Inpatient midwifery staffing levels and postpartum readmissions: a retrospective multicentre longitudinal study.

BACKGROUND: Preventing readmission to hospital after giving birth is a key priority, as rates have been rising along with associated costs. There are many contributing factors to readmission, and some are thought to be preventable. Nurse and midwife understaffing has been linked to deficits in care quality. This study explores the relationship between staffing levels and readmission rates in maternity settings. METHODS: We conducted a retrospective longitudinal study using routinely collected individual patient data in three maternity services in England from 2015 to 2020. Data on admissions, discharges and case-mix were extracted from hospital administration systems. Staffing and workload were calculated in Hours Per Patient day per shift in the first two 12-hour shifts of the index (birth) admission. Postpartum readmissions and staffing exposures for all birthing admissions were entered into a hierarchical multivariable logistic regression model to estimate the odds of readmission when staffing was below the mean level for the maternity service. RESULTS: 64 250 maternal admissions resulted in birth and 2903 mothers were readmitted within 30 days of discharge (4.5%). Absolute levels of staffing ranged between 2.3 and 4.1 individuals per midwife in the three services. Below average midwifery staffing was associated with higher rates of postpartum readmissions within 7 days of discharge (adjusted OR (aOR) 1.108, 95% CI 1.003 to 1.223). The effect was smaller and not statistically significant for readmissions within 30 days of discharge (aOR 1.080, 95% CI 0.994 to 1.174). Below average maternity assistant staffing was associated with lower rates of postpartum readmissions (7 days, aOR 0.957, 95% CI 0.867 to 1.057; 30 days aOR 0.965, 95% CI 0.887 to 1.049, both not statistically significant). CONCLUSION: We found evidence that lower than expected midwifery staffing levels is associated with more postpartum readmissions. The nature of the relationship requires further investigation including examining potential mediating factors and reasons for readmission in maternity populations.

Universal Genetic Testing vs. Guideline-Directed Testing for Hereditary Cancer Syndromes Among Traditionally Underrepresented Patients in a Community Oncology Program.

Background Detection of pathogenic germline variants (PGVs) has implications for cancer screening, prognosis, treatment selection, clinical trial enrollment, and family testing. Published guidelines provide indications for PGV testing, determined by clinical and demographic factors, but their applicability in an ethnically and racially diverse community hospital population is unknown. This study describes the diagnostic and incremental yield of universal multi-gene panel testing in a diverse population in a community cancer practice. Methods We completed a prospective study of proactive germline genetic sequencing among patients with solid tumor malignancies at a community-based oncology practice in downtown Jacksonville, FL, between June 2020 and September 2021. The patients were unselected for cancer type, stage, family history, race/ethnicity, and age. PGVs identified using an 84-gene next-generation sequencing (NGS) tumor genomic testing platform were stratified by penetrance. National Comprehensive Cancer Networks (NCCN) guidelines determined incremental PGV rates. Results Two hundred twenty-three patients were enrolled, with a median age of 63 years, 78.5% female. 32.7% were Black/African American, and 5.4% were Hispanic. 39.9% of patients were commercially insured, Medicare/Medicaid insured 52.5%, and 2.7% were uninsured. The most common cancers in this cohort were breast (61.9%), lung (10.3%), and colorectal (7.2%). Twenty-three patients (10.3%) carried one or more PGVs, and 50.2% carried a variant of uncertain significance (VUS). Though there was no significant difference in the rate of PGVs based on race/ethnicity, African Americans were numerically more likely to have a VUS reported than whites (P=0.059). Eighteen (8.1%) patients had incremental clinically actionable findings that practice guidelines would not have detected, which was higher in non-whites. Conclusions In this racially/ethnically and socioeconomically diverse cohort, universal multi-gene panel testing (MGPT) increased diagnostic yield over targeted guideline-informed testing. Rates of VUS and incremental PGV were higher in non-white populations.

