The role of preoperative aspartate aminotransferase-to-platelet ratio index in predicting complications following total hip arthroplasty.

BACKGROUND: The purpose of this study was to investigate the relationship between preoperative aspartate aminotransferase-to-platelet ratio index (APRI) and postoperative complications following total hip arthroplasty (THA). METHODS: All THA for osteoarthritis patients from 2007 to 2020 within the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) database were included in this study. Subjects were subsequently divided into cohorts based on APRI. Four groups, including normal range, some liver damage, significant fibrosis, and cirrhosis groups, were created. Comparisons between groups were made for demographics, past medical history, and rate of major and minor complications. Other outcomes included readmission, reoperation, discharge destination, mortality, periprosthetic fracture, and postoperative hip dislocation. Multivariate logistic regression analysis was performed to determine the role of preoperative APRI in predicting adverse outcomes. Statistical significance was set at p < 0.05. RESULTS: In total, 104,633 primary THA patients were included in this study. Of these, 103,678 (99.1%) were in the normal APRI group, 444 (0.4%) had some liver damage, 256 (0.2%) had significant fibrosis, and 253 (0.2%) had cirrhosis. When controlling for demographics and relevant past medical history, the abnormal APRI groups had a significantly higher likelihood of major complication, minor complication, intraoperative or postoperative bleeding requiring transfusion, readmission, and non-home discharge (all p < 0.05) compared to normal APRI individuals. CONCLUSIONS: Abnormal preoperative APRI is linked with an increasing number of adverse outcomes following THA for osteoarthritis for patients across the United States. LEVEL OF EVIDENCE: Level I.

Multi-extreme conditions at the Second Target Station.

Three concepts for the application of multi-extreme conditions under in situ neutron scattering are described here. The first concept is a neutron diamond anvil cell made from a non-magnetic alloy. It is shrunk in size to fit existing magnets and future magnet designs and is designed for best pressure stability upon cooling. This will allow for maximum pressures above 10 GPa to be applied simultaneously with (steady-state) high magnetic field and (ultra-)low temperature. Additionally, an implementation of miniature coils for neutron diamond cells is presented for pulsed-field applications. The second concept presents a set-up for laser-heating a neutron diamond cell using a defocused CO2 laser. Cell, anvil, and gasket stability will be achieved through stroboscopic measurements and maximum temperatures of 1500 K are anticipated at pressures to the megabar. The third concept presents a hybrid levitator to enable measurements of solids and liquids at temperatures in excess of 4000 K. This will be accomplished by a combination of bulk induction and surface laser heating and hyperbaric conditions to reduce evaporation rates. The potential for deployment of these multi-extreme environments within this first instrument suite of the Second Target Station is described with a special focus on VERDI, PIONEER, CENTAUR, and CHESS. Furthermore, considerations for deployment on future instruments, such as the one proposed as TITAN, are discussed. Overall, the development of these multi-extremes at the Second Target Station, but also beyond, will be highly advantageous for future experimentation and will give access to parameter space previously not possible for neutron scattering.

Engineering topological states in atom-based semiconductor quantum dots.

The realization of controllable fermionic quantum systems via quantum simulation is instrumental for exploring many of the most intriguing effects in condensed-matter physics1-3. Semiconductor quantum dots are particularly promising for quantum simulation as they can be engineered to achieve strong quantum correlations. However, although simulation of the Fermi-Hubbard model4 and Nagaoka ferromagnetism5 have been reported before, the simplest one-dimensional model of strongly correlated topological matter, the many-body Su-Schrieffer-Heeger (SSH) model6-11, has so far remained elusive-mostly owing to the challenge of precisely engineering long-range interactions between electrons to reproduce the chosen Hamiltonian. Here we show that for precision-placed atoms in silicon with strong Coulomb confinement, we can engineer a minimum of six all-epitaxial in-plane gates to tune the energy levels across a linear array of ten quantum dots to realize both the trivial and the topological phases of the many-body SSH model. The strong on-site energies (about 25 millielectronvolts) and the ability to engineer gates with subnanometre precision in a unique staggered design allow us to tune the ratio between intercell and intracell electron transport to observe clear signatures of a topological phase with two conductance peaks at quarter-filling, compared with the ten conductance peaks of the trivial phase. The demonstration of the SSH model in a fermionic system isomorphic to qubits showcases our highly controllable quantum system and its usefulness for future simulations of strongly interacting electrons.

