD and additional post-professional education opportunities are necessary to ensure that patients with TMD are not underserved by the profession of PT by newly graduated PTs.

Effect of Injury Prevention Programs on Lower Extremity Performance in Youth Athletes: A Systematic Review.

BACKGROUND: Understanding how existing youth injury prevention programs affect specific modifiable injury risk factors will inform future program development for youth athletes. OBJECTIVE: To comprehensively evaluate the effects of injury prevention programs on the modifiable intrinsic risk factors associated with lower extremity performance in youth athletes. DATA SOURCES: This systematic review followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. A systematic search of the literature was performed using multiple databases (PubMed, EBSCOhost [including CINAHL, Medline, and SPORTDiscus], and PEDro). Secondary references were appraised for relevant articles. Article types included randomized or cluster randomized controlled trials and randomized cohort designs with youth athletes engaged in organized sports, along with outcomes that included at least 1 physical performance outcome measure. STUDY SELECTION: Eight studies met inclusion and exclusion criteria and were reviewed by 2 independent reviewers, with a third consulted in the case of disagreement, which was not needed. STUDY DESIGN: Systematic review. LEVEL OF EVIDENCE: Level 3. DATA EXTRACTION: Included studies underwent review of methodological quality using the Physiotherapy Evidence Database scale. RESULTS: Studies included mixed-sex samples of youth athletes who predominantly participated in soccer at different skill levels. The FIFA 11+ series was the most commonly used injury prevention program. Among studies, the mean percentage of improvement identified was 11.3% for force generation, 5.7% for coordination, 5.2% for posture, and 5.2% for balance. The lowest mean percentage improvement was in speed (2.2%). Endurance was not significantly affected by any of the programs. CONCLUSION: This systematic review shows that injury prevention programs improve several modifiable intrinsic risk factors of lower extremity performance among youth athletes, particularly force generation. However, several intrinsic risk factors were either not significantly affected or specifically addressed by existing programs.

Variable clinical features and genotype-phenotype correlations in 18 patients with late-onset Pompe disease.

BACKGROUND: Pompe disease is a lysosomal storage disorder caused by the deficiency of enzyme acid alpha-glucosidase (GAA) which results in accumulation of glycogen, particularly in the skeletal, cardiac, and smooth muscles. The late-onset form with symptoms presenting in childhood through adulthood, is characterized by proximal muscle weakness, respiratory insufficiency, and unlike the infantile-onset form often with no cardiac involvement. METHODS: We report our experience with 18 adult patients (14 males/4 females) with Pompe disease, several of whom had unique findings and novel pathogenic variants. Patients ranged in ages from 22-74 years (mean 53.7 years) and were diagnosed at an age range of 11-65 years (mean 43.6 years), often after a history of progressive muscle disease of several years' duration. All 18 patients were treated with alglucosidase alfa (Lumizyme) and their response to treatment was monitored by measurements of their pulmonary function and muscle weakness, six-minute walk test (6MWT), and other functional studies. RESULTS: Genetic sequencing revealed that 16 out of 18 individuals had the common c.-32-13T>G splicing variant, and six patients, including two sibships had four novel pathogenic variants: c.1594G>A, c.2655_2656delCG, c.1951-1952delGGinsT, and c.1134C>G. A male with the c.1594G>A variant developed an intracerebral aneurysm at the age of 43 years treated with surgery. Two siblings with the c.2655_2656delCG developed very high antibody titers, one of whom developed a severe infusion reaction. Other clinical features included BiPAP requirement in twelve, tinnitus in seven, scoliosis in five, cardiomyopathy in three, one individual was diagnosed with a cerebral aneurysm who underwent successful Penumbra coil placement, and another individual was diagnosed with both Graves' disease and testicular cancer. CONCLUSIONS: Our study illustrates significant variability in the range of clinical features, and the variable clinical response to enzyme replacement therapy. It also alerts us to the importance of careful monitoring and early management of complications. Possible genotype-phenotype associations with the novel mutations identified may emerge with larger studies.

An analysis of Time 4U, a therapeutic group for women with postnatal depression.

This article examines the effectiveness of the Time4U therapeutic group for women with postnatal depression, introduced seven years ago in Bury. The group is facilitated by a health visitor and primary care mental health nurse, and offers a combination of group therapy, cognitive behavioural therapy, peer support and social support. This paper analyses the scores and evaluations of the mothers who attended in 2012 and shows that the mothers' depression, anxiety and social functioning improved. The reasons for the group's success are discussed and include partnership working between community services, primary mental health services and children's centres.

Assessment of self-help methods to reduce potential exposure to radiological contamination after a large-scale radiological release.

