Optimization of the gamma reaction history diagnostic for double-shell pusher areal density and reaction history measurements on the National Ignition Facility.

The double-shell inertial confinement fusion campaign, which consists of an aluminum ablator, a foam cushion, a high-Z pusher (tungsten or molybdenum), and liquid deuterium-tritium (DT) fuel, aims for its first DT filled implosions on the National Ignition Facility (NIF) in 2024. The high-Z, high density pusher does not allow x-rays to escape the double-shell capsule. Therefore, nuclear diagnostics such as the Gamma Reaction History (GRH) diagnostic on the NIF are crucial for understanding high-Z implosion performance. To optimize the GRH measurement of fusion reaction history and the pusher's areal density, the MCNP6.3-based forward model of the detector was built. When calculating the neutron-induced inelastic gamma ray production, the interaction of neutrons with the compressed fuel was additionally included. By folding the calculated gamma ray spectrum output and the previously calibrated GRH detector responses, the optimum set of GRH energy thresholds for measuring the pusher areal density is determined to be 2.9 and 6.3 MeV for DT double-shell experiments. In addition, the effect of the down-scattering of neutrons on the gamma ray spectrum, the minimum required yield for measurements, and the attenuation of the gamma rays through the pusher are analyzed.

Clinical Characteristics and Mortality of Old and Very Old Patients Hospitalized for Hip Fracture or Acute Medical Conditions.

BACKGROUND: There is increasing interest in healthcare quality and economic implications for hip fracture patients of very old age. However, results are limited by access to comparable control groups. OBJECTIVES: We examined healthcare quality measures including mortality and length of stay (LOS) in hospital of adults aged 60-107 years undergoing hip operations, compared to an age-matched group admitted for acute general medical conditions. DESIGN: Monocentric cross-sectional study. SETTING: Ashford and St Peter's Hospitals NHS Foundation Trust, Surrey, United Kingdom. PARTICIPANTS: A total of 3972 consecutive admissions for hip operation from 1st April 2009 to 30th June 2019 (dataset-1) and 6979 for acute general medical conditions from 1st April 2019 to 29th February 2020 (dataset-2). Respective ages, mean (±standard deviation), were 83.5 years (±9.1) and 79.8 years (±9.8). MEASUREMENTS: Mortality and LOS were assessed with each group divided into five- year age bands and those ≥95 years. RESULTS: There were proportionally more (P <0.001) females admitted for hip operations (72.8%) than for acute general medical conditions (53.8%). Amongst patients admitted with general medical conditions, the frequency of the most serious recorded conditions - including congestive heart failure, stroke, and pneumonia - increased with age. Amongst patients undergoing hip operations, 5.7% died in hospital and 29.3% had a LOS ≥3 weeks. Corresponding values for acute general medical conditions were 10.4% and 11.8%. For those undergoing hip operations in all age categories, the risk of death was lower than for acute general medical group: sex-adjusted odds ratios ranged between 0.27 and 0.67, but the risk of LOS ≥3 weeks was greater: odds ratios ranged between 2.46 and 2.95. CONCLUSIONS: Compared to those admitted with acute general medical conditions, patients admitted for hip operations had a lower risk of death, but a longer hospital LOS. .

Targeting neurotrophin and nitric oxide signaling to promote recovery and ameliorate neurogenic bladder dysfunction following spinal cord injury - Mechanistic concepts and clinical implications.

This review summarizes the presentations made to a workshop entitled "Targeting Neurotrophin and Nitric Oxide Signaling to Promote Recovery and Ameliorate Neurogenic Bladder Dysfunction following Spinal Cord Injury - Mechanistic Concepts and Clinical Implications" at the International Continence Society (ICS) 2022 Vienna Meeting. Spinal cord injury (SCI; T8-T9 contusion/transection) causes impaired mobility, neurogenic detrusor overactivity (NDO), detrusor sphincter dyssynergia (DSD) and subsequent decreased quality of life. This workshop discussed the potential of future therapeutic agents that manage the lesion and its consequences, in particular possibilities to reduce the lesion itself and manage pathophysiological changes to the lower urinary tract (LUT). Attenuation of the spinal cord lesion itself was discussed with respect to the potential of a trio of agents: LM11A-3, a p75 neurotrophin receptor modulator to counter activation of local apoptotic pathways; LM22B-10 to promote neuronal growth by targeting tropomyosin-related kinase (Trk) receptors; and cinaciguat, a soluble guanylate cyclase (sGC) activator as an agent promoting angiogenesis at the injury site. The workshop also discussed targets on the bladder to block selectivity sites associated with detrusor overactivity and poor urinary filling profiles, such as purinergic pathways controlling excess contractile activity and afferent signaling, as well as excess fibrosis. Finally, the importance of increased mechanosensitive signaling as a contributor to DSD was considered, as well as potential drug targets. Overall, an emphasis was placed on targets that help restore function and reduce pathological LUT consequences, rather than downregulate normal function.