Development of a Dual-Fluorescent-Reporter System in Clostridioides difficile Reveals a Division of Labor between Virulence and Transmission Gene Expression.

The bacterial pathogen Clostridioides difficile causes gastroenteritis by producing toxins and transmits disease by making resistant spores. Toxin and spore production are energy-expensive processes that are regulated by multiple transcription factors in response to many environmental inputs. While toxin and sporulation genes are both induced in only a subset of C. difficile cells, the relationship between these two subpopulations remains unclear. To address whether C. difficile coordinates the generation of these subpopulations, we developed a dual-transcriptional-reporter system that allows toxin and sporulation gene expression to be simultaneously visualized at the single-cell level using chromosomally encoded mScarlet and mNeonGreen fluorescent transcriptional reporters. We then adapted an automated image analysis pipeline to quantify toxin and sporulation gene expression in thousands of individual cells under different medium conditions and in different genetic backgrounds. These analyses revealed that toxin and sporulation gene expression rarely overlap during growth on agar plates, whereas broth culture increases this overlap. Our results suggest that certain growth conditions promote a "division of labor" between transmission and virulence gene expression, highlighting how environmental inputs influence these subpopulations. Our data further suggest that the RstA transcriptional regulator skews the population to activate sporulation genes rather than toxin genes. Given that recent work has revealed population-wide heterogeneity for numerous cellular processes in C. difficile, we anticipate that our dual-reporter system will be broadly useful for determining the overlap between these subpopulations. IMPORTANCE Clostridioides difficile is an important nosocomial pathogen that causes severe diarrhea by producing toxins and transmits disease by producing spores. While both processes are crucial for C. difficile disease, only a subset of cells express toxins and/or undergo sporulation. Whether C. difficile coordinates the subset of cells inducing these energy-expensive processes remains unknown. To address this question, we developed a dual-fluorescent-reporter system coupled with an automated image analysis pipeline to rapidly compare the expression of two genes of interest across thousands of cells. Using this system, we discovered that certain growth conditions, particularly growth on agar plates, induce a "division of labor" between toxin and sporulation gene expression. Since C. difficile exhibits phenotypic heterogeneity for numerous vital cellular processes, this novel dual-reporter system will enable future studies aimed at understanding how C. difficile coordinates various subpopulations throughout its infectious disease cycle.

European Society of Coloproctology Colorectal Robotic Surgery Training for the Trainers Course - the first pilot experience.

AIM: Currently, there is no established colorectal specific robotic surgery Train the Trainer (TTT) course. The aim was to develop and evaluate such a course which can then be further developed to be incorporated within the planned European Society of Coloproctology (ESCP)/European School of Coloproctology (ESC) robotic colorectal surgery training curriculum. METHOD: After identifying the need for such a course within a training programme, the course was developed by a subgroup of the ESCP/ESC. A scoping literature review was performed and the content and materials for the course were developed by a team consisting of two gastroenterologists with a combined experience of 30 years of facilitating TTT courses, a robotic surgeon and proctor with laparoscopic TTT faculty experience and experienced robotic and laparoscopic colorectal trainers. The course was evaluated by asking delegates to complete pre- and post-course questionnaires. RESULTS: There were eight delegates on the course from across Europe. Delegates increased their knowledge of each of the course learning objectives and identified learning points in order to change practice. The feedback from the delegates of the course was positive across several areas and all felt that they had achieved their own personal objectives in attending the course. CONCLUSION: This pilot robotic colorectal TTT course has achieved its aim and demonstrated many positives. There is a need for such a course and the evaluation processes have provided opportunities for reflection, which will allow the development/tailoring of future robotic colorectal TTT courses to help develop robotic training further.

