An Atypical Parvovirus Drives Chronic Tubulointerstitial Nephropathy and Kidney Fibrosis.

The occurrence of a spontaneous nephropathy with intranuclear inclusions in laboratory mice has puzzled pathologists for over 4 decades, because its etiology remains elusive. The condition is more severe in immunodeficient animals, suggesting an infectious cause. Using metagenomics, we identify the causative agent as an atypical virus, termed "mouse kidney parvovirus" (MKPV), belonging to a divergent genus of Parvoviridae. MKPV was identified in animal facilities in Australia and North America, is transmitted via a fecal-oral or urinary-oral route, and is controlled by the adaptive immune system. Detailed analysis of the clinical course and histopathological features demonstrated a stepwise progression of pathology ranging from sporadic tubular inclusions to tubular degeneration and interstitial fibrosis and culminating in renal failure. In summary, we identify a widely distributed pathogen in laboratory mice and establish MKPV-induced nephropathy as a new tool for elucidating mechanisms of tubulointerstitial fibrosis that shares molecular features with chronic kidney disease in humans.

Limits on inferring T cell specificity from partial information.

A key challenge in molecular biology is to decipher the mapping of protein sequence to function. To perform this mapping requires the identification of sequence features most informative about function. Here, we quantify the amount of information (in bits) that T cell receptor (TCR) sequence features provide about antigen specificity. We identify informative features by their degree of conservation among antigen-specific receptors relative to null expectations. We find that TCR specificity synergistically depends on the hypervariable regions of both receptor chains, with a degree of synergy that strongly depends on the ligand. Using a coincidence-based approach to measuring information enables us to directly bound the accuracy with which TCR specificity can be predicted from partial matches to reference sequences. We anticipate that our statistical framework will be of use for developing machine learning models for TCR specificity prediction and for optimizing TCRs for cell therapies. The proposed coincidence-based information measures might find further applications in bounding the performance of pairwise classifiers in other fields.

Transverse endoplasmic reticulum expansion in hereditary spastic paraplegia corticospinal axons.

Hereditary spastic paraplegias (HSPs) comprise a large group of inherited neurologic disorders affecting the longest corticospinal axons (SPG1-86 plus others), with shared manifestations of lower extremity spasticity and gait impairment. Common autosomal dominant HSPs are caused by mutations in genes encoding the microtubule-severing ATPase spastin (SPAST; SPG4), the membrane-bound GTPase atlastin-1 (ATL1; SPG3A) and the reticulon-like, microtubule-binding protein REEP1 (REEP1; SPG31). These proteins bind one another and function in shaping the tubular endoplasmic reticulum (ER) network. Typically, mouse models of HSPs have mild, later onset phenotypes, possibly reflecting far shorter lengths of their corticospinal axons relative to humans. Here, we have generated a robust, double mutant mouse model of HSP in which atlastin-1 is genetically modified with a K80A knock-in (KI) missense change that abolishes its GTPase activity, whereas its binding partner Reep1 is knocked out. Atl1KI/KI/Reep1-/- mice exhibit early onset and rapidly progressive declines in several motor function tests. Also, ER in mutant corticospinal axons dramatically expands transversely and periodically in a mutation dosage-dependent manner to create a ladder-like appearance, on the basis of reconstructions of focused ion beam-scanning electron microscopy datasets using machine learning-based auto-segmentation. In lockstep with changes in ER morphology, axonal mitochondria are fragmented and proportions of hypophosphorylated neurofilament H and M subunits are dramatically increased in Atl1KI/KI/Reep1-/- spinal cord. Co-occurrence of these findings links ER morphology changes to alterations in mitochondrial morphology and cytoskeletal organization. Atl1KI/KI/Reep1-/- mice represent an early onset rodent HSP model with robust behavioral and cellular readouts for testing novel therapies.

Linear Mixed Model of Virus Disinfection by Free Chlorine to Harmonize Data Collected across Broad Environmental Conditions.

