The Structural and Functional Correlates of Frailty in Persons With Human Immunodeficiency Virus.

BACKGROUND: Persons with HIV (PWH) are at increased risk of frailty, a clinically recognizable state of increased vulnerability resulting from aging-associated decline in multiple physiologic systems. Frailty is often defined by the Fried criteria, which includes subjective and objective standards concerning health resiliency. However, these frailty metrics do not incorporate cognitive performance or neuroimaging measures. METHODS: We compared structural (diffusion tensor imaging [DTI]) and functional (cerebral blood flow [CBF]) neuroimaging markers in PWH with frailty and cognitive performance. Virologically controlled PWH were dichotomized as either frail (≥3) or nonfrail (<3) using the Fried criteria. Cognitive Z-scores, both domain (executive, psychomotor speed, language, and memory) and global, were derived from a battery of tests. We identified three regions of reduced CBF, based on a voxel-wise comparison of frail PWH compared with nonfrail PWH. These clusters (bilateral frontal and posterior cingulate) were subsequently used as seed regions of interest (ROIs) for DTI probabilistic white matter tractography. RESULTS: White matter integrity connecting the ROIs was significantly decreased in frail compared with nonfrail PWH. No differences in cognition were observed between frail and nonfrail PWH. However, reductions in white matter integrity among these ROIs was significantly associated with worse psychomotor speed and executive function across the entire cohort. CONCLUSIONS: We conclude that frailty in PWH can lead to structural and functional brain changes, including subtle changes that are not detectable by standard neuropsychological tests. Multimodal neuroimaging in conjunction with frailty assessment could identify pathological brain changes observed in PWH.

Frequency-Specific Microcurrent for Treatment of Longstanding Congenital Muscular Torticollis.

PURPOSE: This case describes the first episode of care, using conservative treatment, massage, and frequency-specific microcurrent (FSM), for a 19-month-old boy with grade 8 left congenital muscular torticollis with fibrotic nodules. METHODS: Ten weeks of physical therapy provided stretching, strengthening, massage, and parent education, adding FSM in weeks 3 to 10 for this patient. RESULTS: Full passive cervical rotation and lateral flexion, 4/5 lateral cervical flexion strength, improved head tilt, and inability to palpate fibrotic nodules were achieved by week 8, with partial home program adherence. CONCLUSIONS AND RECOMMENDATIONS FOR PRACTICE: Excellent outcomes were achieved with conservative care in a patient with poor prognosis and likelihood of surgical referral. Combining stretching, strengthening, massage, postural reeducation, and FSM resulted in full range and good strength in an exceptionally short time. The combination of massage and FSM, not previously reported, are tools that may be effective in congenital muscular torticollis treatment.

Gut microbiome composition may be an indicator of preclinical Alzheimer's disease.

Alzheimer's disease (AD) pathology is thought to progress from normal cognition through preclinical disease and ultimately to symptomatic AD with cognitive impairment. Recent work suggests that the gut microbiome of symptomatic patients with AD has an altered taxonomic composition compared with that of healthy, cognitively normal control individuals. However, knowledge about changes in the gut microbiome before the onset of symptomatic AD is limited. In this cross-sectional study that accounted for clinical covariates and dietary intake, we compared the taxonomic composition and gut microbial function in a cohort of 164 cognitively normal individuals, 49 of whom showed biomarker evidence of early preclinical AD. Gut microbial taxonomic profiles of individuals with preclinical AD were distinct from those of individuals without evidence of preclinical AD. The change in gut microbiome composition correlated with ß-amyloid (Aß) and tau pathological biomarkers but not with biomarkers of neurodegeneration, suggesting that the gut microbiome may change early in the disease process. We identified specific gut bacterial taxa associated with preclinical AD. Inclusion of these microbiome features improved the accuracy, sensitivity, and specificity of machine learning classifiers for predicting preclinical AD status when tested on a subset of the cohort (65 of the 164 participants). Gut microbiome correlates of preclinical AD neuropathology may improve our understanding of AD etiology and may help to identify gut-derived markers of AD risk.

The ASQ-TRAK: Validating a culturally adapted developmental screening tool for Australian Aboriginal children.