Soluble Guanylate Cyclase Activators to Treat Benign Prostatic Hyperplasia and associated LUTS.

This review summarises the presentations during a workshop session entitled "The Use of Soluble Guanylate Cyclase Activators to Treat Benign Prostatic Hyperplasia, Obstruction and Fibrosis - Mechanistic Concepts and Clinical Implications" at the International Continence Society (ICS) 2021 Melbourne Virtual meeting. Benign prostatic hyperplasia (BPH) is a highly prevalent condition that can result in bladder outflow obstruction (BOO) and development of lower urinary tract symptoms (LUTS), and by 80 years of age is present in about 75% of men. Current pharmacological therapies include α-adrenoceptor antagonists, 5α-reductase inhibitors, and the phosphodiesterase type 5 (PDE5) inhibitor, tadalafil. The efficacy of tadalafil suggests a role for nitric oxide (NO•) through activation of soluble guanylate cyclase (sGC) and production of cyclic guanosine 3'5'-monophosphate (cGMP), a cyclic nucleotide that relaxes smooth muscle, reduces neurotransmitter release and also acts as an antifibrotic agent. Patient refractoriness to tadalafil may be, for example, due to sGC inactivation due to oxidative stress. The workshop discussed the superiority of cinaciguat, an sGC activator that functions even when the enzyme is oxidised, over PDE5 inhibitors, and potentially its use in combination with agents that reduce formation of reactive oxygen species.

Calcineurin-dependent regulation of gap junction conductance and connexin phosphorylation in guinea pig left atrium.

Atrial fibrillation (AF) occurs from disordered atrial action potential conduction and is associated with reduced gap junction electrical conductance (Gj). The Ca2+ and calmodulin-dependent phosphatase, calcineurin, reduces Gj in ventricular myocardium via a protein phosphatase-1 (PP1)-dependent pathway culminating in phosphorylation of serine368 on connexin43 (pSer368-Cx43). However, characterisation of corresponding pathways in left atrial myocardium, which have a more complex connexin subtype profile, is undefined and was the aim of this study. Gj was measured in guinea-pig left atrium from the frequency-dependent variation of intracellular impedance; intracellular [Ca2+], ([Ca2+]i) in low-Na solution was measured by Fura-2 fluorescence. Phosphorylation of guinea-pig Ser368-Cx43 residues was measured by Western blot; Cx40 was immunoprecipitated and probed for serine/threonine residue phosphorylation. Low-Na solution reversibly reduced Gj, in turn attenuated or prevented by calcineurin inhibitors cyclosporin-A or CAIP, respectively. Moreover, Ser368-Cx43 phosphorylation in low-Na solution was also prevented by CAIP. Changes were partially prevented by fostreicin (FST), a protein phosphatase-2A (PP2A) inhibitor; but not by tautomycin, a PP1 inhibitor. Serine/threonine residues on Cx40 were also phosphorylated in low-Na solution; prevented by CAIP and attenuated by FST. Reduced Gj with raised [Ca2+]i is paralleled by a changed Cx43/Cx40 phosphorylation status; changes mediated by calcineurin and PP2A-dependent pathways, but not PP1. The pharmacological profile underlying changes to guinea-pig atrial gap junction electrical conductance with raised intracellular [Ca2+]i is fundamentally different from that in ventricular myocardium. This provides a targeted drug model whereby atrial and ventricular myocardium can be selectively targeted to correct conduction defects.

Meningitis following cerebrospinal fluid-cutaneous fistula secondary to combined spinal-epidural anaesthesia for elective caesarean delivery.

