TUBB4B is essential for the cytoskeletal architecture of cochlear supporting cells and motile cilia development.

Microtubules are essential for various cellular processes. The functional diversity of microtubules is attributed to the incorporation of various α- and ß-tubulin isotypes encoded by different genes. In this work, we investigated the functional role of ß4B-tubulin isotype (TUBB4B) in hearing and vision as mutations in TUBB4B are associated with sensorineural disease. Using a Tubb4b knockout mouse model, our findings demonstrate that TUBB4B is essential for hearing. Mice lacking TUBB4B are profoundly deaf due to defects in the inner and middle ear. Specifically, in the inner ear, the absence of TUBB4B lead to disorganized and reduced densities of microtubules in pillar cells, suggesting a critical role for TUBB4B in providing mechanical support for auditory transmission. In the middle ear, Tubb4b-/- mice exhibit motile cilia defects in epithelial cells, leading to the development of otitis media. However, Tubb4b deletion does not affect photoreceptor function or cause retinal degeneration. Intriguingly, ß6-tubulin levels increase in retinas lacking ß4B-tubulin isotype, suggesting a functional compensation mechanism. Our findings illustrate the essential roles of TUBB4B in hearing but not in vision in mice, highlighting the distinct functions of tubulin isotypes in different sensory systems.

The ApoA1-mimetic peptide 4F blocks flavivirus NS1-triggered endothelial dysfunction and protects against lethal dengue virus challenge.

Flavivirus infections result in a variety of outcomes, from clinically inapparent infections to severe, sometimes fatal cases characterized by hemorrhagic manifestations and vascular leakage leading to shock (dengue), meningomyeloencephalitis (West Nile), and congenital abnormalities (Zika). Although there are approved vaccines against several flaviviruses, potentially enhancing cross-reactive immune responses have complicated the development and implementation of vaccines against dengue and Zika viruses, and no specific therapeutics currently exist. The flavivirus nonstructural protein 1 (NS1) is a promising antiviral target because it is a conserved multifunctional virulence factor that directly triggers vascular leak. We previously showed that interactions between NS1 and the ApoA1 lipoprotein modulate DENV infection. Here, we evaluated the potential of the ApoA1-mimetic peptide, 4F, to interfere with endothelial dysfunction mediated by the NS1 protein of dengue, Zika, and West Nile flaviviruses. In an in vitro model consisting of human endothelial cell monolayers, 4F inhibited NS1-induced hyperpermeability, as measured by a transendothelial electrical resistance assay, and prevented NS1-triggered disruption of the endothelial glycocalyx layer. We also demonstrate that treatment with 4F inhibited NS1 interaction with endothelial cells. Finally, we show that 4F protects against lethal DENV challenge in a mouse model, reducing morbidity and mortality in a dose-dependent manner. Our data demonstrate the potential of 4F to inhibit flavivirus NS1-mediated pathology and severe dengue disease in mice and suggest that 4F can also serve as a molecular tool to probe different NS1 functions in vitro and in vivo.

The Canadian Prospective Cohort Study to understand progression in multiple sclerosis: baseline characteristics.

Background: Disease progression is observed across the spectrum of people with multiple sclerosis (MS) and identification of effective treatment strategies to halt progression remains one of the greatest unmet clinical needs. Objectives: The Canadian Prospective Cohort Study to Understand Progression in MS (CanProCo) was designed to evaluate a wide range of factors associated with the onset and rate of clinical disease progression in MS and to describe the interplay between these factors. Design: A prospective cohort study. Methods: CanProCo is a national, prospective, observational cohort study that has recruited 944 individuals from 5 large academic MS centers in Canada. Participants include people with radiologically isolated syndrome (RIS), early relapsing-remitting and primary progressive MS (RRMS, PPMS), and healthy controls (HCs). Annually, participants complete self-reported questionnaires, undergo clinical evaluation and, if clinically indicated, magnetic resonance images (MRIs) of the brain and cervical spinal cord; in a subset of participants (n = 399), blood, and research MRIs of the brain and cervical spinal cord are collected. Linkages to health administrative databases are available at three sites. Results: Overall, 944 participants were recruited (53 HCs, 63 RIS, 751 RRMS, 77 PPMS). RIS and MS participants had a mean age of 39.0 years and 70.5% female. The mean time since diagnosis was 2.7 years. There were differences observed in the Expanded Disability Status Scale score and components of the MS performance test (walking speed test, manual dexterity test, processing speed test, and low-contrast visual acuity) between RIS and MS subtypes. Questionnaires revealed more symptoms of depression and anxiety and impaired physical and mental quality of life in people with RIS/MS versus HCs and differences across RIS/MS subtypes. Conclusion: Physical and mental neurological disability is prevalent even in the earliest stages of MS. Transdisciplinary approaches such as those used in CanProCo are needed to better characterize clinical progression in MS. Additional CanProCo results, including MRI, biological, and pharmaco-economic data will be forthcoming. Going forward, CanProCo's data sharing and collaborative vision will facilitate numerous global collaborations, which will inform the development and implementation of effective interventions for people with MS around the world.