Differential effects of 'resurrecting' Csp pseudoproteases during Clostridioides difficile spore germination.

Clostridioides difficile is a spore-forming bacterial pathogen that is the leading cause of hospital-acquired gastroenteritis. C. difficile infections begin when its spore form germinates in the gut upon sensing bile acids. These germinants induce a proteolytic signaling cascade controlled by three members of the subtilisin-like serine protease family, CspA, CspB, and CspC. Notably, even though CspC and CspA are both pseudoproteases, they are nevertheless required to sense germinants and activate the protease, CspB. Thus, CspC and CspA are part of a growing list of pseudoenzymes that play important roles in regulating cellular processes. However, despite their importance, the structural properties of pseudoenzymes that allow them to function as regulators remain poorly understood. Our recently solved crystal structure of CspC revealed that its pseudoactive site residues align closely with the catalytic triad of CspB, suggesting that it might be possible to 'resurrect' the ancestral protease activity of the CspC and CspA pseudoproteases. Here, we demonstrate that restoring the catalytic triad to these pseudoproteases fails to resurrect their protease activity. We further show that the pseudoactive site substitutions differentially affect the stability and function of the CspC and CspA pseudoproteases: the substitutions destabilized CspC and impaired spore germination without affecting CspA stability or function. Thus, our results surprisingly reveal that the presence of a catalytic triad does not necessarily predict protease activity. Since homologs of C. difficile CspA occasionally carry an intact catalytic triad, our results indicate that bioinformatic predictions of enzyme activity may underestimate pseudoenzymes in rare cases.

The CspC pseudoprotease regulates germination of Clostridioides difficile spores in response to multiple environmental signals.

The gastrointestinal pathogen, Clostridioides difficile, initiates infection when its metabolically dormant spore form germinates in the mammalian gut. While most spore-forming bacteria use transmembrane germinant receptors to sense nutrient germinants, C. difficile is thought to use the soluble pseudoprotease, CspC, to detect bile acid germinants. To gain insight into CspC's unique mechanism of action, we solved its crystal structure. Guided by this structure, we identified CspC mutations that confer either hypo- or hyper-sensitivity to bile acid germinant. Surprisingly, hyper-sensitive CspC variants exhibited bile acid-independent germination as well as increased sensitivity to amino acid and/or calcium co-germinants. Since mutations in specific residues altered CspC's responsiveness to these different signals, CspC plays a critical role in regulating C. difficile spore germination in response to multiple environmental signals. Taken together, these studies implicate CspC as being intimately involved in the detection of distinct classes of co-germinants in addition to bile acids and thus raises the possibility that CspC functions as a signaling node rather than a ligand-binding receptor.

Development and acceptability of a video-based vaccine promotion tutorial for obstetric care providers.

A prenatal care provider's recommendation for maternal vaccines is one of the strongest predictors of vaccine acceptance during pregnancy. Aside from basic talking points, few resources exist to help obstetric care providers effectively navigate conversations with vaccine hesitant patients. This paper describes the development and acceptability of "VaxChat," an hour-long, evidence-based video tutorial aimed at improving obstetric care providers' ability to promote maternal vaccines. Between June and November 2017, 62 obstetric care providers registered to receive continuing medical education credit for viewing VaxChat. Of the post-tutorial responses received, over 90% said VaxChat increased their knowledge of what to say to vaccine hesitant patients, increased their confidence in addressing vaccinations with their pregnant patients, and will help them improve their practice culture regarding maternal vaccine promotion. Eighty percent intend to change how they approach vaccine conversations. These data suggest VaxChat may be a welcome complement to existing provider-to-patient talking points.

