Types of abuse and risk factors associated with elder abuse

PRINCIPLES Detecting elder abuse is challenging because it is a taboo, and many cases remain unreported. This study aimed to identify types of elder abuse and to investigate its associated risk factors. METHODS Retrospective analyses of 903 dossiers created at an Independent Complaints Authority for Old Age in the Canton of Zurich, Switzerland, from January 1, 2008 to October 31, 2012. Characteristics of victims and perpetrators, types of abuse, and associated risk factors related to the victim or the perpetrator were assessed. Bi- and multivariate analysis were used to identify abuse and neglect determinants. RESULTS A total of 150 cases reflected at least one form of elder abuse or neglect; 104 cases were categorised as abuse with at least one type of abuse (overall 135 mentions), 46 cases were categorised as neglect (active or passive). Psychological abuse was the most reported form (47%), followed by financial (35%), physical (30%) and anticonstitutional abuse (18%). In 81% of the 150 cases at least two risk factors existed. In 13% no associated risk factor could be identified. Compared with neglect, elders with abuse were less likely to be a nursing home resident than living at home (odds ratio [OR] 0.02, 95% confidence interval [CI] 0.00-0.19). In addition, they were more likely to be cohabiting with their perpetrators (OR 18.01, 95% CI 4.43-73.19). CONCLUSION For the majority of the reported elder abuse cases at least two associated risk factors could be identified. Knowledge about these red flags and a multifaceted strategy are needed to identify and prevent elder abuse

Genetic Influences on Brain Gene Expression in Rats Selected for Tameness and Aggression

Inter-individual differences in many behaviors are partly due to genetic differences, but the identification of the genes and variants that influence behavior remains challenging. Here, we studied an F2 intercross of two outbred lines of rats selected for tame and aggressive behavior towards humans for more than 64 generations. By using a mapping approach that is able to identify genetic loci segregating within the lines, we identified four times more loci influencing tameness and aggression than by an approach that assumes fixation of causative alleles, suggesting that many causative loci were not driven to fixation by the selection. We used RNA sequencing in 150 F2 animals to identify hundreds of loci that influence brain gene expression. Several of these loci colocalize with tameness loci and may reflect the same genetic variants. Through analyses of correlations between allele effects on behavior and gene expression, differential expression between the tame and aggressive rat selection lines, and correlations between gene expression and tameness in F2 animals, we identify the genes Gltscr2, Lgi4, Zfp40 and Slc17a7 as candidate contributors to the strikingly different behavior of the tame and aggressive animals

21-Hydroxylase-Specific CD8+ T Cells in Autoimmune Addison’s Disease Are Restricted by HLA-A2 and HLA-C7 Molecules

Objectives: CD8+ T cells targeting 21-hydroxylase (21OH) are presumed to play a central role in the destruction of adrenocortical cells in autoimmune Addison’s disease (AAD). Earlier reports have suggested two immunodominant CD8+ T cell epitopes within 21OH: LLNATIAEV (21OH342-350), restricted by HLA-A2, and EPLARLEL (21OH431-438), restricted by HLA-B8. We aimed to characterize polyclonal CD8+ T cell responses to the proposed epitopes in a larger patient cohort with AAD. Methods: Recombinant fluorescent HLA-peptide multimer reagents were used to quantify antigen-specific CD8+ T cells by flow cytometry. Interferon-gamma (IFNγ) Elispot and biochemical assays were used to functionally investigate the 21OH-specific T cells, and to map the exactly defined epitopes of 21OH. Results: We found a significantly higher frequency of HLA-A2 restricted LLNATIAEV-specific cells in patients with AAD than in controls. These cells could also be expanded in vitro in an antigen specific manner and displayed a robust antigen-specific IFNγ production. In contrast, only negligible frequencies of EPLARLEL-specific T cells were detected in both patients and controls with limited IFNγ response. However, significant IFNγ production was observed in response to a longer peptide encompassing EPLARLEL, 21OH430-447, suggesting alternative dominant epitopes. Accordingly, we discovered that the slightly offset ARLELFVVL (21OH434-442) peptide is a novel dominant epitope restricted by HLA-C7 and not by HLA-B8 as initially postulated. Conclusion: We have identified two dominant 21OH epitopes targeted by CD8+ T cells in AAD, restricted by HLA-A2 and HLA-C7, respectively. To our knowledge, this is the first HLA-C7 restricted epitope described for an autoimmune disease.publishedVersio

Retargeting of UniCAR T cells with an in vivo synthesized target module directed against CD19 positive tumor cells