Cerebrospinal fluid-cutaneous fistula is a rare complication associated with neuraxial procedures. Here, we describe a case of fistula formation related to combined spinal-epidural anaesthesia for elective caesarean delivery, where the epidural catheter was removed only two hours later. The clear fluid leaking persistently from the site of the skin puncture associated with the epidural insertion site was confirmed to be cerebrospinal fluid with an increased beta-trace protein, and the fistula was closed with skin sutures. Subsequently, the patient presented with neurological signs and symptoms consistent with meningitis and was treated empirically with intravenous antibiotics. Cerebrospinal fluid-cutaneous fistula formation with secondary meningitis is an exceptionally rare event in obstetric anaesthesia.

International collaboration during the COVID-19 crisis: autumn 2020 developments.

After the initial shock of the early months of the global COVID-19 pandemic, international collaboration in COVID-19 research continues to show aberrant patterns compared to coronavirus research in pre-COVID times. The most affected nations tend to produce the greatest number of coronavirus articles, with output closely coupled to the rate of infection. COVID-19 research has fewer nations and smaller teams than pre-COVID research, a trend which intensifies throughout the pandemic. The United States remains the single largest contributor to the global publication output, but contrary to China's dominance in the initial months of the pandemic, China's contribution falls as the national COVID-19 caseload drops. China-USA collaborations drop as the pandemic continues, perhaps due to China's reduced rate of publication on the topic, and perhaps due to political obstacles, or a combination of these factors.

Recommendations for detection and rapid management of carbapenemase-producing Enterobacterales outbreaks.

There is large heterogeneity in approaches to tackling nosocomial outbreaks caused by carbapenemase-producing Enterobacterales (CPE), however there is limited guidance on how to approach their management. Rapid and robust infection prevention and control interventions can be effective in preventing and reducing the impact of outbreaks in healthcare environments. We present a stepwise approach to aspects of CPE outbreak management, including the development of an action plan, engagement and communication with key stakeholders, developing a dynamic risk assessment, and staff education. These can provide a blueprint for organisations to create templates and checklists to inform their own outbreak response.

Functional, histological and molecular characteristics of human exstrophy detrusor.

INTRODUCTION: Bladder exstrophy is a congenital anomaly involving foetal exposure and protrusion of the open bladder through an incomplete lower abdominal wall. Techniques to surgically correct exstrophy after birth have greatly improved, but it still presents a major challenge to achieve continence and a good quality of life for patients and their families as the pathophysiology of bladder dysfunction is unknown. OBJECTIVES: A multimodal approach was used to characterise the histological and biomechanical properties of exstrophy detrusor. These were correlated with myocyte responses to agonists and an evaluation of developmental signalling pathways to evaluate the cause of bladder dysfunction in exstrophy. STUDY DESIGN: Detrusor muscle specimens were obtained during corrective surgery from four exstrophy groups: neonatal (1-3 days, n = 8), younger children (7 months-5 years, n = 13) and older children (8-14 years, n = 11) undergoing secondary procedures and cloacal exstrophy (16 days-9 years, n = 9); control specimens were obtained from children (3 months-9 years, n = 14) undergoing surgery for other pathologies but with normal bladder function. Five lines of experiments were undertaken: measurement of connective tissue to detrusor muscle ratio, contractile responses to electrical and agonist stimulation; in vitro biomechanical stiffness, intracellular Ca2+ responses to contractile agonists and immunohistochemistry for proteins (MMP-7, cyclinD1, ß-catenin and c-myc) involved in fibrosis generation. Exstrophy data were compared with those from the control group. RESULTS: Exstrophy tissue demonstrated reduced smooth muscle compared with connective tissue, reduced contractile responses and greater mechanical stiffness. However, intracellular Ca2+ responses to agonists were maintained. These changes were greatest in neonatal and cloacal exstrophy samples and least in those from older paediatric bladders. Immunolabelled MMP-7, ß-catenin and c-myc were reduced in exstrophy samples. DISCUSSION: These results highlight the reality that newborns with exstrophy have significantly reduced compliance and bladder underactivity, which may persist or return to normal values with surgery and age. The primary cause of underactivity is increased connective tissue in relation to detrusor muscle; however, detrusor myocyte function remains normal. Finally, the increase of the smooth muscle content in the paediatric bladder group indicates a remodelling response of the bladder to surgical correction and time. Excess gestational fibrosis is associated with changed expression of key proteins in the Wnt-signalling pathway, a potential aetiological factor and therapeutic target. CONCLUSION: Results point to connective tissue deposition as the primary pathological process that determines bladder function with normal myocyte function. Future research that reduces connective tissue deposition may lead to improvement in outcomes for these children.