Drain Usage in Head and Neck Surgery: A National Survey of Thirty-five Surgeons across Ten Units

Introduction Drain usage is commonplace in head and neck surgery. There is an increasing body of literature disputing their routine placement in certain procedures. The aim of this study is to explore modern-day practice in terms of drain usage and the use of haemostatic agents. Methods A simple questionnaire was devised and sent to 35 ENT Surgeons across 10 units nationally. Results There was an overall response rate of 77.1% (n=27). There was considerable heterogeneity amongst surgeons in terms of indication for insertion, how the decision is made to remove the drain and if any alternative/adjunctive haemostatic agents are being used. Discussion The management of drains is poorly defined and guidelines are lacking. With increased pressure on resources, the risk of infection and discomfort to the patient, further reflection is required to evaluate if careful patient selection rather than habitual drain insertion in every case is more appropriate.

Ostwald's rule of stages and metastable transitions in the hydrogen-water system at high pressure.

Although the hydrogenous analogue of the D2-D2O system has been well explored in the regimes above 1 GPa, and below 0.2 GPa, there have been very few studies in the region between these pressures. The recent discovery in the range 0.5-0.7 GPa of a new phase, C0, that possesses a new clathrate structure with a new H2O network, along with the proposal of another structure stable at similar conditions, has prompted further studies of the hydrogen water system in this intermediate pressure region. Here, we report the results of neutron-diffraction experiments that observed transitions from metastable to stable structures in the D2-D2O system around 0.2-0.3 GPa between 130 K and 280 K. These metastable structures were observed in the stability region of the sII hydrogen hydrate clathrate and computational studies of their relative enthalpies suggest that transition sequence observed is in line with Ostwald's 'Rule of Stages'.

Systematic review: non A-E, seronegative or indeterminate hepatitis; what is this deadly disease?

BACKGROUND: A significant proportion of cases of acute liver failure (ALF) do not have an identifiable cause; so called "non A-E," "non A, non B, non C," "seronegative" or "indeterminate" hepatitis. However, this entity is clinically not well described. AIM: To collate the known incidence and outcomes in indeterminate hepatitis. This systematic review sought to identify potential aetiologies that ought to be considered, and identify likely future objectives in classification and treatment strategies for indeterminate hepatitis. METHODS: Literature review to determine aetiological factors, prevalence and outcomes relating to indeterminate hepatitis. RESULTS: There is significant heterogeneity within the reported cases of indeterminate hepatitis in the literature. Some of the potential infective aetiologies which are reviewed here include: parvovirus B19 (PVB19), herpes simplex virus (HSV), Toga-Like Virus and the Annelloviridae (including SEN-V). Interestingly, this condition predominately affects middle aged women, with subacute progression of the liver failure. In addition, the prognosis of indeterminate hepatitis is poor, with reduced spontaneous survival compared with other causes of acute liver failure and increased need for emergency liver transplantation. CONCLUSIONS: Whilst various pathological processes have been implicated in the development of indeterminate hepatitis, the specific cause remains elusive. There is an urgent need for general consensus on a specific definition and exclusion of confounding aetiologies with coordinated multicentre investigation of this rare condition to identify aetiology and develop therapies to reduce the significant mortality and need for emergency liver transplantation associated with this condition.

An international review and meta-analysis of prehabilitation compared to usual care for cancer patients.