Liquid biopsies for colorectal cancer: a narrative review of ongoing clinical trials and the current use of this technology at a comprehensive cancer center.

Objective: In this review, we summarize ongoing clinical trials involving liquid biopsies (LB) for colorectal cancer (CRC), outlining the current landscape and the future implementation of this technology. We also describe the current use of LB in CRC treatment at our institution, the Mayo Clinic Enterprise. Background: The use of LB in CRC treatment merits close attention. Their role is being evaluated in the screening, non-intervention, intervention, and surveillance settings through many active trials. This, coupled with the technique's rapid integration into clinical practice, creates constant evolution of care. Methods: Review of ClinicalTrials.gov was performed identifying relevant and active trials involving LB for CRC. "Colorectal cancer" plus other terms including "liquid biopsies" and "ctDNA" were used as search terms, identifying 35 active trials. Conclusions: LB use for the CRC is actively being investigated and requires close attention. Based on current evidence, Mayo Clinic Enterprise currently uses LB in the non-interventional, interventional and surveillance setting, but not for screening. Results of these trials may further establish the use of LB in the management of CRC.

Virtual screening and biological evaluation of PPARγ antagonists as potential anti-prostate cancer agents.

The peroxisome proliferator-activated receptor gamma (PPARγ) was identified as an oncogene and it plays a key role in prostate cancer (PC) development and progression. PPARγ antagonists have been shown to inhibit PC cell growth. Herein, we describe a virtual screening-based approach that led to the discovery of novel PPARγ antagonist chemotypes that bind at the allosteric pocket. Arg288, Lys367, and His449 appear to be important for PPARγ antagonist binding.

Natural clays with an inherent uranium component that nevertheless sequester uranium from contaminated water.

Clays present a cost effective and sustainable method for removing uranium and heavy metals from drinking water because of their cation exchange capabilities. However, managing muddy suspensions is problematic; therefore, clay pellets as presented in this article are a promising alternative. Three standard clays and two regional clays were evaluated for sorption, both in powder form and in pellet structure for comparison. The objective was to evaluate individual sorption processes and assess the effect on uranium sorption due to the process of altering the clay powder to produce pellets. The sorption capacity of the pellets is sufficiently large to not only sorb the intrinsic non-bonded uranium but to continue to sorb uranium from contaminated water. Furthermore, the uranyl cation was also removed preferentially in the presence of Pb2+ and Cd2+ heavy metal cations, hydronium ions, and more importantly the naturally occurring cations, Na1+, Ca2+, and Mg2+ that occur in abundant concentrations. Clay pellets as well as powders reduced uranium concentrations, and in extreme cases from 450 ppb, 15 times the Environmental Protection Agency maximum contaminant level to non-detectable limits. Clay pellets are excellent candidates for the safe and manageable removal of uranium and heavy metals to produce potable water.

Cognitive impairment in early onset epilepsy is associated with reduced left thalamic volume.

OBJECTIVE: The objective of this study was to investigate whether reduction of thalamic volumes in children with early onset epilepsy (CWEOE) is associated with cognitive impairment. METHODS: This is a nested case-control study including a prospectively recruited cohort of 76 children with newly-diagnosed early onset epilepsy (onset <5years age) and 14 healthy controls presenting to hospitals within NHS Lothian and Fife. Quantitative volumetric analysis of subcortical structures was performed using volumetric T1-weighted magnetic resonance imaging (MRI) and correlated with the results of formal neurocognitive and clinical assessment. False discovery rate was used to correct for multiple comparisons as appropriate with q<0.05 used to define statistical significance. RESULTS: Age, gender, and intracranial volume (ICV)-adjusted left thalamic volumes were significantly reduced in CWEOE with cognitive impairment compared to CWEOE without impairment (5295mm3 vs 6418mm3, q=0.008) or healthy controls (5295mm3 vs 6410mm3, q<0.001). The differences in left thalamic volume remained if gray matter or cortical/cerebellar volumes were used as covariates rather than ICV (q<0.05). The degree of volume reduction correlated with the severity of cognitive impairment (q=0.048). SIGNIFICANCE: Reduced left thalamic volume may be a biomarker for cognitive impairment in CWEOE and could help inform the need for further formal cognitive evaluations and interventions.