BACKGROUND: Developmental monitoring, performed using culturally relevant tools, is of critical importance for all young children. The ASQ-TRAK is the culturally and linguistically adapted Ages and Stages Questionnaire (ASQ-3), a developmental screening tool, for Australian Aboriginal children. While the ASQ-TRAK has been well received in practice, investigating its psychometric properties will enable professionals to make informed decisions about its use. AIMS: To conduct a rigorous validation study of the ASQ-TRAK by applying Kane's argument-based approach. SUBJECTS: The ASQ-TRAK, Bayley-III and/or BDI-2 were administered cross-sectionally to 336 Australian Aboriginal children aged 2-48 months across ten participating sites in the Northern Territory and South Australia. A sample of staff and caregivers completed feedback surveys about the ASQ-TRAK. RESULTS: ASQ-TRAK domain scores were moderately positively correlated with corresponding domain scores on the Bayley-III or BDI-2. Inter-rater and inter-instrument reliability were high. Sensitivity (83%), specificity (83%) and negative predictive value (99%) were acceptable. Staff and caregivers expressed high levels of satisfaction with the ASQ-TRAK. CONCLUSIONS: Regular developmental screening can provide important information about developmental vulnerability and the need for services. The ASQ-TRAK should be administered by trained Aboriginal community-based workers and the implementation approach carefully planned. Areas for future research include longitudinal follow-up of children, investigating existing norms and cut-off scores, and considering the appropriateness of the ASQ-TRAK with Aboriginal people from different locations. The ASQ-TRAK has the potential to fill an important gap by enabling better access to high-quality developmental monitoring and targeted early intervention.

Falls: a marker of preclinical Alzheimer disease: a cohort study protocol.

INTRODUCTION: Progression to symptomatic Alzheimer disease (AD) occurs slowly over a series of preclinical stages. Declining functional mobility may be an early indicator of loss of brain network integration and may lead to an increased risk of experiencing falls. It is unknown whether measures of functional mobility and falls are preclinical markers of AD. The purpose of this study is to examine (1) the relationship between falls and functional mobility with AD biomarkers to determine when falls occur within the temporal progression to symptomatic Alzheimer disease, and (2) the attentional compared with perceptual/motor systems that underlie falls and functional mobility changes seen with AD. METHODS AND ANALYSIS: This longitudinal cohort study will be conducted at the Knight Alzheimer Disease Research Center. Approximately 350 cognitively normal participants (with and without preclinical AD) will complete an in-home visit every year for 4 years. During each yearly assessment, functional mobility will be assessed using the Performance Oriented Mobility Assessment, Timed Up and Go, and Timed Up and Go dual task. Data regarding falls (including number and severity) will be collected monthly by self-report and confirmed through interviews. This study will leverage ongoing neuropsychological assessments and neuroimaging (including molecular imaging using positron emission tomography and MRI) performed by the Knight Alzheimer Disease Research Center. Relationships between falls and biomarkers of amyloid, tau and neurodegeneration will be evaluated. ETHICS AND DISSEMINATION: This study was approved by the Washington University in St. Louis Institutional Review Board (reference number 201807135). Written informed consent will be obtained in the home prior to the collection of any study data. Results will be published in peer-reviewed publications and presented at national and international conferences. TRIAL REGISTRATION NUMBER: NCT04949529; Pre-results.

Serial monitoring of humoral antibody-mediated rejection of cardiac allografts by C4d staining of interstitial capillaries.

C4d "staining" of interstitial capillaries of endomyocardial biopsies serves as an indicator of a humoral component of cardiac allograft rejection. In the present study, two cardiac allograft recipients were monitored serially for both cellular and humoral rejection. Cellular rejection, evaluated by light microscopy, and humoral rejection, judged by C4d immunofluorescent "staining", were treated with appropriate immunosuppressants. Weekly serial biopsies of the first patient revealed maximal humoral rejection (3+) after 1 week but diminished to 2+ thereafter. Cellular rejection was graded as 3A after 3 weeks but declined steadily to negligible cellular rejection through week 15. Whereas, cellular rejection peaked at 14-21 days, humoral rejection was greatest in the early post-transplant period. Biopsies of the second patient for 12 weeks revealed grade 1A to 1B moderate cellular rejection. Humoral rejection peaked at 3+ "staining" for C4d after 1 week transplant, and then wavered between 2+ (moderate "staining") and 1+ (weak "staining"). Results revealed the significance not only of traditional light microscopy in evaluating the severity of cellular rejection in endomyocardial biopsies of cardiac allotransplants, but also the value of C4d immunofluorescent "staining" of interstitial capillaries as an indicator of humoral rejection episodes, which may require modified therapy.