PURPOSE: The purpose of the study is to systematically review and synthesise randomised controlled trials investigating the effectiveness of prehabilitation compared to usual care for newly diagnosed, adult-onset cancer patients. METHODS: MEDLINE, EMBASE, PsycINFO, CINAHL and SSCI were searched up to April 2017. Studies were included if disease-related, treatment-related, patient-reported and health service utilisation outcomes were assessed. Two reviewers independently reviewed and appraised the risk of bias of each study. RESULTS: Eighteen studies were included. Interventions comprised one or more of the following components: psychological support, education and exercise. Meta-analyses found that pelvic floor muscle training (PFMT) significantly increased odds of continence at 3 months (OR = 3.29, 95% CI = 1.57-6.91), but did not significantly reduce daily pad use at 6 months post-surgery Mean Difference (MD)= ( = - 0.96, 95% CI = - 2.04-0.12) for prostate cancer patients. Although quality of life improved due to PFMT, functional ability or distress did not. Further meta-analyses indicated that pre-surgical exercise significantly reduced length of hospital stay (MD = - 4.18, 95% CI = - 5.43-- 2.93) and significantly lowered odds of post-surgery complications (OR = 0.25, 95% CI = 0.10-0.66) for lung cancer patients. Psychology-based prehabilitation significantly improved mood, physical well-being and immune function for prostate cancer patients and improved fatigue and psychological outcomes and a trend for better quality of life among breast cancer patients. Risk of bias was high for most studies. CONCLUSIONS: Prehabilitation appears to benefit cancer patients. Rigorous trials are needed to investigate the effectiveness of prehabilitation among other cancer sites and other related effects. The cost-effectiveness of prehabilitation remains unanswered. IMPLICATIONS FOR CANCER SURVIVORS: Providing interventions earlier in the care pathway may lead to better outcomes for patients during survivorship.

The penalty points system in Ireland - Does it remain effective 14 years on?

INTRODUCTION: Road traffic accidents (RTAs) are the leading cause of trauma related mortality in Ireland. The penalty points system (PPS) was introduced in Ireland in 2002 to incentivise safer driving and reduce injury. Its early effect was studied previously1 which concluded that there was a slight reduction in RTA related femoral shaft fractures (a sensitive indicator of high energy trauma) and a dramatic reduction in RTA related discharges. We hypothesized that over the following 14 years, the penalty points system might lose its effectiveness. METHODS: Data was again collected from the same HIPE departments from six Dublin teaching hospitals and also University Hospital Waterford (to represent both an urban and a more rural population cohort respectively) examining RTA related femoral shaft fractures over an identical 6 month period (October-April). RTA related discharge data over an identical 6 month period was again acquired and analysed from Beaumont Hospital, Dublin (identical data source to previous study). These results were compared with the identical 6 month period in 2001/02 & 2002/03 (October-April). RESULTS: The total number of RTA related femoral shaft fracture discharges in Dublin decreased from 16 post introduction of PPS in the 2002/03 6-month period to 7 in 2015/16 6-month period. The number remained the same in the Waterford region (n = 5). The total RTA related discharges in Beaumont Hospital, Dublin decreased from 70 post PPS introduction to 57 in the 2015/16 6-month period. This represents an incidence rate of 4.5/1000 discharges (vs 6.9 post introduction) which was a statistically significant reduction (p = 0.014). The mean length of stay for these patients reduced from 13 to 7.7 days. There were consistent reductions in head injury (major & minor), lower limb fracture and facial fracture since the introduction of the PPS. The upper limb, pelvic/acetabular and thoracic injuries remained largely unchanged. Whilst RTA related spinal and abdominal injuries decreased after the introduction of the PPS, this study shows that these injuries have unfortunately increased since the post-PPS study in 2002/03. CONCLUSIONS: These results further support the effectiveness of the penalty points system and at a time where road death figures are under the spotlight, endorse the efficacious strategies implemented by the road safety authority in Ireland.

Review article: hepatitis E-a concise review of virology, epidemiology, clinical presentation and therapy.