Postdischarge Mortality in a Cohort Hospitalized With Anorexia Nervosa.

OBJECTIVE: To characterize mortality after hospital discharge in cohorts with and without anorexia nervosa (AN). METHODS: We obtained data for all hospitalizations for psychiatric reasons in Canada (except Quebec) between April 1, 2006, and March 31, 2021 (n = 1.3 million admissions). Cases of AN were identified using ICD-10 (F50.0 and F50.1) codes. First admissions during this interval for AN and other psychiatric conditions were linked to vital statistics data. Mortality was characterized through cross-tabulation, Cox proportional hazards models, and competing cause regression. RESULTS: After adjustment for age and sex, there was no significant difference in mortality between AN and those with other psychiatric conditions (HR = 1.04; p = 0.644). Among AN admissions, 25% (95% CI 18.6-31.4) of deaths were attributed to psychiatric conditions (ICD-F codes), with 88% of these (comprising 22% of all deaths in the AN group) having AN itself identified as the underlying cause of death. In contrast, only 8% of deaths among non-AN admissions were attributed to a mental disorder. DISCUSSION: Prevention of premature mortality in the general psychiatric population emphasizes modification of metabolic (e.g., hyperlipidemia) and lifestyle-related (e.g., sedentary behavior) risk factors. However, as AN itself makes a major contribution to mortality, specialized preventive strategies may be required.

The association between neighborhood socioeconomic deprivation and mental health in low- and middle-income countries: A scoping review.

BACKGROUND: Environmental research on mental health primarily originates from high-income countries, while information about the rest of the world remains limited. AIMS: This study examined: (1) the available published research evidence regarding the association between neighborhood-level deprivation and indicators of mental health and illness in low- and middle-income countries (LMICs), and (2) the gaps in the relevant research in LMIC settings that should be addressed in future studies. METHOD: First, we systematically searched for relevant primary studies in electronic databases (Ovid Medline, Scopus, Socindex, and PsycINFO) and citations in the reference lists. Then, a two-stage screening procedure was employed to select the relevant studies by screening the titles and abstracts and reviewing the selected full texts by independent researchers. After charting the data from the selected study reports, we collated, summarized, and discussed the results. RESULTS: We retrieved 51 studies across 19 LMICs, with only one study originating from a low-income country. Most studies focused on adult mental health topics and few explored children's mental health. Notably, a significant majority of these studies (N = 37) reported a positive association between neighborhood deprivation and mental health/disorder. However, the research methods used varied significantly, and there were several methodological limitations. CONCLUSIONS: This review highlights the need for more original studies in LMICs on the association between neighborhood deprivation and mental health, employing stronger methodologies.

Psychiatric Comorbidity Does Not Enhance Prescription Opioid Use in Inflammatory Bowel Disease as It Does in the General Population.