Isospin Mixing Reveals

The thermonuclear ^{30}P(p,γ)^{31}S reaction rate is critical for modeling the final elemental and isotopic abundances of ONe nova nucleosynthesis, which affect the calibration of proposed nova thermometers and the identification of presolar nova grains, respectively. Unfortunately, the rate of this reaction is essentially unconstrained experimentally, because the strengths of key ^{31}S proton capture resonance states are not known, largely due to uncertainties in their spins and parities. Using the ß decay of ^{31}Cl, we have observed the ß-delayed γ decay of a ^{31}S state at E_{x}=6390.2(7) keV, with a ^{30}P(p,γ)^{31}S resonance energy of E_{r}=259.3(8) keV, in the middle of the ^{30}P(p,γ)^{31}S Gamow window for peak nova temperatures. This state exhibits isospin mixing with the nearby isobaric analog state at E_{x}=6279.0(6) keV, giving it an unambiguous spin and parity of 3/2^{+} and making it an important l=0 resonance for proton capture on ^{30}P.

Diagnosing Paroxysmal Atrial Fibrillation: Are Biomarkers the Solution to This Elusive Arrhythmia?

Atrial fibrillation (AF) is the commonest sustained arrhythmia globally and results in significantly increased morbidity and mortality including a fivefold risk of stroke. Paroxysmal atrial fibrillation (PAF) constitutes approximately half of all AF cases and is thought to represent an early stage of the disease. This intermittent form of atrial arrhythmia can be a challenge to identify and as a result many affected individuals are not prescribed appropriate antithrombotic therapy and hence are at risk of stroke and thromboembolism. Despite these adverse outcomes there have been relatively few diagnostic advances in the field since the introduction of the Holter monitor in 1949. This review aims to establish the available evidence for electrophysiological, molecular, and morphological biomarkers to improve the detection of PAF with reference to the underlying mechanisms for the condition.

Development of a sporicidal test method for Clostridium difficile.

BACKGROUND: Disinfectants with claimed activity against Clostridium difficile must be evaluated to ensure efficacy against the spores that comprise an environmental source of patient infection. Unfortunately there is, at present, no generally accepted method for evaluating these disinfectants. In the absence of such a method, laboratories have to adapt protocols that were not designed for products used in medical environments and consequently may use inappropriate test organisms, exposure times, and pass criteria. AIM: To develop and evaluate a method for testing the activity of disinfectants against C. difficile spores using exposure times and pass criteria which are relevant to clinical application. METHODS: A Joint Working Party of the Healthcare Infection Society (HIS) and the Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections (ARHAI) of the Department of Health in England was assembled. The Working Party adapted a previously described enzyme-based method for spore purification (the Clospore method) using an exposure time of 5 min and a 5 log10 kill as a pass criterion. FINDINGS: Evaluation of the method by three laboratories demonstrated that the method is simple to follow and that the results are repeatable and reproducible. CONCLUSION: The method described by the Working Party produces a clean suspension with a high titre of spores. It is recommended that, for a disinfectant used in the environment, the product should demonstrate a 5 log10 reduction in 5 min under clean or dirty conditions to fulfil the requirements of the test.

Developing the first national antimicrobial prescribing and stewardship competences.

Antimicrobial resistance is a national and worldwide threat to the future of healthcare. Educating both healthcare staff and the public in the prudent use of antimicrobials is an essential part of antimicrobial stewardship programmes that aim to contain and control resistance and preserve the usefulness of currently available antibiotics. Using current available evidence, regulatory documents and national antimicrobial stewardship guidance for primary and secondary care, five dimensions for antimicrobial prescribing and stewardship competences have been developed in England, through an independent multiprofessional group led by the Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infection (ARHAI) of the Department of Health (England). They are designed to complement the generic competency framework for all prescribers from the UK National Prescribing Centre (now part of National Institute for Health and Care Excellence) and are relevant to all independent prescribers, including doctors, dentists and non-medical practitioners. The antimicrobial prescribing and stewardship competences published jointly by ARHAI and PHE in 2013 are believed to be the first of their kind. Implementation of these competences will be an important contribution to the delivery of the UK government's 5 year Antimicrobial Resistance Strategy.

