The therapeutic potential of the neuroactive peptides of soluble amyloid precursor protein-alpha in Alzheimer's disease and related neurological disorders.

Soluble amyloid precursor protein-alpha (sAPPα) is a multi-functional brain-derived protein that has neuroprotective, neurogenic and neurotropic properties. Moreover, it is known to facilitate synaptic function and promote neural repair. These properties suggest sAPPα may be useful as a therapeutic agent for the treatment of neurological diseases characterized by synaptic failure and neuronal loss, such as occurs in Alzheimer's disease, and for neural repair following traumatic brain injury and stroke. However, sAPPα's relatively large size and the difficulty of ongoing delivery of therapeutics to the brain mean this is not currently practicable. Importantly, however, sAPPα is composed of several neuroactive domains that each possess properties that collectively are remarkably similar to those of sAPPα itself. Here, we review the molecular structure of sAPPα and identify the domains that contribute to its overall functionality. Four peptide motifs present as possible targets for therapeutic development. We review their physiochemical and neuroactive properties, both within sAPPα and as isolated peptides, and discuss their potential for future development as multipurpose therapeutic agents for the treatment of Alzheimer's disease and other disorders of neuronal function. Further, we discuss the role of heparin binding sites, found within sAPPα's structure and overlapping with the neuroactive domains, as sites for interactions with effector proteins and synaptic receptors. The potential role of the neuroactive peptides known as Cationic Arginine-Rich Peptides (CARPs) as neuroprotective motifs is also reviewed. Mechanisms of peptide delivery to the brain are briefly discussed. Finally, we summarise the potential benefits and pitfalls of using the isolated peptides, either individually or in combination, for the treatment of neurological diseases.

Utilizing kidneys from a donor with bile-cast nephropathy.

Here we discuss the successful utilization of a pair of deceased donor kidneys with bile-cast nephropathy. The donor had a kidney donor profile index of 48% and an acute kidney injury requiring continuous renal replacement therapy. Peak donor bilirubin was 40.5 mg/dL, and renal wedge biopsies showed bile-cast nephropathy. Both recipients had delayed graft function lasting up to 4 weeks. The 4-month biopsies showed mild interstitial fibrosis, tubular atrophy, and a resolution of bile casts. These kidney allografts showed the reversible course of cholemic nephropathy and the potential for increasing the utilization of previously discarded kidneys.

Outcomes of Early Thrombotic Microangiopathy in Renal Transplantation.

BACKGROUND: Alternate complement dysregulation postrenal transplantation can result in thrombotic microangiopathy (TMA). There is a scarcity of data regarding outcomes based on the timing of TMA post-transplant, coupled with a lack of follow-up biopsy findings post TMA diagnosis. This study aims to assess allograft and patient outcomes in individuals developing early TMA, defined within 4 months post-transplantation, and explore any differences in follow-up surveillance biopsies compared to a non-TMA group. DESIGN: This is a single center retrospective study between January 1, 2002 and October 10, 2019. Patients who developed TMA within 4 months post-transplantation were compared to a propensity matched non-TMA group. RESULTS: Thirty-one patients developed TMA within 4 months of renal transplantation. Index TMA biopsy featured noticeable glomerular, and vascular lesions along with acute tubular injury. Four-month surveillance biopsy showed significant glomerulitis, transplant glomerulopathy and chronic interstitial fibrosis as compared to non-TMA group. However, at 1 year, these differences were no longer significant. There was no significant difference in patient survival (TMA vs. non-TMA, p = 0.083); however, death censored graft survival was significantly lower in the TMA group (p < 0.001). TMA patients had a significantly lower estimated glomerular filtration rate at 4 months and at 1 year as compared to the non-TMA group. CONCLUSION: Early onset TMA post renal transplant leads to decreased renal function and lower graft survival. Early recognition and prompt treatment may help in reducing the adverse outcomes.

Evaluating e-Connect: Mitigating Race by Gender Disparities in Behavioral Health Referral Among Youths on Probation, Northeast United States, 2019.

Addressing the behavioral health needs of youths involved in the justice system is key to reducing recidivism risk and preventing long-term system involvement. However, rates of treatment referral and initiation remain low, especially among minoritized youths and boys. The e-Connect System, a digital, clinical decision support system, addresses this problem by increasing rates of behavioral health treatment referral and initiation rates among youths on probation. In this study, we examine whether e-Connect helps improve equity in referral and treatment initiation outcomes. (Am J Public Health. 2023;113(12):1267-1270. https://doi.org/10.2105/AJPH.2023.307417).