INTRODUCTION: Little is known about patterns of opioid prescribing in inflammatory bowel disease (IBD), but pain is common in persons with IBD. We estimated the incidence and prevalence of opioid use in adults with IBD and an unaffected reference cohort and assessed factors that modified opioid use. METHODS: Using population-based health administrative data from Manitoba, Canada, we identified 5233 persons with incident IBD and 26 150 persons without IBD matched 5:1 on sex, birth year, and region from 1997 to 2016. New and prevalent opioid prescription dispensations were quantified, and patterns related to duration of use were identified. Generalized linear models were used to test the association between IBD, psychiatric comorbidity, and opioid use adjusting for sociodemographic characteristics, physical comorbidities, and healthcare use. RESULTS: Opioids were dispensed to 27% of persons with IBD and to 12.9% of the unaffected reference cohort. The unadjusted crude incidence per 1000 person-years of opioid use was nearly twice as high for the IBD cohort (88.63; 95% CI, 82.73-91.99) vs the reference cohort (45.02; 95% CI, 43.49-45.82; relative risk 1.97; 95% CI, 1.86-2.08). The incidence rate per 1000 person-years was highest in those 18-44 years at diagnosis (98.01; 95% CI, 91.45-104.57). The relative increase in opioid use by persons with IBD compared to reference cohort was lower among persons with psychiatric comorbidity relative to the increased opioid use among persons with IBD and reference cohort without psychiatric comorbidity. DISCUSSION: The use of opioids is more common in people with IBD than in people without IBD. This does not appear to be driven by psychiatric comorbidity.

The use of opioids is more common in people with inflammatory bowel disease (IBD) than in people without IBD. Psychiatric comorbidity does not significantly impact chronic opioid use in persons with IBD as it does in unaffected controls.

The influence of education in predicting conversion from Subjective cognitive decline (SCD) to objective cognitive impairment: A systematic review and meta-analysis.

BACKGROUND: Subjective cognitive decline (SCD) is considered a pre-symptomatic stage of dementia characterized by cognitive complaints. The ability of education to reduce the risk of dementia is well known. Our objective is to investigate the influence of education on the risk of progression from SCD to MCI or dementia. METHODS: Prospective longitudinal studies of adults (≥50 years) with SCD evaluating progression to objective cognitive decline, MCI, or dementia were selected. Pooled estimates (random effects model) and 95 % confidence intervals were calculated, exploring heterogeneity. Standardized education differences, Odds Ratio, or Hazard Ratio between converters and non-converters were estimated. RESULTS: The systematic review carried out showed that high education, as well as other cognitive reserve proxies, delays cognitive decline. The first meta-analysis showed a significant association of SCD with conversion in both high and low education strata. A second meta-analysis considering education as a continuous variable found that SCD converters showed two years less education than non-converters. CONCLUSIONS: Our results suggest that education has a delaying effect against cognitive decline progression. The presumed improvement in accurately detecting cognitive decline associated with better metacognitive skills in higher-educated SCD participants does not seem to neutralize the incremental risk of objective cognitive decline associated with lower educational attainment.

Multicenter, multivendor validation of liver quantitative susceptibility mapping in patients with iron overload at 1.5 T and 3 T.

PURPOSE: To evaluate the repeatability and reproducibility of QSM of the liver via single breath-hold chemical shift-encoded MRI at both 1.5 T and 3 T in a multicenter, multivendor study in subjects with iron overload. METHODS: This prospective study included four academic medical centers with three different MRI vendors at 1.5 T and 3 T. Subjects with known or suspected liver iron overload underwent multi-echo spoiled gradient-recalled-echo scans at each field strength. A subset received repeatability testing at either 1.5 T or 3 T. Susceptibility and R 2 * $$ {\mathrm{R}}_2^{\ast } $$ maps were reconstructed from the multi-echo images and analyzed at a single center. QSM-measured susceptibility was compared with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ and a commercial R2-based liver iron concentration method across centers and field strengths using linear regression and F-tests on the intercept and slope. Field-strength reproducibility and test/retest repeatability were evaluated using Bland-Altman analysis. RESULTS: A total of 155/80 data sets (test/retest) were available at 1.5 T, and 159/70 data sets (test/retest) were available at 3 T. Calibrations across sites were reproducible, with some variability (e.g., susceptibility slope with liver iron concentration ranged from 0.102 to 0.123 g/[mg · $$ \cdotp $$ ppm] across centers at 1.5 T). Field strength reproducibility was good (concordance correlation coefficient = 0.862), and test/retest repeatability was excellent (intraclass correlation coefficient = 0.951). CONCLUSION: QSM as an imaging biomarker of liver iron overload is feasible and repeatable across centers and MR vendors. It may be complementary with R 2 * $$ {\mathrm{R}}_2^{\ast } $$ as they are obtained from the same acquisition. Although good reproducibility was observed, liver QSM may benefit from standardization of acquisition parameters. Overall, QSM is a promising method for liver iron quantification.