Regulation of ACh release from guinea pig bladder urothelial cells: potential role in bladder filling sensations.

BACKGROUND AND PURPOSE: The aim of this study was to quantify and characterize the mechanism of non-neuronal ACh release from bladder urothelial cells and to determine if urothelial cells could be a site of action of anti-muscarinic drugs. EXPERIMENTAL APPROACH: A novel technique was developed whereby ACh could be measured from freshly isolated guinea pig urothelial cells in suspension following mechanical stimulation. Various agents were used to manipulate possible ACh release pathways in turn and to study the effects of muscarinic receptor activation and inhibition on urothelial ATP release. KEY RESULTS: Minimal mechanical stimulus achieved full ACh release, indicating a small dynamic range and possible all-or-none signal. ACh release involved a mechanism dependent on the anion channel CFTR and intracellular calcium concentration, but was independent of extracellular calcium, vesicular trafficking, connexins or pannexins, organic cation transporters and was not affected by botulinum-A toxin. Stimulating ACh receptors increased ATP production and antagonizing them reduced ATP release, suggesting a link between ACh and ATP release. CONCLUSIONS AND IMPLICATIONS: These results suggest that release of non-neuronal ACh from the urothelium is large enough and well located to act as a modulator of ATP release. It is hypothesized that this pathway may contribute to the actions of anti-muscarinic drugs in reducing the symptoms of lower urinary tract syndromes. Additionally the involvement of CFTR in ACh release suggests an exciting new direction for the treatment of these conditions.

T-type Ca2+ channels and the urinary and male genital tracts.

T-type Ca(2+) channels are widely expressed throughout the urinary and male genital tracts, generally alongside L-type Ca(2+) channels. The use of pharmacological blockers of these channels has suggested functional roles in all regions, with the possible exception of the ureter. Their functional expression is apparent not just in smooth muscle cells but also in interstitial cells that lie in close proximity to muscle, nerve and epithelial components of these tissues. Thus, T-type Ca(2+) channels can contribute directly to modulation of muscle function and indirectly to changes of epithelial and nerve function. T-type Ca(2+) channel activity modulates phasic contractile activity, especially in conjunction with Ca(2+)-activated K(+) channels, and also to agonist-dependent responses in different tissues. Upregulation of channel density occurs in pathological conditions associated with enhanced contractile responses, e.g. overactive bladder, but it is unclear if this is causal or a response to the pathological state. Moreover, T-type Ca(2+) channels may have a role in the development of prostate tumours regulating the secretion of mitogens from neuroendocrine cells. Although a number of selective channel blockers exist, their relative selectivity over L-type Ca(2+) channels is often low and makes evaluation of T-type Ca(2+) channel function in the whole organism difficult.

Point prevalence survey of urinary catheterisation in care homes and where they were inserted, 2012.

The extent to which the use of catheter care bundles and other interventions has led to a reduction in urinary catheterisation rates is unknown. We aimed to determine current urinary catheterisation rates in care homes with residents over 65 years old, and determine the extent to which residents are discharged from the hospital setting with urinary catheters. A point prevalence questionnaire survey was used in care homes that looked after residents over 65 years in six UK health boards or primary care trusts, to determine urinary catheterisation rates, and where these catheters were inserted. Questionnaires for 445 of 461 care homes (96.5%) were completed, 425 of 445 care homes cared for residents over 65 years; 888 (6.9%) of 12,827 residents had a urethral (82.5%) or supra-pubic (17.5%) urinary catheter. Over half of all catheters (both urethral and suprapubic, 57.4%, 509 of 888 catheters), and 3.1% of all residents had a catheter inserted while the residents were hospital inpatients, and then discharged back to the care home still catheterised. There was a significant variation in urinary catheterisation rates in the care homes surveyed, and rates remain similar to previous English surveys in 2003 and 2009. More still needs to be done to understand the variation in urinary catheterisation rates in care homes and reduce these rates, including the numbers of residents that are discharged from hospital with a urinary catheter.