Placental growth factor (alone or in combination with soluble fms-like tyrosine kinase 1) as an aid to the assessment of women with suspected pre-eclampsia: systematic review and economic analysis.

BACKGROUND: Pre-eclampsia (PE) prediction based on blood pressure, presence of protein in the urine, symptoms and laboratory test abnormalities can result in false-positive diagnoses. This may lead to unnecessary antenatal admissions and preterm delivery. Blood tests that measure placental growth factor (PlGF) or the ratio of soluble fms-like tyrosine kinase 1 (sFlt-1) to PlGF could aid prediction of PE if either were added to routine clinical assessment or used as a replacement for proteinuria testing. OBJECTIVES: To evaluate the diagnostic accuracy and cost-effectiveness of PlGF-based tests for patients referred to secondary care with suspected PE in weeks 20-37 of pregnancy. DESIGN: Systematic reviews and an economic analysis. DATA SOURCES: Bibliographic databases including MEDLINE, EMBASE, Web of Science and The Cochrane Library and Database of Abstracts of Reviews of Effects were searched up to July 2015 for English-language references. Conferences, websites, systematic reviews and confidential company submissions were also accessed. REVIEW METHODS: Systematic reviews of test accuracy and economic studies were conducted to inform an economic analysis. Test accuracy studies were required to include women with suspected PE and report quantitatively the accuracy of PlGF-based tests; their risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) criteria. The economic studies review had broad eligibility criteria to capture any types of economic analysis; critical appraisal employed standard checklists consistent with National Institute for Health and Care Excellence criteria. Study selection, critical appraisal and data extraction in both reviews were performed by two reviewers. ECONOMIC ANALYSIS: An independent economic analysis was conducted based on a decision tree model, using the best evidence available. The model evaluates costs (2014, GBP) from a NHS and Personal Social Services perspective. Given the short analysis time horizon, no discounting was undertaken. RESULTS: Four studies were included in the systematic review of test accuracy: two on Alere's Triage® PlGF test (Alere, Inc., San Diego, CA, USA) for predicting PE requiring delivery within a specified time and two on Roche Diagnostics' Elecsys® sFlt-1 to PlGF ratio test (Roche Diagnostics GmbH, Mannheim, Germany) for predicting PE within a specified time. Three studies were included in the systematic review of economic studies, and two confidential company economic analyses were assessed separately. Study heterogeneity precluded meta-analyses of test accuracy or cost-analysis outcomes, so narrative syntheses were conducted to inform the independent economic model. The model predicts that, when supplementing routine clinical assessment for rule-out and rule-in of PE, the two tests would be cost-saving in weeks 20-35 of gestation, and marginally cost-saving in weeks 35-37, but with minuscule impact on quality of life. Length of neonatal intensive care unit stay was the most influential parameter in sensitivity analyses. All other sensitivity analyses had negligible effects on results. LIMITATIONS: No head-to-head comparisons of the tests were identified. No studies investigated accuracy of PlGF-based tests when used as a replacement for proteinuria testing. Test accuracy studies were found to be at high risk of clinical review bias. CONCLUSIONS: The Triage and Elecsys tests would save money if added to routine clinical assessment for PE. The magnitude of savings is uncertain, but the tests remain cost-saving under worst-case assumptions. Further research is required to clarify how the test results would be interpreted and applied in clinical practice. STUDY REGISTRATION: This study is registered as PROSPERO CRD42015017670. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Can Creatine Supplementation Improve Body Composition and Objective Physical Function in Rheumatoid Arthritis Patients? A Randomized Controlled Trial.