Foundry manufacturing of octave-spanning microcombs.

Soliton microcombs provide a chip-based, octave-spanning source for self-referencing and optical metrology. We use a silicon nitride integrated photonics foundry to manufacture 280 single-chip solutions of octave-spanning microcombs on a wafer. By group-velocity dispersion (GVD) engineering with the waveguide cross section, we shape the soliton spectrum for dispersive-wave spectral enhancements at the frequencies for f-2f self-referencing. Moreover, we demonstrate the other considerations, including models for soliton spectrum design, ultra-broadband resonator external coupling, low-loss edge couplers, and the nonlinear self-interactions of few-cycle solitons. To cover the fabrication tolerance, we systematically scan 336 parameter sets of resonator width and radius, ensuring at least one device on each chip can yield an octave-spanning comb with an electronically detectable carrier-envelope offset frequency, which has been supported by our experiment. Our design and testing process permit highly repeatable creation of single-chip solutions of soliton microcombs optimized for pump operation ∼100 mW and high comb mode power for f-2f detection, which is the central component of a compact microsystem for optical metrology.

Investigation of ComBat Harmonization on Radiomic and Deep Features from Multi-Center Abdominal MRI Data.

ComBat harmonization has been developed to remove non-biological variations for data in multi-center research applying artificial intelligence (AI). We investigated the effectiveness of ComBat harmonization on radiomic and deep features extracted from large, multi-center abdominal MRI data. A retrospective study was conducted on T2-weighted (T2W) abdominal MRI data retrieved from individual patients with suspected or known chronic liver disease at three study sites. MRI data were acquired using systems from three manufacturers and two field strengths. Radiomic features and deep features were extracted using the PyRadiomics pipeline and a Swin Transformer. ComBat was used to harmonize radiomic and deep features across different manufacturers and field strengths. Student's t-test, ANOVA test, and Cohen's F score were applied to assess the difference in individual features before and after ComBat harmonization. Between two field strengths, 76.7%, 52.9%, and 26.7% of radiomic features, and 89.0%, 56.5%, and 0.1% of deep features from three manufacturers were significantly different. Among the three manufacturers, 90.1% and 75.0% of radiomic features and 89.3% and 84.1% of deep features from two field strengths were significantly different. After ComBat harmonization, there were no significant differences in radiomic and deep features among manufacturers or field strengths based on t-tests or ANOVA tests. Reduced Cohen's F scores were consistently observed after ComBat harmonization. ComBat harmonization effectively harmonizes radiomic and deep features by removing the non-biological variations due to system manufacturers and/or field strengths in large multi-center clinical abdominal MRI datasets.

Screening for depression in patients with epilepsy: same questions but different meaning to different patients.

PURPOSE: Patient-reported outcome measures (PROMs) such as the Neurological Disorders Depression Inventory in Epilepsy (NDDI-E), a 6-item epilepsy-specific PROM, is used to screen for major depressive disorder symptoms for patients with epilepsy (PWE). The validity and interpretation of PROMs can be affected by differential item functioning (DIF), which occurs when subgroups of patients with the same underlying health status respond to and interpret questions about their health status differently. This study aims to determine whether NDDI-E items exhibit DIF and to identify subgroups of PWE that exhibit DIF in NDDI-E items. METHODS: Data were from the Calgary Comprehensive Epilepsy Program database, a clinical registry of adult PWE in Calgary, Canada. A tree-based partial credit model based on recursive partitioning (PCTree) was used to identify subgroups that exhibit DIF on NDDI-E items using patients' characteristics as covariates. Differences in the identified subgroups were characterized using multinomial logistic regression. RESULTS: Of the 1,576 patients in this cohort, 806 (51.1%) were female, and the median age was 38.0 years. PCTree identified four patient subgroups defined by employment status, age, and sex. Subgroup 1 were unemployed patients ≤ 26 years old, subgroup 2 were unemployed patients > 26 years, subgroup 3 were employed females, while subgroup 4 were employed male patients. The subgroups exhibited significant differences on education level, comorbidity index scores, marital status, type of epilepsy, and driving status. CONCLUSION: PWE differed in their interpretation and responses to questions about their depression symptoms, and these differences were a function of sociodemographic and clinical characteristics.