After the release of radioactive materials from a large radiological dispersal device (e.g., dirty bomb), improvised nuclear detonation, or nuclear power plant accident, up to hundreds of square miles may be contaminated. A portion of this area will be evacuated; however, people living in the portion that is not evacuated yet is still contaminated with low-levels of radioactive contamination will be asking for ways they can reduce their exposure. Whether cleaning activities can significantly reduce exposure is not fully understood. In this effort, the ability of cleaning activities to remove cesium (137Cs) was studied. The removal efficacy of cleaning with a commercial product, Simple Green®, was compared to cleaning with water for hard surfaces typically seen in residences. The removal efficacy of laundering fabric material surfaces was also determined for a range of conditions (e.g., fabric material type, wash temperature). During these studies, assessments of the implications of these activities (e.g., cross-contamination, resulting waste streams) were also completed. Simple Green and water were effective for removing 137Cs from plastic laminate and vinyl flooring (93.4-96.8%) but were not effective for removing 137Cs from painted wallboard and wood (7.3-68.1%). It was also determined that there was no significant difference between the two cleaners on all of the surfaces, except plastic laminate, for which Simple Green was slightly more effective. Laundering was effective for removing 137Cs contamination from polyester and cotton swatches and cotton comforters (up to 96.8% in the single swatch testing).

Analysis of environmental contamination resulting from catastrophic incidents: part 2. Building laboratory capability by selecting and developing analytical methodologies.

Catastrophic incidents can generate a large number of samples of analytically diverse types, including forensic, clinical, environmental, food, and others. Environmental samples include water, wastewater, soil, air, urban building and infrastructure materials, and surface residue. Such samples may arise not only from contamination from the incident but also from the multitude of activities surrounding the response to the incident, including decontamination. This document summarizes a range of activities to help build laboratory capability in preparation for sample analysis following a catastrophic incident, including selection and development of fit-for-purpose analytical methods for chemical, biological, and radiological contaminants. Fit-for-purpose methods are those which have been selected to meet project specific data quality objectives. For example, methods could be fit for screening contamination in the early phases of investigation of contamination incidents because they are rapid and easily implemented, but those same methods may not be fit for the purpose of remediating the environment to acceptable levels when a more sensitive method is required. While the exact data quality objectives defining fitness-for-purpose can vary with each incident, a governing principle of the method selection and development process for environmental remediation and recovery is based on achieving high throughput while maintaining high quality analytical results. This paper illustrates the result of applying this principle, in the form of a compendium of analytical methods for contaminants of interest. The compendium is based on experience with actual incidents, where appropriate and available. This paper also discusses efforts aimed at adaptation of existing methods to increase fitness-for-purpose and development of innovative methods when necessary. The contaminants of interest are primarily those potentially released through catastrophes resulting from malicious activity. However, the same techniques discussed could also have application to catastrophes resulting from other incidents, such as natural disasters or industrial accidents. Further, the high sample throughput enabled by the techniques discussed could be employed for conventional environmental studies and compliance monitoring, potentially decreasing costs and/or increasing the quantity of data available to decision-makers.

Upper limb neurodynamic test of the radial nerve: a study of responses in symptomatic and asymptomatic subjects.

STUDY DESIGN: Clinical measurement. INTRODUCTION: Nonspecific cervical pain is a common clinical presentation. The role of upper limb neurodynamic tests (ULNT), for evaluation and treatment intervention, is not well defined for this population. PURPOSE OF THE STUDY: This study's purpose was to determine if the radial-biased (RB)-ULNT discriminates any response differences between symptomatic subjects with a positive (+) RB-ULNT (n=36), symptomatic subjects with a negative (-) RB-ULNT (n=24), and asymptomatic subjects (n=60). METHODS: Sixty asymptomatic and 60 subjects presenting with nonspecific cervical and/or unilateral upper extremity pain were compared using the RB-ULNT. Symptomatic subjects were further divided in (+) and (-) RB-ULNT groups due to their response to the RB-ULNT. Within the symptomatic population, a positive response to the RB-ULNT was defined by the symptomatic subject reporting their sensations were increased with contralateral cervical lateral flexion and decreased with ipsilateral cervical lateral flexion. Sensation provocation and location were evaluated using the RB-ULNT in all the subjects during each stage of the testing. RESULTS: Significant differences on stage of reproduction and type of sensations were identified between 1) the (+) RB-ULNT symptomatic subjects, 2) the (-) RB-ULNT symptomatic subjects, and 3) the asymptomatic subjects. The (+) RB-ULNT group showed significantly increased pain responses during the first stage of the RB-ULNT compared with the (-) RB-ULNT group and the asymptomatic subjects. The (+) RB-ULNT also showed significantly decreased glenohumeral abduction passive range of motion when compared with the asymptomatic group. CONCLUSION: Clinically, the differences found between the groups in their response to the RB-ULNT suggest heightened mechanosensitivity in the (+) RB-ULNT group. LEVEL OF EVIDENCE: 3a.