Training and specialisation of psychiatrists in ADHD.

OBJECTIVE: To identify the level of training of Australian psychiatrists in Attention Deficit Hyperactivity Disorder (ADHD), and to compare the number of psychiatrists specialising in ADHD versus other psychiatric conditions on the basis of the prevalence of conditions, by interrogating the RANZCP 'Find a Psychiatrist' database. CONCLUSION: Fewer psychiatrists listed in the RANZCP database specialise in ADHD than in many other psychiatric conditions. Given that 5% of the Australian population suffers from ADHD, the condition can have significant adverse outcomes and is a common comorbidity with other psychiatric conditions, the RANZCP Training Program would be improved by requiring an in-depth knowledge of ADHD. Further training in ADHD would assist many practising psychiatrists.

Alloantibodies after simultaneous liver-kidney transplant: A story of primary nonfunction, retransplantation, and antibody-mediated rejection.

Simultaneous liver-kidney transplant (SLKT) in the presence of antihuman leukocyte antigen (HLA) donor-specific antibodies (DSA) is a well-accepted practice. Herein, we describe the evolution of alloantibodies in a patient who received an SLKT. The pre-SLKT serum sample showed multiple strong DSA. As expected, all DSA cleared in a sample collected 4 days after the SLKT. Because of the primary nonfunction of the liver in the SLKT, the patient had a second liver transplant 4 days later. An abrupt increase in DSA levels against the kidney was detected 10 days after the second liver transplant. These DSA were refractory to treatment, and the transplanted kidney was lost due to antibody-mediated rejection (AMR). A detailed study of the HLA epitopes recognized by DSA and, after normalization with third-party alloantibodies to address the effect of multiple transfusions and liver allograft neutralization, showed that the elimination of these antibodies depended on the HLA antigens expressed by the transplanted liver cells. The return of DSA after removal of the first transplanted liver was associated with AMR in the transplanted kidney.

Successful outcomes with transplanting kidneys from deceased donors with acute kidney injuryon temporary renal replacement therapy.

BACKGROUND AND OBJECTIVES: We aimed to determine outcomes with transplanting kidneys from deceased donors with severe acute kidney injury requiring acute renal replacement therapy (RRT). MATERIALS AND METHODS: A total of 172 recipients received a kidney from donors with acute kidney injury stage 3 (AKIN3) requiring RRT. We compared the study group to 528 recipients who received a kidney from donors with AKIN stage 3 not on RRT and 463 recipients who received < 85% Kidney Donor Profile Index (KDPI) AKIN stage 0 kidney. RESULTS: The study group donors were younger compared to the 2 control groups. Despite higher DGF in the study group, the length of hospital stay and acute rejection were similar. Death censored graft survival (96% AKIN3-RRT vs. 97%AKIN3 no RRT vs. 96% KDPI < 85% AKIN0, P = 0.26) and patient survival with functioning graft at 1 year (95% across all groups, P = 0.402) were similar. The estimated glomerular filtration rate were similar across the 3 groups after first month. Interstitial fibrosis and tubular atrophy score ≥ 2 on protocol biopsy at time 0, 4 and 12 months were similar. Primary nonfunction was rare and associated with high KDPI. CONCLUSIONS: Transplanting selected kidneys from deceased donors with AKIN3 requiring RRT is safe and has good outcomes.

Transplant outcomes using kidneys from high KDPI acute kidney injury donors.

Kidney transplant (KT) outcomes from high kidney donor profile index (KDPI ≥85%) donors with acute kidney injury (AKI) remain underreported. KT from 172 high KDPI Acute Kidney Injury Network (AKIN) stage 0-1 donors and 76 high KDPI AKIN stage 2-3 donors from a single center were retrospectively assessed. The AKIN 2-3 cohort had more delayed graft function (71% vs. 37%, p < .001). At one year, there were no differences in the estimated glomerular filtration rate (44 ± 17 vs. 46 ± 18, p = .42) or fibrosis on protocol biopsy (ci, p = .85). Donor terminal creatinine (p = .59) and length of delayed graft function (p = .39) did not impact one-year eGFR. There were more primary nonfunction (PNF) events in the high KDPI AKIN 2-3 group (5.3% vs. 0.6%, p = .02). With a median follow-up of 3.8 years, one-year death-censored graft failure was 3.5% for AKIN 0-1 and 14.5% for AKIN 2-3 (HR 2.40, 95% CI 1.24-4.63, p = .01). Although AKIN stage 2-3 high KDPI kidneys had comparable one-year eGFR to AKIN stage 0-1 high KDPI kidneys, there were more PNF occurrences and one-year death-censored graft survival was reduced. Given these findings, additional precautions should be undertaken when assessing and utilizing kidneys from severe AKI high KDPI donors.