Recent treatments of leukemias with T cells expressing chimeric antigen receptors (CARs) underline their impressive therapeutic potential but also their risk of severe side effects including cytokine release storms and tumor lysis syndrome. In case of cross-reactivities, CAR T cells may also attack healthy tissues. To overcome these limitations, we previously established a switchable CAR platform technology termed UniCAR. UniCARs are not directed against typical tumor-associated antigens (TAAs) but instead against a unique peptide epitope: Fusion of this peptide epitope to a recombinant antibody domain results in a target module (TM). TMs can cross-link UniCAR T cells with tumor cells and thereby lead to their destruction. So far, we constructed TMs with a short half-life. The fast turnover of such a TM allows to rapidly interrupt the treatment in case severe side effects occur. After elimination of most of the tumor cells, however, longer lasting TMs which have not to be applied via continous infusion would be more convenient for the patient. Here we describe and characterize a TM for retargeting UniCAR T cells to CD19 positive tumor cells. Moreover, we show that the TM can efficiently be produced in vivo from producer cells housed in a sponge-like biomimetic cryogel and, thereby, serving as an in vivo TM factory for an extended retargeting of UniCAR T cells to CD19 positive leukemic cells

AGO Recommendations for the surgical therapy of breast cancer: update 2022

The recommendations of the AGO Breast Committee on the surgical therapy of breast cancer were last updated in March 2022 (www.ago-online.de). Since surgical therapy is one of several partial steps in the treatment of breast cancer, extensive diagnostic and oncological expertise of a breast surgeon and good interdisciplinary cooperation with diagnostic radiologists is of great importance. The most important changes concern localization techniques, resection margins, axillary management in the neoadjuvant setting and the evaluation of the meshes in reconstructive surgery. Based on meta-analyses of randomized studies, the level of recommendation of an intraoperative breast ultrasound for the localization of non-palpable lesions was elevated to “++”. Thus, the technique is considered to be equivalent to wire localization, provided that it is a lesion which can be well represented by sonography, the surgeon has extensive experience in breast ultrasound and has access to a suitable ultrasound device during the operation. In invasive breast cancer, the aim is to reach negative resection margins (“no tumor on ink”), regardless of whether an extensive intraductal component is present or not. Oncoplastic operations can also replace a mastectomy in selected cases due to the large number of existing techniques, and are equivalent to segmental resection in terms of oncological safety at comparable rates of complications. Sentinel node excision is recommended for patients with cN0 status receiving neoadjuvant chemotherapy after completion of chemotherapy. Minimally invasive biopsy is recommended for initially suspect lymph nodes. After neoadjuvant chemotherapy, patients with initially 1 – 3 suspicious lymph nodes and a good response (ycN0) can receive the targeted axillary dissection and the axillary dissection as equivalent options

Prediction of human drug-induced liver injury (DILI) in relation to oral doses and blood concentrations

Drug-induced liver injury (DILI) cannot be accurately predicted by animal models. In addition, currently available in vitro methods do not allow for the estimation of hepatotoxic doses or the determination of an acceptable daily intake (ADI). To overcome this limitation, an in vitro/in silico method was established that predicts the risk of human DILI in relation to oral doses and blood concentrations. This method can be used to estimate DILI risk if the maximal blood concentration (Cmax) of the test compound is known. Moreover, an ADI can be estimated even for compounds without information on blood concentrations. To systematically optimize the in vitro system, two novel test performance metrics were introduced, the toxicity separation index (TSI) which quantifies how well a test differentiates between hepatotoxic and non-hepatotoxic compounds, and the toxicity estimation index (TEI) which measures how well hepatotoxic blood concentrations in vivo can be estimated. In vitro test performance was optimized for a training set of 28 compounds, based on TSI and TEI, demonstrating that (1) concentrations where cytotoxicity first becomes evident in vitro (EC10) yielded better metrics than higher toxicity thresholds (EC50); (2) compound incubation for 48 h was better than 24 h, with no further improvement of TSI after 7 days incubation; (3) metrics were moderately improved by adding gene expression to the test battery; (4) evaluation of pharmacokinetic parameters demonstrated that total blood compound concentrations and the 95%-population-based percentile of Cmax were best suited to estimate human toxicity. With a support vector machine-based classifier, using EC10 and Cmax as variables, the cross-validated sensitivity, specificity and accuracy for hepatotoxicity prediction were 100, 88 and 93%, respectively. Concentrations in the culture medium allowed extrapolation to blood concentrations in vivo that are associated with a specific probability of hepatotoxicity and the corresponding oral doses were obtained by reverse modeling. Application of this in vitro/in silico method to the rat hepatotoxicant pulegone resulted in an ADI that was similar to values previously established based on animal experiments. In conclusion, the proposed method links oral doses and blood concentrations of test compounds to the probability of hepatotoxicity

AGO recommendations for the surgical therapy of the axilla after neoadjuvant chemotherapy: 2021 Update