Patient-reported depression screening measures are prone to differential item functioning (DIF), which occurs when patients with the same levels of depression respond to and interpret the questions on the measures differently, as a result of different socio-demographic characteristics. Heterogeneity in how epilepsy patients interpret and respond to depression measures, if not identified, could lead to measurement biases that threaten the validity of inferences from patient-reported outcome measure scores to inform clinical and healthcare decisions for epilepsy management. Using data from a clinical registry of patients with epilepsy, the tree-based item response theory model was used to examine the presence of DIF in the items comprising the patient-reported Neurological Disorders Depression Inventory in Epilepsy (NDDI-E) scale. Four subgroups of epilepsy patients were noted to exhibit DIF on NDDI-E items. These groups were defined by interactions among employment status, age and sex. These characteristics affect the interpretation of NDDI-E item scores. It is recommended that clinicians carefully scrutinize responses to individual items alongside the overall NDDI-E score in different patient groups to inform clinical decisions for epilepsy management.

TUBB4B is essential for the expansion of differentiating spermatogonia.

Microtubules, polymers of αß-tubulin heterodimers, are essential for various cellular processes. The incorporation of different tubulin isotypes, each encoded by distinct genes, is proposed to contribute to the functional diversity observed in microtubules. However, the functional roles of each tubulin isotype are not completely understood. In this study, we investigated the role of the ß4B-tubulin isotype (Tubb4b) in spermatogenesis, utilizing a Tubb4b knockout mouse model. We showed that ß4B-tubulin is expressed in the germ cells throughout spermatogenesis. ß4B-tubulin was localized to cytoplasmic microtubules, mitotic spindles, manchette, and axonemes of sperm flagella. We found that the absence of ß4B-tubulin resulted in male infertility and failure to produce sperm cells. Our findings demonstrate that a lack of ß4B-tubulin leads to defects in the initial stages of spermatogenesis. Specifically, ß4B-tubulin is needed for the expansion of differentiating spermatogonia, which is essential for the subsequent progression of spermatogenesis.

Sugar-Sweetened Beverages and Adverse Human Health Outcomes: An Umbrella Review of Meta-Analyses of Observational Studies.

Our aim was to conduct an umbrella review of evidence from meta-analyses of observational studies investigating the link between sugar-sweetened beverage consumption and human health outcomes. Using predefined evidence classification criteria, we evaluated evidence from 47 meta-analyses encompassing 22,055,269 individuals. Overall, 79% of these analyses indicated direct associations between greater sugar-sweetened beverage consumption and higher risks of adverse health outcomes. Convincing evidence (class I) supported direct associations between sugar-sweetened beverage consumption and risks of depression, cardiovascular disease, nephrolithiasis, type 2 diabetes mellitus, and higher uric acid concentrations. Highly suggestive evidence (class II) supported associations with risks of nonalcoholic fatty liver disease and dental caries. Out of the remaining 40 meta-analyses, 29 were graded as suggestive or weak in the strength of evidence (classes III and IV), and 11 showed no evidence (class V). These findings inform and provide support for population-based and public health strategies aimed at reducing sugary drink consumption for improved health.

Altering heparan sulfate suppresses cell abnormalities and neuron loss in Drosophila presenilin model of Alzheimer Disease.

We examined the function of heparan-sulfate-modified proteoglycans (HSPGs) in pathways affecting Alzheimer disease (AD)-related cell pathology in human cell lines and mouse astrocytes. Mechanisms of HSPG influences on presenilin-dependent cell loss were evaluated in Drosophila using knockdown of the presenilin homolog, Psn, together with partial loss-of-function of sulfateless (sfl), a gene specifically affecting HS sulfation. HSPG modulation of autophagy, mitochondrial function, and lipid metabolism were shown to be conserved in human cell lines, Drosophila, and mouse astrocytes. RNA interference (RNAi) of Ndst1 reduced intracellular lipid levels in wild-type mouse astrocytes or those expressing humanized variants of APOE, APOE3, and APOE4. Neuron-directed knockdown of Psn in Drosophila produced apoptosis and cell loss in the brain, phenotypes suppressed by reductions in sfl expression. Abnormalities in mitochondria, liposomes, and autophagosome-derived structures in animals with Psn knockdown were also rescued by reduction of sfl. These findings support the direct involvement of HSPGs in AD pathogenesis.