Despite the critical importance of virus disinfection by chlorine, our fundamental understanding of the relative susceptibility of different viruses to chlorine and robust quantitative relationships between virus disinfection rate constants and environmental parameters remains limited. We conducted a systematic review of virus inactivation by free chlorine and used the resulting data set to develop a linear mixed model that estimates chlorine inactivation rate constants for viruses based on experimental conditions. 570 data points were collected in our systematic review, representing 82 viruses over a broad range of environmental conditions. The harmonized inactivation rate constants under reference conditions (pH = 7.53, T = 20 °C, [Cl-] < 50 mM) spanned 5 orders of magnitude, ranging from 0.0196 to 1150 L mg-1 min-1, and uncovered important trends between viruses. Whereas common surrogate bacteriophage MS2 does not serve as a conservative chlorine disinfection surrogate for many human viruses, CVB5 was one of the most resistant viruses in the data set. The model quantifies the role of pH, temperature, and chloride levels across viruses, and an online tool allows users to estimate rate constants for viruses and conditions of interest. Results from the model identified potential shortcomings in current U.S. EPA drinking water disinfection requirements.

Early coronary angiography in NSTEMI: a regional Victorian perspective.

BACKGROUND: Current guidelines highlight a paucity of evidence guiding optimal timing for non-ST-elevation myocardial infarction (NSTEMI) in high-risk and non-high-risk cases. AIM: We assessed long-term major adverse cardiovascular events (MACEs) in NSTEMI patients undergoing early (<24 h) versus delayed (>24 h) coronary angiography at 6 years. Secondary end-points included all-cause mortality and cumulative MACE outcomes. METHODS: Baseline characteristics and clinical outcomes were assessed among 355 patients presenting to a tertiary regional hospital between 2017 and 2018. Cox proportional hazard models were generated for MACE and all-cause mortality outcomes, adjusting for the Global Registry of Acute Coronary Events (GRACE) score, patient demographics, biomarkers and comorbidities. RESULTS: Two hundred and seventy patients were included; 147 (54.4%) and 123 (45.6%) underwent early and delayed coronary angiography respectively. Median time to coronary angiography was 13.3 and 45.4 h respectively. At 6 years, 103 patients (38.1%) experienced MACE; 41 in the early group and 62 in the delayed group (hazard ratio (HR) = 2.23; 95% confidence interval (CI) = 1.50-3.31). After multivariable adjustment, the delayed group had higher rates of MACE (HR = 1.79; 95% CI = 1.19-2.70), all-cause mortality (HR = 2.76; 95% CI = 1.36-5.63) and cumulative MACE (incidence rate ratio = 1.54; 95% CI = 1.12-2.11). Subgroup analysis of MACE outcomes in rural and weekend NSTEMI presentations was not significant between early and delayed coronary angiography (HR = 1.49; 95% CI = 0.83-2.62). CONCLUSION: Higher MACE rates in the delayed intervention group suggest further investigation is needed. Randomised control trials would be well suited to assess the role of early invasive intervention across all NSTEMI risk groups.

The Easter Egg Weevil (Pachyrhynchus) genome reveals syntenic patterns in Coleoptera across 200 million years of evolution.

Patterns of genomic architecture across insects remain largely undocumented or decoupled from a broader phylogenetic context. For instance, it is unknown whether translocation rates differ between insect orders. We address broad scale patterns of genome architecture across Insecta by examining synteny in a phylogenetic framework from open-source insect genomes. To accomplish this, we add a chromosome level genome to a crucial lineage, Coleoptera. Our assembly of the Pachyrhynchus sulphureomaculatus genome is the first chromosome scale genome for the hyperdiverse Phytophaga lineage and currently the largest insect genome assembled to this scale. The genome is significantly larger than those of other weevils, and this increase in size is caused by repetitive elements. Our results also indicate that, among beetles, there are instances of long-lasting (>200 Ma) localization of genes to a particular chromosome with few translocation events. While some chromosomes have a paucity of translocations, intra-chromosomal synteny was almost absent, with gene order thoroughly shuffled along a chromosome. This large amount of reshuffling within chromosomes with few inter-chromosomal events contrasts with patterns seen in mammals in which the chromosomes tend to exchange larger blocks of material more readily. To place our findings in an evolutionary context, we compared syntenic patterns across Insecta in a phylogenetic framework. For the first time, we find that synteny decays at an exponential rate relative to phylogenetic distance. Additionally, there are significant differences in decay rates between insect orders, this pattern was not driven by Lepidoptera alone which has a substantially different rate.