Progressive decline of function in renal allografts with normal 1-year biopsies: Gene expression studies fail to identify a classifier.

Histologic findings on 1-year biopsies such as inflammation with fibrosis and transplant glomerulopathy predict renal allograft loss by 5 years. However, almost half of the patients with graft loss have a 1-year biopsy that is either normal or has only interstitial fibrosis. The goal of this study was to determine if there was a gene expression profile in these relatively normal 1-year biopsies that predicted subsequent decline in renal function. Using transcriptome microarrays we measured intragraft mRNA levels in a retrospective Discovery cohort (170 patients with a normal/minimal fibrosis 1-year biopsy, 54 with progressive decline in function/graft loss and 116 with stable function) and developed a nested 10-fold cross-validated gene classifier that predicted progressive decline in renal function (positive predictive value = 38 ± 34%%; negative predictive value = 73 ± 30%, c-statistic = .59). In a prospective, multicenter Validation cohort (270 patients with Normal/Interstitial Fibrosis [IF]), the classifier had a 20% positive predictive value, 85% negative predictive value and .58 c-statistic. Importantly, the majority of patients with graft loss in the prospective study had 1-year biopsies scored as Normal or IF. We conclude predicting graft loss in many renal allograft recipients (i.e., those with a relatively normal 1-year biopsy and eGFR > 40) remains difficult.

Ambient Atmospheric Deposition of Anthropogenic Microfibers and Microplastics on the Western Periphery of Europe (Ireland).

Microfibers (mf) are the most common type of microplastic in the environment. Few studies have focused on their abundance in atmospheric deposition in background environments. In the current study, we collected wet-only and bulk rainfall from four precipitation chemistry monitoring stations, primarily located in coastal areas around Ireland. Anthropogenic mf were observed in all samples; the average deposition across the four study sites was 80 mf m-2 day-1. Wet-only mf deposition was 70 mf m-2 day-1 compared with bulk deposition of 100 mf m-2 day-1. The wet-only collectors were estimated to capture ∼70% of the bulk collectors, suggesting that dry deposition makes up at least 30% of total deposition. Meteorological variables, i.e., relative humidity, rainfall volume, wind speed, and wind direction, were significantly related to mf abundance, suggesting that rainfall washout and air mass movement are important predictors of mf deposition in background regions. In total, 15% of all anthropogenic mf were identified as plastic. The most abundant polymer type was polyester or polyethylene terephthalate at 71%, followed by polyacrylonitrile at 11%, polyethylene at 11%, and polypropylene at 4%. The average deposition of plastic mf was 12 mf m-2 day-1.

Association of elevated pre-operative HbA1c and post-operative complications in patients undergoing gynaecological oncology surgery.

HbA1c testing provides average blood glucose control, an elevated result may be associated with adverse post-operative outcomes. Our objective was to evaluate the association between elevated pre-operative HbA1c and post-operative complications in patients undergoing major gynaecological oncology surgery. HbA1c was measured pre-operatively in 364 patients. We identified 65 (16%) patients at risk of developing diabetes with borderline HbA1c measurements.Patients with borderline HbA1c (42-47 mmol/mol) had almost double the incidence of infections compared to patients with normal HbA1c (15.8% vs. 6.5%, p=.038). There were significantly less infections between patients with a normal HbA1c (<42 mmol/mol) and those with an HbA1c of over 42 mmol/mol (6.5% vs. 22.8%, p<.05). There was an association between elevated HbA1c and infective complications especially in patients with a borderline HbA1c. It is suggested that knowing HbA1c status, intervention can be made to prevent post-operative infective complications and improve outcomes.Impact statementWhat is already known on this subject? Obesity is a common risk factor for gynaecological cancer and elevated HbA1c. Chronically elevated HbA1c may lower immunity. An association has been shown previously between elevated HbA1c and post-operative complications.What the results of this study add? This study examined infective complications in patients undergoing gynaecological surgery; showing that patients with a borderline HbA1c (42-47 mmol/mol), especially those with a diagnosis of diabetes to be most at risk. This suggests that pre-operative HbA1c should be used routinely to guide care rather than diabetic status alone to prevent post-operative infections.What the implications are of these findings for clinical practice and/or further research? More research needs to be carried out to find the optimal pre-operative HbA1c targets to reduce post-operative infection rates. Work needs to be done in conjunction with general practitioners to help patients to reduce their HbA1c prior to treatment.

