Evolving Landscape of Carbapenem-Resistant

OBJECTIVES: The increased identification of carbapenem-resistant METHODS: A total of 169 CR-PA isolated from clinical specimens at a single centre in Houston, TX, USA were studied. Among them, 61 isolates collected between 1999 and 2005 were defined as historical strains, and 108 collected between 2017 and 2018 were defined as contemporary strains. Antimicrobial susceptibilities against selected β-lactams was determined. WGS data were used for the identification of antimicrobial resistance determinants and phylogenetic analysis. RESULTS: Non-susceptibility to ceftolozane/tazobactam and ceftazidime/avibactam increased from 2% (1/59) to 17% (18/108) and from 7% (4/59) to 17% (18/108) from the historical to the contemporary collection, respectively. Carbapenemase genes, which were not identified in the historical collection, were harboured by 4.6% (5/108) of the contemporary strains, and the prevalence of ESBL genes also increased from 3.3% (2/61) to 16% (17/108). Genes encoding acquired β-lactamases were largely confined to the high-risk clones. Among ceftolozane/tazobactam-resistant isolates, non-susceptibility to ceftazidime/avibactam, imipenem/relebactam and cefiderocol was observed in 94% (15/16), 56% (9/16) and 12.5% (2/16), respectively. Resistance to ceftolozane/tazobactam and imipenem/relebactam was primarily associated with the presence of exogenous β-lactamases. CONCLUSIONS: Acquisition of exogenous carbapenemases and ESBLs may be a worrisome trend i

Evolving Landscape of Carbapenem-Resistant Pseudomonas aeruginosa at a Single Centre in the USA

OBJECTIVES: The increased identification of carbapenem-resistant METHODS: A total of 169 CR-PA isolated from clinical specimens at a single centre in Houston, TX, USA were studied. Among them, 61 isolates collected between 1999 and 2005 were defined as historical strains, and 108 collected between 2017 and 2018 were defined as contemporary strains. Antimicrobial susceptibilities against selected β-lactams was determined. WGS data were used for the identification of antimicrobial resistance determinants and phylogenetic analysis. RESULTS: Non-susceptibility to ceftolozane/tazobactam and ceftazidime/avibactam increased from 2% (1/59) to 17% (18/108) and from 7% (4/59) to 17% (18/108) from the historical to the contemporary collection, respectively. Carbapenemase genes, which were not identified in the historical collection, were harboured by 4.6% (5/108) of the contemporary strains, and the prevalence of ESBL genes also increased from 3.3% (2/61) to 16% (17/108). Genes encoding acquired β-lactamases were largely confined to the high-risk clones. Among ceftolozane/tazobactam-resistant isolates, non-susceptibility to ceftazidime/avibactam, imipenem/relebactam and cefiderocol was observed in 94% (15/16), 56% (9/16) and 12.5% (2/16), respectively. Resistance to ceftolozane/tazobactam and imipenem/relebactam was primarily associated with the presence of exogenous β-lactamases. CONCLUSIONS: Acquisition of exogenous carbapenemases and ESBLs may be a worrisome trend i

Achieving maternal and child health gains in Afghanistan: a Countdown to 2015 country case study

Background After the fall of the Taliban in 2001, Afghanistan experienced a tumultuous period of democracy overshadowed by confl ict, widespread insurgency, and an infl ow of development assistance. Although there have been several cross-sectional assessments of health gains over the last decade, there has been no systematic analysis of progress and factors infl uencing maternal and child health in Afghanistan. Methods We undertook a comprehensive, systematic assessment of reproductive, maternal, newborn, and child health in Afghanistan over the last decade. Given the paucity of high-quality data before 2001, we relied mainly on 11 nationally representative surveys conducted between 2003 and 2013. We estimated national and subnational time trends for key reproductive, maternal, and child health indicators, and used linear regression methods to determine predictors of change in health-care service use. All analyses were weighted for sampling and design eff ects. Additional information was collated and analysed about health system performance from third party surveys and about human resources from the Afghan Ministry of Public Health. Findings Between 2003 and 2015, Afghanistan experienced a 29% decline in mortality of children younger than 5 years. Although defi nite reductions in maternal mortality remain uncertain, concurrent improvements in essential maternal health interventions suggest parallel survival gains in mothers. In a little over a decade (2003–13 inclusive), coverage of several maternal care interventions increased—eg, for antenatal care (16% to 53%), skilled birth attendance (14% to 46%), and births in a health facility (13% to 39%). Childhood vaccination coverage rates for the basic vaccines from the Expanded Programme of Immunisation (eg, BCG, measles, diphtheria-tetanus-pertussis, and three doses of polio) doubled over this period (about 40% to about 80%). Between 2005 and 2013, the number of deployed facility and community-based health-care professionals also increased, including for nurses (738 to 5766), midwives (211 to 3333), general physicians (403 to 5990), and community health workers (2682 to 28 837). Multivariable analysis of factors contributing to overall changes in skilled birth attendance and facility births suggests independent contributions of maternal literacy, deployment of community midwives, and proximity to a facility. Interpretation Despite confl ict and poverty, Afghanistan has made reasonable progress in its reproductive, maternal, newborn, and child health indicators over the last decade based on contributions of factors within and outside the health sector. However, equitable access to health care remains a challenge and present delivery models have high transactional costs, aff ecting sustainability. To maintain and further accelerate health and development gains, future strategies in Afghanistan will need to focus on investments in improving social determinants of health and targeted cost-eff ective interventions to address major causes of maternal and newborn mortality