OBJECTIVE: Rheumatoid cachexia (muscle wasting) in rheumatoid arthritis (RA) patients contributes to substantial reductions in strength and impaired physical function. The objective of this randomized controlled trial was to investigate the effectiveness of oral creatine (Cr) supplementation in increasing lean mass and improving strength and physical function in RA patients. METHODS: In a double-blind design, 40 RA patients were randomized to either 12 weeks' supplementation of Cr or placebo. Body composition (dual x-ray absorptiometry and bioelectrical impedance spectroscopy [BIS]), strength, and objectively assessed physical function were measured at baseline, day 6, week 12, and week 24. Data analysis was performed by analysis of covariance. RESULTS: Cr supplementation increased appendicular lean mass (ALM; a surrogate measure of muscle mass) by mean ± SE 0.52 ± 0.13 kg (P = 0.004 versus placebo), and total LM by 0.60 ± 0.37 kg (P = 0.158). The change in LM concurred with the gain in intracellular water (0.64 ± 0.22 liters; P = 0.035) measured by BIS. Despite increasing ALM, Cr supplementation, relative to placebo, failed to improve isometric knee extensor strength (P = 0.408), handgrip strength (P = 0.833), or objectively assessed physical function (P = 0.335-0.764). CONCLUSION: In patients with RA, Cr supplementation increased muscle mass, but not strength or objective physical function. No treatment-related adverse effects were reported, suggesting that Cr supplementation may offer a safe and acceptable adjunct treatment for attenuating muscle loss; this treatment may be beneficial for patients experiencing severe rheumatoid cachexia.

Neuromodulation for intractable headaches.

Intractable chronic headaches are a major challenge for both patients and healthcare professionals. Over the last two decades, implantable electrical neuromodulators, previously established to manage other forms of chronic pain, have been used increasingly for intractable primary and secondary headache disorders. We review the current approaches to the management of refractory headaches using neuromodulation. Indications, operative considerations and complications are discussed based on our experience and a review of the literature. The field of neuromodulation has been rapidly advancing, with many new targets being discovered and novel devices being developed for treating craniofacial pain. We discuss some of these targets, detailing the latest advances in the area of neuromodulation for intractable headaches.

Activity Increase Despite Arthritis (AIDA): design of a Phase II randomised controlled trial evaluating an active management booklet for hip and knee osteoarthritis [ISRCTN24554946].

BACKGROUND: Hip and knee osteoarthritis is a common cause of pain and disability, which can be improved by exercise interventions. However, regular exercise is uncommon in this group because the low physical activity level in the general population is probably reduced even further by pain related fear of movement. The best method of encouraging increased activity in this patient group is not known. A booklet has been developed for patients with hip or knee osteoarthritis. It focuses on changing disadvantageous beliefs and encouraging increased physical activity. METHODS/DESIGN: This paper describes the design of a Phase II randomised controlled trial (RCT) to test the effectiveness of this new booklet for patients with hip and knee osteoarthritis in influencing illness and treatment beliefs, and to assess the feasibility of conducting a larger definitive RCT in terms of health status and exercise behaviour. A computerised search of four general medical practice patients' record databases will identify patients older than 50 years of age who have consulted with hip or knee pain in the previous twelve months. A random sample of 120 will be invited to participate in the RCT comparing the new booklet with a control booklet, and we expect 100 to return final questionnaires. This trial will assess the feasibility of recruitment and randomisation, the suitability of the control intervention and outcome measurement tools, and will provide an estimate of effect size. Outcomes will include beliefs about hip and knee pain, beliefs about exercise, fear avoidance, level of physical activity, health status and health service costs. They will be measured at baseline, one month and three months. DISCUSSION: We discuss the merits of testing effectiveness in a phase II trial, in terms of intermediate outcome measures, whilst testing the processes for a larger definitive trial. We also discuss the advantages and disadvantages of testing the psychometric properties of the primary outcome measures concurrently with the trial. TRIAL REGISTRATION: Current Controlled Trials ISRCTN24554946.