A method to reduce variability in scoring antibody-mediated rejection in renal allografts: implications for clinical trials - a retrospective study.

Poor reproducibility in scoring antibody-mediated rejection (ABMR) using the Banff criteria might limit the use of histology in clinical trials. We evaluated the reproducibility of Banff scoring of 67 biopsies by six renal pathologists at three institutions. Agreement by any two pathologists was poor: 44.8-65.7% for glomerulitis, 44.8-67.2% for peritubular capillaritis, and 53.7-80.6% for chronic glomerulopathy (cg). All pathologists agreed on cg0 (n = 20) and cg3 (n = 9) cases, however, many disagreed on scores of cg1 or cg2. The range for the incidence of composite diagnoses by individual pathologists was: 16.4-22.4% for no ABMR; 17.9-47.8% for active ABMR; and 35.8-59.7% for chronic, active antibody-mediated rejection (cABMR). A "majority rules" approach was then tested in which the scores of three pathologists were used to reach an agreement. This increased consensus both for individual scores (ex. 67.2-77.6% for cg) and for composite diagnoses (ex. 74.6-86.6% cABMR). Modeling using these results showed that differences in individual scoring could affect the outcome assessment in a mock study of cABMR. We conclude that the Banff schema has high variability and a majority rules approach could be used to adjudicate differences between pathologists and reduce variability in scoring in clinical trials.

Occupational Challenges in Military Service Members With Chronic Mild Traumatic Brain Injury.

OBJECTIVE: The purpose of this study was to identify the needs of military service members with chronic symptoms after mild traumatic brain injury (mTBI) that fall within the scope of occupational therapy practice. METHOD: In this qualitative descriptive study, service members with a history of mTBI (N = 12) participated in semistructured interviews about their injury history, symptoms, daily routines, challenges, and plans. RESULTS: Two main themes were identified: occupational changes and plans for the future. Occupational changes contains six subthemes: (1) rest and sleep, (2) activities of daily living and instrumental activities of daily living, (3) work, (4) social participation, (5) play and leisure, and (6) education. Plans for the future contains three subthemes: (1) supports, (2) barriers, and (3) fears. CONCLUSION: Occupational therapists who work with this population should consider all areas of occupation, especially sleep, during assessment and treatment planning. Some clients may require additional support for preparing for civilian life.

Revisiting Influenza Vaccination Exemption.

Serious adverse events after immunizations are rare. We review the case of a man who, 50 years earlier, experienced a serious adverse neurologic event 2 weeks after receiving influenza vaccine. He had received no subsequent seasonal influenza vaccinations, but after the risks and benefits were considered, he was vaccinated without adverse event that season.

The fraction of cancer attributable to modifiable risk factors in England, Wales, Scotland, Northern Ireland, and the United Kingdom in 2015.