Illuminating the Numbers: Integrating Mathematical Models to Optimize Photomedicine Dosimetry and Combination Therapies

Cancer photomedicine offers unique mechanisms for inducing local tumor damage with the potential to stimulate local and systemic anti-tumor immunity. Optically-active nanomedicine offers these features as well as spatiotemporal control of tumor-focused drug release to realize synergistic combination therapies. Achieving quantitative dosimetry is a major challenge, and dosimetry is fundamental to photomedicine for personalizing and tailoring therapeutic regimens to specific patients and anatomical locations. The challenge of dosimetry is perhaps greater for photomedicine than many standard therapies given the complexity of light delivery and light–tissue interactions as well as the resulting photochemistry responsible for tumor damage and drug-release, in addition to the usual intricacies of therapeutic agent delivery. An emerging multidisciplinary approach in oncology utilizes mathematical and computational models to iteratively and quantitively analyze complex dosimetry, and biological response parameters. These models are parameterized by preclinical and clinical observations and then tested against previously unseen data. Such calibrated and validated models can be deployed to simulate treatment doses, protocols, and combinations that have not yet been experimentally or clinically evaluated and can provide testable optimal treatment outcomes in a practical workflow. Here, we foresee the utility of these computational approaches to guide adaptive therapy, and how mathematical models might be further developed and integrated as a novel methodology to guide precision photomedicine

Cefiderocol Heteroresistance Associated With Mutations in TonB-Dependent Receptor Genes in Pseudomonas aeruginosa of Clinical Origin

The siderophore-cephalosporin cefiderocol (FDC) presents a promising treatment option for carbapenem-resistant (CR) P. aeruginosa (PA). FDC circumvents traditional porin and efflux-mediated resistance by utilizing TonB-dependent receptors (TBDRs) to access the periplasmic space. Emerging FDC resistance has been associated with loss of function mutations within TBDR genes or the regulatory genes controlling TBDR expression. Further, difficulties with antimicrobial susceptibility testing (AST) and unexpected negative clinical treatment outcomes have prompted concerns for heteroresistance, where a single lineage isolate contains resistant subpopulations not detectable by standard AST. This study aimed to evaluate the prevalence of TBDR mutations among clinical isolates of P. aeruginosa and the phenotypic effect on FDC susceptibility and heteroresistance. We evaluated the sequence of pirR, pirS, pirA, piuA, or piuD from 498 unique isolates collected before the introduction of FDC from four clinical sites in Portland, OR (1), Houston, TX (2), and Santiago, Chile (1). At some clinical sites, TBDR mutations were seen in up to 25% of isolates, and insertion, deletion, or frameshift mutations were predicted to impair protein function were seen in 3% of all isolates (n = 15). Using population analysis profile testing, we found that P. aeruginosa with major TBDR mutations were enriched for a heteroresistant phenotype and undergo a shift in the susceptibility distribution of the population as compared to susceptible strains with wild-type TBDR genes. Our results indicate that mutations in TBDR genes predate the clinical introduction of FDC, and these mutations may predispose to the emergence of FDC resistance

Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers

PURPOSE: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. EXPERIMENTAL DESIGN: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array. RESULTS: Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody-drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd-treated colon cancer model. CONCLUSIONS: We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317