AR inhibitors identified by high-throughput microscopy detection of conformational change and subcellular localization.

Signaling via the androgen receptor (AR) plays an important role in human health and disease. All currently available anti-androgens prevent ligand access to the receptor, either by limiting androgen synthesis or by competitive antagonism at the ligand binding domain. It is unknown to what extent various steps of receptor activation may be separable and distinctly targeted by inhibitors. We have previously described the use of fluorescent protein fusions to AR to monitor its subcellular distribution and ligand-induced conformational change by fluorescence resonance energy transfer (FRET). We have now used a microscopy-based screen to identify inhibitors that prevent AR conformational change or nuclear accumulation after ligand activation. Hits were secondarily selected on the basis of their ability to inhibit AR transcription at a PSA-luciferase promoter and were tested for effects on (3)H-DHT binding to AR in cells. We find a strong correlation between compounds that block DHT binding and those that inhibit nuclear accumulation. These compounds are structurally distinct from known antagonists. Additional compounds blocked AR conformational change but did not affect DHT binding or nuclear localization of AR. One compound increased ligand-induced FRET yet functioned as a potent inhibitor. These results suggest that multiple inhibitory conformations of AR are possible and can be induced by diverse mechanisms. The lead compounds described here may be candidates for the development of novel antiandrogens and may help identify new therapeutic targets.

Design and implementation of cell-based assays to model human disease.

Cell-based assays, if appropriately designed, can be used to rapidly identify molecular mechanisms of human disease and develop novel therapeutics. In the last 20 years, many genes that cause or contribute to diverse disorders, including cancer and neurodegenerative disease, have been identified. With such genes in hand, scientists have created numerous model systems to dissect the molecular mechanisms of basic cellular and developmental biology. Meanwhile, techniques for high-throughput screening that use large chemical libraries have been developed, as have cDNA and RNA interference libraries that cover the entire human genome. By combining cell-based assays with chemical and genetic screens, we now have vastly improved our ability to dissect molecular mechanisms of disease and to identify therapeutic targets and therapeutic lead compounds. However, cell-based screening systems have yet to yield many fundamental insights into disease pathogenesis, and the development of therapeutic leads is frustratingly slow. This may be due to a failure of such assays to accurately reflect key aspects of pathogenesis. This Review attempts to guide the design of productive cellular models of human disease that may be used in high-throughput chemical and genetic screens. We emphasize two points: (i) model systems should use quantifiable molecular indicators of a pathogenic process, and (ii) small chemical libraries that include molecules with known biological activity and/or acceptable safety profiles are very useful.

Selective activation of estrogen receptor-beta transcriptional pathways by an herbal extract.

Novel estrogenic therapies are needed that ameliorate menopausal symptoms and have the bone-sparing effects of endogenous estrogens but do not promote breast or uterine cancer. Recent evidence suggests that selective activation of the estrogen receptor (ER)-beta subtype inhibits breast cancer cell proliferation. To establish whether ERbeta-selective ligands represent a viable approach to improve hormone therapy, we investigated whether the estrogenic activities present in an herbal extract, MF101, used to treat hot flashes, are ERbeta selective. MF101 promoted ERbeta, but not ERalpha, activation of an estrogen response element upstream of the luciferase reporter gene. MF101 also selectively regulates transcription of endogenous genes through ERbeta. The ERbeta selectivity was not due to differential binding because MF101 binds equally to ERalpha and ERbeta. Fluorescence resonance energy transfer and protease digestion studies showed that MF101 produces a different conformation in ERalpha from ERbeta when compared with the conformations produced by estradiol. The specific conformational change induced by MF101 allows ERbeta to bind to an estrogen response element and recruit coregulatory proteins that are required for gene activation. MF101 did not activate the ERalpha-regulated proliferative genes, c-myc and cyclin D1, or stimulate MCF-7 breast cancer cell proliferation or tumor formation in a mouse xenograft model. Our results demonstrate that herbal ERbeta-selective estrogens may be a safer alternative for hormone therapy than estrogens that nonselectively activate both ER subtypes.