Frequency and impact of musculoskeletal symptoms on quality of life in MEN2B.

OBJECTIVE: To investigate the impact of musculoskeletal (MSK)-related symptoms on the quality of life of patients with multiple endocrine neoplasia Type 2b (MEN2B). DESIGN: An online survey was distributed by the Association for Multiple Endocrine Neoplasia Disorders (AMEND) to their members and worldwide via a social media group for MEN2B patients. METHODS: The survey consisted of a detailed questionnaire analysing the MSK-related symptoms and structural deformities of MEN2B patients and their impact on patient's lives. PARTICIPANTS: Forty-eight participants completed the survey. RESULTS: Participants reported several musculoskeletal complaints; the most prevalent being musculoskeletal weakness at 73% (n = 35) and pain 58% (n = 28). The median pain score was 7 (interquartile range [IQR]: 5-8) and the frequency of pain was daily in 44% (n = 15) and constant in 21% (n = 7). Structural complaints were common with 63% (n = 30) stating their physique was 'different' and 40% (n = 19) describing marfanoid body features. Spinal curvature and foot deformities were the commonest structural abnormalities with scoliosis 70% (n = 16) and pes cavus 63% (n = 22) prevailing. Dental problems were mentioned by 69% (n = 33) with interdental spacing being the most common complaint at 61% (n = 20). The musculoskeletal symptoms of MEN2B had a median impact of 6 (IQR: 3-9) on quality of life (QOL) with structural deformities 53% (n = 18) and pain 26% (n = 9) listed as having the highest impact. Poor MSK health affected exercise, work and mobility. CONCLUSIONS: We report a high prevalence of musculoskeletal-related complaints in MEN2B which significantly affects QOL. This suggests a need to provide better holistic care including a multidisciplinary team with physiotherapist, orthopaedic and dental specialist input.

Comprehensive History and Physicals are Common Before Low-Risk Surgery and Associated With Preoperative Test Overuse.

INTRODUCTION: The Centers for Medicare and Medicaid Services (CMS) recently eliminated the requirement for preoperative history and physicals (H&Ps) prior to ambulatory surgery. We sought to assess variations in separately billed preoperative H&P utilization prior to low-risk ambulatory surgery, describe any relationship with preoperative testing, and identify independent predictors of these consultations prior to this policy change to help characterize the potential unnecessary utilization of these consultations and potential unnecessary preoperative testing prior to low-risk surgery. MATERIALS AND METHODS: A retrospective cohort study was performed using claims data from a hospital value collaborative in Michigan from January 2015 to June 2019 and included patients undergoing one of three ambulatory procedures: breast lumpectomy, laparoscopic cholecystectomy, and laparoscopic inguinal hernia repair. Rates of preoperative H&P visits within 30 d of surgical procedure were determined. H&P and preoperative testing associations were explored, and patient-level, practice-level, and hospital-level determinants of utilization were assessed with regression models. Risk and reliability-adjusted caterpillar plots were generated to demonstrate hospital-level variations in utilization. RESULTS: 50,775 patients were included with 50.5% having a preoperative H&P visit, with these visits being more common for patients with increased comorbidities (1.9 ± 2.2 vs 1.4 ± 1.9; P < 0.0001). Preoperative testing was associated with H&P visits (57.2% vs 41.4%; P < 0.0001). After adjusting for patient case-mix and interhospital and intrahospital variations in H&P visits, utilization remained with significant associations in patients with increased comorbidities. CONCLUSIONS: Preoperative H&P visits were common before three low-risk ambulatory surgical procedures across Michigan and were associated with higher rates of low-value preoperative testing, suggesting that preoperative H&P visits may create clinical momentum leading to unnecessary testing. These findings will inform strategies to tailor preoperative care before low-risk surgical procedures and may lead to reduced utilization of low-value preoperative testing.