Contextual and Granular Policy Enforcement in Database-backed Applications

Database-backed applications rely on inlined policy checks to process users' private and confidential data in a policy-compliant manner as traditional database access control mechanisms cannot enforce complex policies. However, application bugs due to missed checks are common in such applications, which result in data breaches. While separating policy from code is a natural solution, many data protection policies specify restrictions based on the context in which data is accessed and how the data is used. Enforcing these restrictions automatically presents significant challenges, as the information needed to determine context requires a tight coupling between policy enforcement and an application's implementation. We present Estrela, a framework for enforcing contextual and granular data access policies. Working from the observation that API endpoints can be associated with salient contextual information in most database-backed applications, Estrela allows developers to specify API-specific restrictions on data access and use. Estrela provides a clean separation between policy specification and the application's implementation, which facilitates easier auditing and maintenance of policies. Policies in Estrela consist of pre-evaluation and post-evaluation conditions, which provide the means to modulate database access before a query is issued, and to impose finer-grained constraints on information release after the evaluation of query, respectively. We build a prototype of Estrela and apply it to retrofit several real world applications (from 1000-80k LOC) to enforce different contextual policies. Our evaluation shows that Estrela can enforce policies with minimal overheads

Segmentation of diagnostic tissue compartments on whole slide images with renal thrombotic microangiopathies (TMAs)

The thrombotic microangiopathies (TMAs) manifest in renal biopsy histology with a broad spectrum of acute and chronic findings. Precise diagnostic criteria for a renal biopsy diagnosis of TMA are missing. As a first step towards a machine learning- and computer vision-based analysis of wholes slide images from renal biopsies, we trained a segmentation model for the decisive diagnostic kidney tissue compartments artery, arteriole, glomerulus on a set of whole slide images from renal biopsies with TMAs and Mimickers (distinct diseases with a similar nephropathological appearance as TMA like severe benign nephrosclerosis, various vasculitides, Bevacizumab-plug glomerulopathy, arteriolar light chain deposition disease). Our segmentation model combines a U-Net-based tissue detection with a Shifted windows-transformer architecture to reach excellent segmentation results for even the most severely altered glomeruli, arterioles and arteries, even on unseen staining domains from a different nephropathology lab. With accurate automatic segmentation of the decisive renal biopsy compartments in human renal vasculopathies, we have laid the foundation for large-scale compartment-specific machine learning and computer vision analysis of renal biopsy repositories with TMAs.Comment: 12 pages, 3 figure

Co-clinical Trial of Novel Bispecific Anti-HER2 Antibody Zanidatamab in Patient-Derived Xenografts

Zanidatamab is a bispecific human epidermal growth factor receptor 2 (HER2)-targeted antibody that has demonstrated antitumor activity in a broad range of HER2-amplified/expressing solid tumors. We determined the antitumor activity of zanidatamab in patient-derived xenograft (PDX) models developed from pretreatment or postprogression biopsies on the first-in-human zanidatamab phase I study (NCT02892123). Of 36 tumors implanted, 19 PDX models were established (52.7% take rate) from 17 patients. Established PDXs represented a broad range of HER2-expressing cancers, and in vivo testing demonstrated an association between antitumor activity in PDXs and matched patients in 7 of 8 co-clinical models tested. We also identified amplification of MET as a potential mechanism of acquired resistance to zanidatamab and demonstrated that MET inhibitors have single-agent activity and can enhance zanidatamab activity in vitro and in vivo. These findings provide evidence that PDXs can be developed from pretreatment biopsies in clinical trials and may provide insight into mechanisms of resistance

Addressing Women's Non-Maternal Healthcare Financing in Developing Countries: What Can We Learn from the Experiences of Rural Indian Women?

Background and Objectives: This paper focuses on the inadequate attention on women’s non-maternal healthcare in lowand middle-income countries. The study assessed the purchase of and financial access to non-maternal healthcare. It also scoped for mainstreaming household financial resources in this regard to suggest for alternatives. Methods: A household survey through multi-stage stratified sampling in the state of Orissa interviewed rural women above 15 years who were neither pregnant nor had any pregnancy-related outcome six weeks preceding the survey. The questions explored on the processes, determinants and outcomes of health seeking for non-maternal ailments. The outcome measures were healthcare access, cost of care and financial access. The independent variables for bivariate and multivariate analyses were contextual factors, health seeking and financing pattern. Results: The survey obtained a response rate of 98.64 % and among 800 women, 43.8 % had no schooling and 51 % were above 60 years. Each woman reported at least one episode of non-maternal ailment; financial constraints prevented 68% from receiving timely and complete care. Distress coping measures (e.g. borrowings) dominated the financing source (67.9%) followed by community–based measures (32.1%). Only 6 % had financial risk-protection; financial risk of not obtaining care doubled for women aged over 60 years (OR 2.00, 95 % CI 0.84–4.80), seeking outpatient consultation (OR 2.01, 95 % CI 0.89–4.81), facing unfavourable household response (OR 2.04, 95 % CI 1.09–3.83), and lacking other financia