Earthworm bioassays and seedling emergence for monitoring toxicity, aging and bioaccumulation of anthropogenic waste indicator compounds in biosolids-amended soil.

Land application of biosolids (treated sewage sludge) can be an important route for introducing xenobiotic compounds into terrestrial environments. There is a paucity of available information on the effects of biosolids amendment on terrestrial organisms. In this study, the influence of biosolids and biosolids aging on earthworm (Eisenia fetida) reproduction and survival and lettuce (Lactuca sativa) seedling emergence was investigated. Earthworms were exposed to soils amended with varying quantities of biosolids (0, 1, 2, 3, or 4% dry mass). To investigate the influence of biosolids aging, the biosolids used in the study were aged for differing lengths of time (2 or 8 weeks) prior to exposure. All of the adult earthworms survived in the biosolids-amended soils at all concentrations that were aged for 2 weeks; however, only 20% of the adults survived in the soil amended with the highest concentration of biosolids and aged for 8 weeks. Reproduction as measured by mean number of juveniles and unhatched cocoons produced per treatment correlated inversely with biosolids concentration, although the effects were generally more pronounced in the 8-week aged biosolids-soil samples. Latent seedling emergence and reduced seedling fitness correlated inversely with biosolids concentration, but these effects were tempered in the 8-week aged versus the 2-week aged soil-biosolids mixtures. Anthropogenic waste indicator compounds (AWIs) were measured in the biosolids, biosolids-soil mixtures, and earthworm samples. Where possible, bioaccumulation factors (BAFs) were calculated or estimated. A wide variety of AWIs were detected in the biosolids (51 AWIs) and earthworm samples (≤19 AWI). The earthworms exposed to the 8-week aged biosolids-soil mixtures tended to accumulate greater quantities of AWIs compared to the 2-week aged mixture, suggesting that the bioavailability of some AWIs was enhanced with aging. The BAFs for a given AWI varied with treatment. Notably large BAFs were determined for some AWIs. For example, the maximum BAF determined for para-cresol, methyl salicylate, bisphenol-A, and cholesterol was greater than 100 in some treatments.

Paternally inherited microdeletion at 15q11.2 confirms a significant role for the SNORD116 C/D box snoRNA cluster in Prader-Willi syndrome.

Prader-Willi syndrome (PWS) is a neurobehavioral disorder manifested by infantile hypotonia and feeding difficulties in infancy, followed by morbid obesity secondary to hyperphagia. It is caused by deficiency of paternally expressed transcript(s) within the human chromosome region 15q11.2. PWS patients harboring balanced chromosomal translocations with breakpoints within small nuclear ribonucleoprotein polypeptide N (SNRPN) have provided indirect evidence for a role for the imprinted C/D box containing small nucleolar RNA (snoRNA) genes encoded downstream of SNRPN. In addition, recently published data provide strong evidence in support of a role for the snoRNA SNORD116 cluster (HBII-85) in PWS etiology. In this study, we performed detailed phenotypic, cytogenetic, and molecular analyses including chromosome analysis, array comparative genomic hybridization (array CGH), expression studies, and single-nucleotide polymorphism (SNP) genotyping for parent-of-origin determination of the 15q11.2 microdeletion on an 11-year-old child expressing the major components of the PWS phenotype. This child had an ∼236.29 kb microdeletion at 15q11.2 within the larger Prader-Willi/Angelman syndrome critical region that included the SNORD116 cluster of snoRNAs. Analysis of SNP genotypes in proband and mother provided evidence in support of the deletion being on the paternal chromosome 15. This child also met most of the major PWS diagnostic criteria including infantile hypotonia, early-onset morbid obesity, and hypogonadism. Identification and characterization of this case provide unequivocal evidence for a critical role for the SNORD116 snoRNA molecules in PWS pathogenesis. Array CGH testing for genomic copy-number changes in cases with complex phenotypes is proving to be invaluable in detecting novel alterations and enabling better genotype-phenotype correlations.