Renal Dysfunction and Arrhythmia Association in Patients Receiving Milrinone After Cardiac Surgery.

OBJECTIVE: The altered pharmacokinetics of milrinone in renal impairment could result in an increased risk of cardiac arrhythmias. This study aimed to determine if there is an association between new-onset arrhythmias and renal impairment after cardiac surgery following milrinone administration. DESIGN: A retrospective cohort study. SETTING: A single-center tertiary care hospital. PARTICIPANTS: Adult patients who received a milrinone infusion in the intensive care unit (ICU) setting after coronary artery bypass graft, valvuloplasty, annuloplasty, or a combination of these surgeries from July 1, 2014 to July 1, 2021. Renal impairment was defined using a creatinine clearance <60 mL/min, calculated using the Cockcroft-Gault equation. INTERVENTIONS: Patients received a weight-based continuous intravenous infusion of milrinone. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the presence of new arrhythmias after the initial administration of a weight-based continuous intravenous infusion of milrinone postcardiac surgery. Of the 197 patients who met inclusion, there was no difference in the presence of new arrhythmias (42.9% v 40.3%, p = 0.76) or in the time to first new arrhythmia from milrinone initiation in those with renal impairment compared to those without renal impairment (29.1 hours v 33.3 hours, p = 0.54). Patients with renal impairment had a longer hospital stay than patients without renal impairment (17.5 days v 13.9 days, p = 0.016). Arrhythmia type, length of ICU stay, ICU mortality, and hospital mortality were not different between the cohorts. CONCLUSIONS: There was no association between new arrhythmias, milrinone, and renal impairment in patients postcardiac surgery.

Matrix/mineral ratio and domain size variation with bone tissue age: A photothermal infrared study.

Atomic force microscopy-infrared spectroscopy (AFM-IR) and optical photothermal infrared spectroscopy (O-PTIR), which feature spectroscopic imaging spatial resolution down to âˆ¼ 50 nm and âˆ¼ 500 nm, respectively, were employed to characterize the nano- to microscale chemical compositional changes in bone. Since these changes are known to be age dependent, fluorescently labelled bone samples were employed. The average matrix/mineral ratio values decrease as the bone tissue matures as measured by both AFM-IR and O-PTIR, which agrees with previously published FTIR and Raman spectroscopy results. IR ratio maps obtained by AFM-IR reveal variation in matrix/mineral ratio-generating micron-scale bands running parallel to the bone surface as well as smaller domains within these bands ranging from âˆ¼ 50 to 700 nm in size, which is consistent with the previously published length scale of nanomechanical heterogeneity. The matrix/mineral changes do not exhibit a smooth gradient with tissue age. Rather, the matrix/mineral transition occurs sharply within the length scale of 100-200 nm. O-PTIR also reveals matrix/mineral band domains running parallel to the bone surface, resulting in waves of matrix/mineral ratios progressing from the youngest to most mature tissue. Both AFM-IR and O-PTIR show a greater variation in matrix/mineral ratio value for younger tissue as compared to older tissue. Together, this data confirms O-PTIR and AFM-IR as techniques that visualize bulk spectroscopic data consistent with higher-order imaging techniques such as Raman and FTIR, while revealing novel insight into how mineralization patterns vary as bone tissue ages.

Wild-type sTREM2 blocks Aß aggregation and neurotoxicity, but the Alzheimer's R47H mutant increases Aß aggregation.