BACKGROUND: Changing population-level exposure to modifiable risk factors is a key driver of changing cancer incidence. Understanding these changes is therefore vital when prioritising risk-reduction policies, in order to have the biggest impact on reducing cancer incidence. UK figures on the number of risk factor-attributable cancers are updated here to reflect changing behaviour as assessed in representative national surveys, and new epidemiological evidence. Figures are also presented by UK constituent country because prevalence of risk factor exposure varies between them. METHODS: Population attributable fractions (PAFs) were calculated for combinations of risk factor and cancer type with sufficient/convincing evidence of a causal association. Relative risks (RRs) were drawn from meta-analyses of cohort studies where possible. Prevalence of exposure to risk factors was obtained from nationally representative population surveys. Cancer incidence data for 2015 were sourced from national data releases and, where needed, personal communications. PAF calculations were stratified by age, sex and risk factor exposure level and then combined to create summary PAFs by cancer type, sex and country. RESULTS: Nearly four in ten (37.7%) cancer cases in 2015 in the UK were attributable to known risk factors. The proportion was around two percentage points higher in UK males (38.6%) than in UK females (36.8%). Comparing UK countries, the attributable proportion was highest in Scotland (41.5% for persons) and lowest in England (37.3% for persons). Tobacco smoking contributed by far the largest proportion of attributable cancer cases, followed by overweight/obesity, accounting for 15.1% and 6.3%, respectively, of all cases in the UK in 2015. For 10 cancer types, including two of the five most common cancer types in the UK (lung cancer and melanoma skin cancer), more than 70% of UK cancer cases were attributable to known risk factors. CONCLUSION: Tobacco and overweight/obesity remain the top contributors of attributable cancer cases. Tobacco smoking has the highest PAF because it greatly increases cancer risk and has a large number of cancer types associated with it. Overweight/obesity has the second-highest PAF because it affects a high proportion of the UK population and is also linked with many cancer types. Public health policy may seek to mitigate the level of harm associated with exposure or reduce exposure levels-both approaches may effectively impact cancer incidence. Differences in PAFs between countries and sexes are primarily due to varying prevalence of exposure to risk factors and varying proportions of specific cancer types. This variation in turn is affected by socio-demographic differences which drive differences in exposure to theoretically avoidable 'lifestyle' factors. PAFs at UK country level have not been available previously and they should be used by policymakers in devolved nations. PAFs are estimates based on the best available data, limitations in those data would generally bias toward underestimation of PAFs. Regular collection of risk factor exposure prevalence data which corresponds with epidemiological evidence is vital for analyses like this and should remain a priority for the UK Government and devolved Administrations.

Measuring Childhood Adversity in Life Course Cardiovascular Research: A Systematic Review.

OBJECTIVE: Identifying the life course health effects of childhood adversity is a burgeoning area of research, particularly in relation to cardiovascular disease (CVD). However, adversity measurement varies widely across studies, which may hamper our ability to make comparisons across studies and identify mechanisms linking adversity to CVD. The purposes of this review are to summarize adversity measurement approaches in the context of CVD, identify gaps, and make recommendations for future research. METHODS: PubMed and PsycINFO searches were conducted through June 2016. Studies were selected if CVD end point or predisease risk markers were investigated in association with a measure of childhood adversity. Forty-three studies were reviewed. A meta-analysis was not conducted because of the variation in exposures and outcomes assessed. RESULTS: Adversity measurement was heterogeneous across studies. Metrics included different sets of adverse events, relational factors, and socioeconomic indicators. Thirty-seven percent measured childhood adversity prospectively, 23% examined a CVD end point, and 77% treated adversity as an unweighted summary score. Despite the heterogeneity in measurement, most studies found a positive association between childhood adversity and CVD risk, and the association seems to be dose-response. CONCLUSIONS: The literature on childhood adversity and CVD would benefit from improving consistency of measurement, using weighted adversity composites, modeling adversity trajectories over time, and considering socioeconomic status as an antecedent factor instead of a component part of an adversity score. We suggest conceptual and analytic strategies to enhance, refine, and replicate the observed association between childhood adversity and CVD risk.

Schlemm's canal is a unique vessel with a combination of blood vascular and lymphatic phenotypes that forms by a novel developmental process.

Schlemm's canal (SC) plays central roles in ocular physiology. These roles depend on the molecular phenotypes of SC endothelial cells (SECs). Both the specific phenotype of SECs and development of SC remain poorly defined. To allow a modern and extensive analysis of SC and its origins, we developed a new whole-mount procedure to visualize its development in the context of surrounding tissues. We then applied genetic lineage tracing, specific-fluorescent reporter genes, immunofluorescence, high-resolution confocal microscopy, and three-dimensional (3D) rendering to study SC. Using these techniques, we show that SECs have a unique phenotype that is a blend of both blood and lymphatic endothelial cell phenotypes. By analyzing whole mounts of postnatal mouse eyes progressively to adulthood, we show that SC develops from blood vessels through a newly discovered process that we name "canalogenesis." Functional inhibition of KDR (VEGFR2), a critical receptor in initiating angiogenesis, shows that this receptor is required during canalogenesis. Unlike angiogenesis and similar to stages of vasculogenesis, during canalogenesis tip cells divide and form branched chains prior to vessel formation. Differing from both angiogenesis and vasculogenesis, during canalogenesis SECs express Prox1, a master regulator of lymphangiogenesis and lymphatic phenotypes. Thus, SC development resembles a blend of vascular developmental programs. These advances define SC as a unique vessel with a combination of blood vascular and lymphatic phenotypes. They are important for dissecting its functions that are essential for ocular health and normal vision.