Protective Effects of Hepatocyte Stress Defenders, Nrf1 and Nrf2, against MASLD Progression.

Progression of metabolic dysfunction-associated steatites liver disease (MASLD) to steatohepatitis (MASH) is driven by stress-inducing lipids that promote liver inflammation and fibrosis, and MASH can lead to cirrhosis and hepatocellular carcinoma. Previously, we showed coordinated defenses regulated by transcription factors, nuclear factor erythroid 2-related factor-1 (Nrf1) and -2 (Nrf2), protect against hepatic lipid stress. Here, we investigated protective effects of hepatocyte Nrf1 and Nrf2 against MASH-linked liver fibrosis and tumorigenesis. Male and female mice with flox alleles for genes encoding Nrf1 (Nfe2l1), Nrf2 (Nfe2l2), or both were fed a MASH-inducing diet enriched with high fat, fructose, and cholesterol (HFFC) or a control diet for 24-52 weeks. During this period, hepatocyte Nrf1, Nrf2, or combined deficiency for ~7 days, ~7 weeks, and ~35 weeks was induced by administering mice hepatocyte-targeting adeno-associated virus (AAV) expressing Cre recombinase. The effects on MASH, markers of liver fibrosis and proliferation, and liver tumorigenesis were compared to control mice receiving AAV-expressing green fluorescent protein. Also, to assess the impact of Nrf1 and Nrf2 induction on liver fibrosis, HFFC diet-fed C57bl/6J mice received weekly injections of carbon tetrachloride, and from week 16 to 24, mice were treated with the Nrf2-activating drug bardoxolone, hepatocyte overexpression of human NRF1 (hNRF1), or both, and these groups were compared to control. Compared to the control diet, 24-week feeding with the HFFC diet increased bodyweight as well as liver weight, steatosis, and inflammation. It also increased hepatocyte proliferation and a marker of liver damage, p62. Hepatocyte Nrf1 and combined deficiency increased liver steatosis in control diet-fed but not HFFC diet-fed mice, and increased liver inflammation under both diet conditions. Hepatocyte Nrf1 deficiency also increased hepatocyte proliferation, whereas combined deficiency did not, and this also occurred for p62 level in control diet-fed conditions. In 52-week HFFC diet-fed mice, 35 weeks of hepatocyte Nrf1 deficiency, but not combined deficiency, resulted in more liver tumors in male mice, but not in female mice. In contrast, hepatocyte Nrf2 deficiency had no effect on any of these parameters. However, in the 15-week CCL4-exposed and 24-week HFFC diet-fed mice, Nrf2 induction with bardoxolone reduced liver steatosis, inflammation, fibrosis, and proliferation. Induction of hepatic Nrf1 activity with hNRF1 enhanced the effect of bardoxolone on steatosis and may have stimulated liver progenitor cells. Physiologic Nrf1 delays MASLD progression, Nrf2 induction alleviates MASH, and combined enhancement synergistically protects against steatosis and may facilitate liver repair.

APIR: Aggregating Universal Proteomics Database Search Algorithms for Peptide Identification with FDR Control.

Advances in mass spectrometry (MS) have enabled high-throughput analysis of proteomes in biological systems. The state-of-the-art MS data analysis relies on database search algorithms to quantify proteins by identifying peptide-spectrum matches (PSMs), which convert mass spectra to peptide sequences. Different database search algorithms use distinct search strategies and thus may identify unique PSMs. However, no existing approaches can aggregate all user-specified database search algorithms with a guaranteed increase in the number of identified peptides and a control on the false discovery rate (FDR). To fill in this gap, we proposed a statistical framework, Aggregation of Peptide Identification Results (APIR), that is universally compatible with all database search algorithms. Notably, under an FDR threshold, APIR is guaranteed to identify at least as many, if not more, peptides as individual database search algorithms do. Evaluation of APIR on a complex proteomics standard dataset showed that APIR outpowers individual database search algorithms and empirically controls the FDR. Real data studies showed that APIR can identify disease-related proteins and post-translational modifications missed by some individual database search algorithms. The APIR framework is easily extendable to aggregating discoveries made by multiple algorithms in other high-throughput biomedical data analysis, e.g., differential gene expression analysis on RNA sequencing data. The APIR R package is available at https://github.com/yiling0210/APIR.