TREM2 is a pattern recognition receptor, expressed on microglia and myeloid cells, detecting lipids and Aß and inducing an innate immune response. Missense mutations (e.g., R47H) of TREM2 increase risk of Alzheimer's disease (AD). The soluble ectodomain of wild-type TREM2 (sTREM2) has been shown to protect against AD in vivo, but the underlying mechanisms are unclear. We show that Aß oligomers bind to cellular TREM2, inducing shedding of the sTREM2 domain. Wild-type sTREM2 bound to Aß oligomers (measured by single-molecule imaging, dot blots, and Bio-Layer Interferometry) inhibited Aß oligomerization and disaggregated preformed Aß oligomers and protofibrils (measured by transmission electron microscopy, dot blots, and size-exclusion chromatography). Wild-type sTREM2 also inhibited Aß fibrillization (measured by imaging and thioflavin T fluorescence) and blocked Aß-induced neurotoxicity (measured by permeabilization of artificial membranes and by loss of neurons in primary neuronal-glial cocultures). In contrast, the R47H AD-risk variant of sTREM2 is less able to bind and disaggregate oligomeric Aß but rather promotes Aß protofibril formation and neurotoxicity. Thus, in addition to inducing an immune response, wild-type TREM2 may protect against amyloid pathology by the Aß-induced release of sTREM2, which blocks Aß aggregation and neurotoxicity. In contrast, R47H sTREM2 promotes Aß aggregation into protofibril that may be toxic to neurons. These findings may explain how wild-type sTREM2 apparently protects against AD in vivo and why a single copy of the R47H variant gene is associated with increased AD risk.

Type 2 Diabetes Management, Control and Outcomes During the COVID-19 Pandemic in Older US Veterans: an Observational Study.

BACKGROUND: The COVID-19 pandemic required a change in outpatient care delivery models, including shifting from in-person to virtual visits, which may have impacted care of vulnerable patients. OBJECTIVE: To describe the changes in management, control, and outcomes in older people with type 2 diabetes (T2D) associated with the shift from in-person to virtual visits. DESIGN AND PARTICIPANTS: In veterans aged ≥ 65 years with T2D, we assessed the rates of visits (in person, virtual), A1c measurements, antidiabetic deintensification/intensification, ER visits and hospitalizations (for hypoglycemia, hyperglycemia, other causes), and A1c level, in March 2020 and April-November 2020 (pandemic period). We used negative binomial regression to assess change over time (reference: pre-pandemic period, July 2018 to February 2020), by baseline Charlson Comorbidity Index (CCI; > 2 vs. <= 2) and A1c level. KEY RESULTS: Among 740,602 veterans (mean age 74.2 [SD 6.6] years), there were 55% (95% CI 52-58%) fewer in-person visits, 821% (95% CI 793-856%) more virtual visits, 6% (95% CI 1-11%) fewer A1c measurements, and 14% (95% CI 10-17%) more treatment intensification during the pandemic, relative to baseline. Patients with CCI > 2 had a 14% (95% CI 12-16%) smaller relative increase in virtual visits than those with CCI <= 2. We observed a seasonality of A1c level and treatment modification, but no association of either with the pandemic. After a decrease at the beginning of the pandemic, there was a rebound in other-cause (but not hypo- and hyperglycemia-related) ER visits and hospitalizations from June to November 2020. CONCLUSION: Despite a shift to virtual visits and a decrease in A1c measurement during the pandemic, we observed no association with A1c level or short-term T2D-related outcomes, providing some reassurance about the adequacy of virtual visits. Further studies should assess the longer-term effects of shifting to virtual visits in different populations to help individualize care, improve efficiency, and maintain appropriate care while reducing overuse.

Genomic Characterization and Curation of UCEs Improves Species Tree Reconstruction.