For many decades, the standard procedure to treat breast cancer included complete dissection of the axillary lymph nodes. The aim was to determine histological node status, which was then used as the basis for adjuvant therapy, and to ensure locoregional tumour control. In addition to the debate on how to optimise the therapeutic strategies of systemic treatment and radiotherapy, the current discussion focuses on improving surgical procedures to treat breast cancer. As neoadjuvant chemotherapy is becoming increasingly important, the surgical procedures used to treat breast cancer, whether they are breast surgery or axillary dissection, are changing. Based on the currently available data, carrying out SLNE prior to neoadjuvant chemotherapy is not recommended. In contrast, surgical axillary management after neoadjuvant chemotherapy is considered the procedure of choice for axillary staging and can range from SLNE to TAD and ALND. To reduce the rate of false negatives during surgical staging of the axilla in pN+(CNB) stage before NACT and ycN0 after NACT, targeted axillary dissection (TAD), the removal of > 2 SLNs (SLNE, no untargeted axillary sampling), immunohistochemistry to detect isolated tumour cells and micro-metastases, and marking positive lymph nodes before NACT should be the standard approach. This most recent update on surgical axillary management describes the significance of isolated tumour cells and micro-metastasis after neoadjuvant chemotherapy and the clinical consequences of low volume residual disease diagnosed using SLNE and TAD and provides an overview of this year's AGO recommendations for surgical management of the axilla during primary surgery and in relation to neoadjuvant chemotherapy

Examining the generalizability of research findings from archival data

This initiative examined systematically the extent to which a large set of archival research findings generalizes across contexts. We repeated the key analyses for 29 original strategic management effects in the same context (direct reproduction) as well as in 52 novel time periods and geographies; 45% of the reproductions returned results matching the original reports together with 55% of tests in different spans of years and 40% of tests in novel geographies. Some original findings were associated with multiple new tests. Reproducibility was the best predictor of generalizability—for the findings that proved directly reproducible, 84% emerged in other available time periods and 57% emerged in other geographies. Overall, only limited empirical evidence emerged for context sensitivity. In a forecasting survey, independent scientists were able to anticipate which effects would find support in tests in new samples

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance

INTRODUCTION Investment in Africa over the past year with regard to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) sequencing has led to a massive increase in the number of sequences, which, to date, exceeds 100,000 sequences generated to track the pandemic on the continent. These sequences have profoundly affected how public health officials in Africa have navigated the COVID-19 pandemic. RATIONALE We demonstrate how the first 100,000 SARS-CoV-2 sequences from Africa have helped monitor the epidemic on the continent, how genomic surveillance expanded over the course of the pandemic, and how we adapted our sequencing methods to deal with an evolving virus. Finally, we also examine how viral lineages have spread across the continent in a phylogeographic framework to gain insights into the underlying temporal and spatial transmission dynamics for several variants of concern (VOCs). RESULTS Our results indicate that the number of countries in Africa that can sequence the virus within their own borders is growing and that this is coupled with a shorter turnaround time from the time of sampling to sequence submission. Ongoing evolution necessitated the continual updating of primer sets, and, as a result, eight primer sets were designed in tandem with viral evolution and used to ensure effective sequencing of the virus. The pandemic unfolded through multiple waves of infection that were each driven by distinct genetic lineages, with B.1-like ancestral strains associated with the first pandemic wave of infections in 2020. Successive waves on the continent were fueled by different VOCs, with Alpha and Beta cocirculating in distinct spatial patterns during the second wave and Delta and Omicron affecting the whole continent during the third and fourth waves, respectively. Phylogeographic reconstruction points toward distinct differences in viral importation and exportation patterns associated with the Alpha, Beta, Delta, and Omicron variants and subvariants, when considering both Africa versus the rest of the world and viral dissemination within the continent. Our epidemiological and phylogenetic inferences therefore underscore the heterogeneous nature of the pandemic on the continent and highlight key insights and challenges, for instance, recognizing the limitations of low testing proportions. We also highlight the early warning capacity that genomic surveillance in Africa has had for the rest of the world with the detection of new lineages and variants, the most recent being the characterization of various Omicron subvariants. CONCLUSION Sustained investment for diagnostics and genomic surveillance in Africa is needed as the virus continues to evolve. This is important not only to help combat SARS-CoV-2 on the continent but also because it can be used as a platform to help address the many emerging and reemerging infectious disease threats in Africa. In particular, capacity building for local sequencing within countries or within the continent should be prioritized because this is generally associated with shorter turnaround times, providing the most benefit to local public health authorities tasked with pandemic response and mitigation and allowing for the fastest reaction to localized outbreaks. These investments are crucial for pandemic preparedness and response and will serve the health of the continent well into the 21st century