The amorphization of crystalline silicon by ball milling.

The transformation of crystalline silicon to amorphous silicon during ball milling was quantitatively measured by x-ray diffraction and electrochemical methods. Amorphous silicon was found to form rapidly from the very initial stages of ball milling. Simultaneously, the grain size of the crystalline silicon phase decreased. Under extended milling times it was found that a maximum of 86 % of the silicon became amorphous. Similarly, the grain size of the crystalline silicon phase could not be reduced below 6 nm. This transformation followed an Avrami kinetic model, which is consistent with a system which reaches a steady state. These observations suggest a mechanism in which ball milling generates defects, resulting in silicon amorphization and grain size reduction, where the degree of amorphization is limited in extent because there exists a limiting silicon grain size below which defects are no longer formed.

Does Age Influence Immunosuppressant Drug Pharmacokinetics in Kidney Transplant Recipients?

BACKGROUND: The pharmacokinetics of immunosuppressant drugs may change with advancing age, potentially affecting patient outcomes. OBJECTIVE: To characterise the effects of age on the pharmacokinetic and exposure parameters of tacrolimus, mycophenolate, and prednisolone. METHODS: Pharmacokinetic profiling, involving whole blood tacrolimus, total and free plasma mycophenolic acid (MPA), total plasma mycophenolic acid glucuronide (MPAG), and total and free plasma prednisolone, was performed in an older and younger adult cohort. Thirteen samples were drawn on a single occasion, pre-oral dose and then at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 9, and 12 h post-dose. Non-compartmental analysis was conducted using the PKNCA package, and pharmacokinetic and exposure parameters were compared between age groups using a Mann-Whitney test. A regression analysis was conducted for free MPA and MPAG using significant variables of interest. RESULTS: This exploratory study included 21 older and 18 younger adults. Dose-adjusted tacrolimus, total MPA and free prednisolone pharmacokinetic parameters were not different between age groups; however, for free MPA and MPAG, older recipients had significantly greater minimum and maximum concentrations, trough concentrations, and half-life. There was a two-fold increase in free MPA exposure in older adults (median dose-adjusted AUC0-12: 1284 vs. 684 µg h/L, p < 0.0001); MPAG exposure similarly increased. Age was significantly associated with free MPA and MPAG exposure, and free MPA exposure was associated with haematocrit (p < 0.05). CONCLUSION: Differences in MPA were found with advancing age and may be due to altered kidney function, haematocrit, plasma protein binding and/or drug absorption. Future research should explore specific covariate contributions to this further.

Metabolic syndrome risk prediction in an Australian sample with first-episode psychosis using the psychosis metabolic risk calculator: A validation study.

OBJECTIVE: To examine the accuracy and likely clinical usefulness of the Psychosis Metabolic Risk Calculator (PsyMetRiC) in predicting up-to six-year risk of incident metabolic syndrome in an Australian sample of young people with first-episode psychosis. METHOD: We conducted a retrospective study at a secondary care early psychosis treatment service among people aged 16-35 years, extracting relevant data at the time of antipsychotic commencement and between one-to-six-years later. We assessed algorithm accuracy primarily via discrimination (C-statistic), calibration (calibration plots) and clinical usefulness (decision curve analysis). Model updating and recalibration generated a site-specific (Australian) PsyMetRiC version. RESULTS: We included 116 people with baseline and follow-up data: 73% male, mean age 20.1 years, mean follow-up 2.6 years, metabolic syndrome prevalence 13%. C-statistics for both partial- (C = 0.71, 95% CI 0.64-0.75) and full-models (C = 0.72, 95% CI 0.65-0.77) were acceptable; however, calibration plots demonstrated consistent under-prediction of risk. Recalibration and updating led to slightly improved C-statistics, greatly improved agreement between observed and predicted risk, and a narrow window of likely clinical usefulness improved significantly. CONCLUSION: An updated and recalibrated PsyMetRiC model, PsyMetRiC-Australia, shows promise. Validation in a large sample is required to confirm its accuracy and clinical usefulness for the Australian population.