Ultraconserved genomic elements (UCEs) are generally treated as independent loci in phylogenetic analyses. The identification pipeline for UCE probes does not require prior knowledge of genetic identity, only selecting loci that are highly conserved, single copy, without repeats, and of a particular length. Here, we characterized UCEs from 11 phylogenomic studies across the animal tree of life, from birds to marine invertebrates. We found that within vertebrate lineages, UCEs are mostly intronic and intergenic, while in invertebrates, the majority are in exons. We then curated four different sets of UCE markers by genomic category from five different studies including: birds, mammals, fish, Hymenoptera (ants, wasps, and bees), and Coleoptera (beetles). Of genes captured by UCEs, we find that many are represented by two or more UCEs, corresponding to nonoverlapping segments of a single gene. We considered these UCEs to be nonindependent, merged all UCEs that belonged to a particular gene, constructed gene and species trees, and then evaluated the subsequent effect of merging cogenic UCEs on gene and species tree reconstruction. Average bootstrap support for merged UCE gene trees was significantly improved across all data sets apparently driven by the increase in loci length. Additionally, we conducted simulations and found that gene trees generated from merged UCEs were more accurate than those generated by unmerged UCEs. As loci length improves gene tree accuracy, this modest degree of UCE characterization and curation impacts downstream analyses and demonstrates the advantages of incorporating basic genomic characterizations into phylogenomic analyses. [Anchored hybrid enrichment; ants; ASTRAL; bait capture; carangimorph; Coleoptera; conserved nonexonic elements; exon capture; gene tree; Hymenoptera; mammal; phylogenomic markers; songbird; species tree; ultraconserved elements; weevils.].

Impact on Health Care Utilization and Costs of a Medicaid Community Health Worker Program in Detroit, 2018-2020: A Randomized Program Evaluation.

Objectives. To compare health care utilization and costs between beneficiaries randomly assigned to usual services versus a community health worker (CHW) program implemented by 3 Medicaid health plans. Methods. From February 2018 to June 2019, beneficiaries residing in Detroit, Michigan's Cody Rouge neighborhood with more than 3 emergency department (ED) visits or at least 1 ambulatory care‒sensitive hospitalization in the previous 12 months were randomized. CHWs reached out to eligible beneficiaries to assess their needs and link them to services. We compared ED and ambulatory care visits, hospitalizations, and related costs over 12 months. Results. In intention-to-treat analyses among 2457 beneficiaries, the 1389 randomized to the CHW program had lower adjusted ratios of ED visits (adjusted rate ratio [ARR] = 0.96; P < .01) and ED visit costs (ARR = 0.96; P < .01), but higher adjusted ratios of ambulatory care costs (ARR = 1.15; P < .01) and no differences in inpatient or total costs compared with the usual-care group. Conclusions. Initial increases in ambulatory care use from effective programs for underserved communities may mitigate savings from decreased acute care use. Longer-term outcomes should be followed to assess potential cost savings from improved health. Trial Registration: ClinicalTrials.gov identifier: NCT03924713. (Am J Public Health. 2022;112(5):766-775. https://doi.org/10.2105/AJPH.2021.306700).

Association of tacrolimus time-to-therapeutic range on renal dysfunction and acute cellular rejection after orthotopic heart transplantation in a high use basiliximab population.

BACKGROUND: Currently, clinicians often delay initiation of tacrolimus after orthotopic heart transplantation (OHT) to help mitigate nephrotoxicity. This study aimed to determine if there is an association between the time-to-therapeutic range (TTT) of tacrolimus, early renal dysfunction, and acute cellular rejection (ACR) after OHT. METHODS: This was a retrospective, single center study with adult patients who underwent OHT from July 2013 to April 2020. Logistic regression analysis was utilized to examine the association of TTT with new renal dysfunction after tacrolimus initiation post-OHT. RESULTS: In a study of 317 patients, the unadjusted analysis showed patients who developed new renal dysfunction after tacrolimus initiation had a numerically shorter TTT (9.5 vs. 11.0 days, P = .065), and were more likely to have supratherapeutic tacrolimus levels (56% vs. 39.2%, P = .010). When adjusted for established risk factors for renal dysfunction, TTT was significantly associated with new renal dysfunction (OR .95; 95% CI [.90, .99], P = .03). There was no association between TTT and the incidence of ACR (11.1 vs. 10.8 days, P = .64). CONCLUSION: When adjusting for known risk factors, a shorter TTT was associated with new renal dysfunction. Supratherapeutic tacrolimus levels were also associated with new renal dysfunction. There was no association between TTT and ACR in the setting of high use basiliximab induction.