Alteration of the hypothalamic-pituitary-gonadal axis in estrogen- and androgen-treated adult male leopard frog, Rana pipiens.

BACKGROUND: Gonadal steroids, in particular 5 alpha-dihydrotestosterone (DHT) and 17 beta-estradiol (E2), have been shown to feed back on the hypothalamic-pituitary-gonadal (HPG) axis of the ranid frog. However, questions still remain on how DHT and E2 impact two of the less-studied components of the ranid HPG axis, the hypothalamus and the gonad, and if the feedback effects are consistently negative. Thus, the goal of the study was to examine the effects of DHT and E2 upon the HPG axis of the gonadally-intact, sexually mature male leopard frogs, Rana pipiens. METHODS: R. pipiens were implanted with silastic capsules containing either cholesterol (Ch, a control), DHT, or E2 for 10 or 30 days. At each time point, steroid-induced changes in hypothalamic GnRH and pituitary LH concentrations, circulating luteinizing hormone (LH), and testicular histology were examined. RESULTS: Frogs implanted with DHT or E2 for 10 days did not show significant alterations in the HPG axis. In contrast, frogs implanted with hormones for 30 days had significantly lower circulating LH (for both DHT and E2), decreased pituitary LH concentration (for E2 only), and disrupted spermatogenesis (for both DHT and E2). The disruption of spermatogenesis was qualitatively similar between DHT and E2, although the effects of E2 were consistently more potent. In both DHT and E2-treated animals, a marked loss of all pre-meiotic germ cells was observed, although the loss of secondary spermatogonia appeared to be the primary cause of disrupted spermatogenesis. Unexpectedly, the presence of post-meiotic germ cells was either unaffected or enhanced by DHT or E2 treatment. CONCLUSIONS: Overall, these results showed that both DHT and E2 inhibited circulating LH and disrupted spermatogenesis progressively in a time-dependent manner, with the longer duration of treatment producing the more pronounced effects. Further, the feedback effects exerted by both steroid hormones upon the HPG axis were largely negative, although the possibility exists for a stimulatory effect upon the post-meiotic germ cells.

Effects of steroid hormones on spermatogenesis and GnRH release in male Leopard frogs, Rana pipiens.

Several lines of evidence suggest reproduction in the ranid frogs is potently regulated by the gonadal steroids, in particular 5alpha-dihydrotestosterone (DHT) and 17beta-estradiol (E(2)), and a non-gonadal steroid, the stress hormone corticosterone (Cort). Little is known about how these steroid hormones act upon the GnRH system to regulate the downstream reproductive events. We address these gaps in our knowledge by investigating the effects of Cort, E(2), and DHT administration on the in vitro release of GnRH and on the spermatogenesis of adult male leopard frog, Rana pipiens. R. pipiens were implanted for 20 days with silastic capsules containing cholesterol (Ch; control), Cort, E(2), or DHT. Upon sacrifice, acute hypothalamic explants were cultured and measured for GnRH release, and testes processed for histological analysis. Although only E(2) implant significantly reduced the gonadosomatic index, all three steroid hormones altered spermatogenesis. Cort modestly but significantly reduced the presence of spermatids. The effects of E(2) and DHT were both stimulatory and inhibitory, depending on the stage of spermatogenesis. None of the steroid hormones altered baseline GnRH release. Interestingly, only E(2) significantly stimulated veratridine-induced GnRH release, suggesting E(2) treatment increased the releasable pool of GnRH and/or enhance the excitability of GnRH neurons. In sum, this is the first study to report the direct measurement of GnRH secretion in a poikilothermic tetrapod. Our results revealed potent but sometimes paradoxical effects of steroid hormones, especially E(2), on the reproductive regulation of the male R. pipiens.