Interplay of Ferritin Accumulation and Ferroportin Loss in Ageing Brain: Implication for Protein Aggregation in Down Syndrome Dementia, Alzheimer's, and Parkinson's Diseases.

Iron accumulates in the ageing brain and in brains with neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), and Down syndrome (DS) dementia. However, the mechanisms of iron deposition and regional selectivity in the brain are ill-understood. The identification of several proteins that are involved in iron homeostasis, transport, and regulation suggests avenues to explore their function in neurodegenerative diseases. To uncover the molecular mechanisms underlying this association, we investigated the distribution and expression of these key iron proteins in brain tissues of patients with AD, DS, PD, and compared them with age-matched controls. Ferritin is an iron storage protein that is deposited in senile plaques in the AD and DS brain, as well as in neuromelanin-containing neurons in the Lewy bodies in PD brain. The transporter of ferrous iron, Divalent metal protein 1 (DMT1), was observed solely in the capillary endothelium and in astrocytes close to the ventricles with unchanged expression in PD. The principal iron transporter, ferroportin, is strikingly reduced in the AD brain compared to age-matched controls. Extensive blood vessel damage in the basal ganglia and deposition of punctate ferritin heavy chain (FTH) and hepcidin were found in the caudate and putamen within striosomes/matrix in both PD and DS brains. We suggest that downregulation of ferroportin could be a key reason for iron mismanagement through disruption of cellular entry and exit pathways of the endothelium. Membrane damage and subsequent impairment of ferroportin and hepcidin causes oxidative stress that contributes to neurodegeneration seen in DS, AD, and in PD subjects. We further propose that a lack of ferritin contributes to neurodegeneration as a consequence of failure to export toxic metals from the cortex in AD/DS and from the substantia nigra and caudate/putamen in PD brain.

The 2019 practice analysis of hand therapy and the use of orthoses by certified hand therapists.

BACKGROUND: In 2019, the Hand Therapy Certification Commission (HTCC), in consultation with Scantron Corporation, performed a practice analysis study of hand therapy, the sixth in a series of similar studies performed byHTCC over a 35-year period. PURPOSE: The primary goal of this study was to update and validate the definition and delineation of hand therapy and to ensure that the test content outline for the Hand Therapy Certification Examination (HTCE) reflects the critical tasks, knowledge, and skills required in the practice of hand therapy. Additionally, HTCC explored specific trends in hand therapy practice, compared findings with previous studies, and gathered data about the frequency, criticality, and performance expectations for the use and fabrication of orthoses by hand therapists. STUDY DESIGN: Quantitative Descriptive. METHODS: More than 40 subject matter experts from the United States and Canada, representing a broad range of experiences and perspectives, developed an updated delineation of the domains, tasks, knowledge, and techniques and tools used in hand therapy practice. A large-scale online survey of all certified hand therapists from the United States, Canada, and other countries was completed to test the profile within the practice of hand therapy. RESULTS: This large-scale online survey overwhelmingly validated the profile of hand therapy. The results affirmed the test specifications for the Hand Therapy Certification Examination; affirmed the definition of hand therapy; and refined the scope of hand therapy practice. New data was gathered regarding the use of orthotics in hand therapy. CONCLUSIONS: This study establishes content validity for the HTCE. It highlights that the specialty of hand therapy is a mature and stable specialty field of occupational therapy and physical therapy. Certified Hand Therapists frequently issue pre-fabricated and fabricate custom orthoses in the course of rehabilitation for clients with hand and arm injuries, and overall consider this a highly critical task in hand therapy practice. LEVEL OF EVIDENCE: N/A.

Intra- and Interexaminer Repeatability of Diagnostic Peri-Implant Clinical Measurement: A Pilot Study.

Despite the crucial role of examiner reliability on quality research and practice, there is still limited literature analyzing factors affecting examiner variability of peri-implant clinical measurements. The present study investigated clinical peri-implant parameters to quantify their repeatability and investigate factors that may affect their accuracy. Thirty-three implants were examined by 4 operators. Peri-implant probing depth (PD), recession (REC), and gingival index (GI) were measured for agreement and included in the analysis. Agreement was quantified using intraclass correlation coefficients (ICCs; 95% confidence interval); mixed linear and logistic regressions were used to assess additional variables. The overall interexaminer agreement was comparable between PD (0.80) and REC (0.78) but significantly worse for GI (0.45; P < .001). Similarly, the intraexaminer agreement was similar for PD (0.81) and REC (0.80) but significantly worse for GI (0.57; P < .05). The magnitude of PD did not influence the agreement. In contrast, increasing disagreement was noted for positive REC (odds ratio [OR]: 3.0), negative REC (OR: 4.8), and lower GI (OR: 4.4). The incidence of bleeding on probing and severity of GI increased for deeper PD (0.113-unit increase per millimeter). Negative and positive values of recession and lower GI were associated with increasing disagreement. Radiographic bone loss, restoration contour, and implant diameter did not affect PD accuracy in this study. In conclusion, within the limitations of the study, GI measurements presented higher variability than PD and REC did. The PD and GI were associated with one another and increased after multiple measurements.

Brain dynamics and structure-function relationships via spectral factorization and the transfer function.

It is shown how the brain's linear transfer function provides a means to systematically analyze brain connectivity and dynamics, and to infer connectivity, eigenmodes, and activity measures such as spectra, evoked responses, coherence, and causality, all of which are widely used in brain monitoring. In particular, the Wilson spectral factorization algorithm is outlined and used to efficiently obtain linear transfer functions from experimental two-point correlation functions. The algorithm is tested on a series of brain-like structures of increasing complexity which include time delays, asymmetry, two-dimensionality, and complex network connectivity. These tests are used to verify the algorithm is suitable for application to brain dynamics, specify sampling requirements for experimental time series, and to verify that its runtime is short enough to obtain accurate results for systems of similar size to current experiments. The results can equally well be applied to inference of the transfer function in complex linear systems other than brains.

Predictive Modeling of Virus Inactivation by UV.

UV254 disinfection strategies are commonly applied to inactivate pathogenic viruses in water, food, air, and on surfaces. There is a need for methods that rapidly predict the kinetics of virus inactivation by UV254, particularly for emerging and difficult-to-culture viruses. We conducted a systematic literature review of inactivation rate constants for a wide range of viruses. Using these data and virus characteristics, we developed and evaluated linear and nonlinear models for predicting inactivation rate constants. Multiple linear regressions performed best for predicting the inactivation kinetics of (+) ssRNA and dsDNA viruses, with cross-validated root mean squared relative prediction errors similar to those associated with experimental rate constants. We tested the models by predicting and measuring inactivation rate constants of a (+) ssRNA mouse coronavirus and a dsDNA marine bacteriophage; the predicted rate constants were within 7% and 71% of the experimental rate constants, respectively, indicating that the prediction was more accurate for the (+) ssRNA virus than the dsDNA virus. Finally, we applied our models to predict the UV254 rate constants of several viruses for which high-quality UV254 inactivation data are not available. Our models will be valuable for predicting inactivation kinetics of emerging or difficult-to-culture viruses.