BACKGROUND: Hepatitis E virus (HEV) is a leading cause of acute icteric hepatitis and acute liver failure in the developing world. During the last decade, there has been increasing recognition of autochthonous (locally acquired) HEV infection in developed countries. Chronic HEV infection is now recognised, and in transplant recipients this may lead to cirrhosis and organ failure. AIM: To detail current understanding of the molecular biology of HEV, diagnostic and therapeutic strategies and propose future directions for basic science and clinical research. METHODS: PubMed was searched for English language articles using the key words "hepatitis E", "viral hepatitis", "autochthonous infection", "antiviral therapy", "liver transplantation", "acute", "chronic", "HEV", "genotype", "transmission" "food-borne", "transfusion". Additional relevant publications were identified from article reference lists. RESULTS: There has been increasing recognition of autochthonous HEV infection in Western countries, mainly associated with genotype 3. Chronic HEV infection has been recognised since 2008, and in transplant recipients this may lead to cirrhosis and organ failure. Modes of transmission include food-borne transmission, transfusion of blood products and solid organ transplantation. Ribavirin therapy is used to treat patients with chronic HEV infection, but new therapies are required as there have been reports of treatment failure with ribavirin. CONCLUSIONS: Autochthonous HEV infection is a clinical issue with increasing burden. Future work should focus on increasing awareness of HEV infection in the developed world, emphasising the need for clinicians to have a low threshold for HEV testing, particularly in immunosuppressed patients. Patients at potential risk of chronic HEV infection must also be educated and given advice regarding prevention of infection.

Cognitive impairment among prostate cancer patients: An overview of reviews.

To identify and clarify definitions and methods of measuring cancer-related cognitive impairment among prostate cancer patients treated with androgen deprivation therapy (ADT) and to assess the incidence and prevalence of cognitive impairment. A systematic review of Medline, EMBASE, PubMed, PsycINFO and CINAHL up to December 2015 was undertaken to identify English-language reviews. A total of 28 reviews were identified describing 20 primary studies. There were no studies of incidence. Reported prevalence rates varied between 10% and 69%. Cognitive domains impaired by ADT included: verbal memory, visuospatial ability and executive functions. Cognitive impairment was infrequently defined and four definitions were reported. A variety of measures and methods were used to assess cognitive function including neuropsychological tests, self-report measures and clinical assessments. The finding that, often, one measure was used to assess more than one aspect of cognition is likely to have contributed to imprecise estimates. There is a need to agree a definition of cognitive impairment in the clinical epidemiology of cancer and to standardise the selection of measures in order to aid accurate assessment and fair comparisons across studies regarding the prevalence of cognitive impairment among prostate cancer patients.

A Clostridium difficile-Specific, Gel-Forming Protein Required for Optimal Spore Germination.

Clostridium difficile is a Gram-positive spore-forming obligate anaerobe that is a leading cause of antibiotic-associated diarrhea worldwide. In order for C. difficile to initiate infection, its aerotolerant spore form must germinate in the gut of mammalian hosts. While almost all spore-forming organisms use transmembrane germinant receptors to trigger germination, C. difficile uses the pseudoprotease CspC to sense bile salt germinants. CspC activates the related subtilisin-like protease CspB, which then proteolytically activates the cortex hydrolase SleC. Activated SleC degrades the protective spore cortex layer, a step that is essential for germination to proceed. Since CspC incorporation into spores also depends on CspA, a related pseudoprotease domain, Csp family proteins play a critical role in germination. However, how Csps are incorporated into spores remains unknown. In this study, we demonstrate that incorporation of the CspC, CspB, and CspA germination regulators into spores depends on CD0311 (renamed GerG), a previously uncharacterized hypothetical protein. The reduced levels of Csps in gerG spores correlate with reduced responsiveness to bile salt germinants and increased germination heterogeneity in single-spore germination assays. Interestingly, asparagine-rich repeat sequences in GerG's central region facilitate spontaneous gel formation in vitro even though they are dispensable for GerG-mediated control of germination. Since GerG is found exclusively in C. difficile, our results suggest that exploiting GerG function could represent a promising avenue for developing C. difficile-specific anti-infective therapies. IMPORTANCE: The spore-forming bacterium Clostridium difficile is a leading cause of health care-associated infections. While a subset of antibiotics can treat C. difficile infections (CDIs), the primary determinant of CDI disease susceptibility is prior antibiotic exposure, since it reduces the colonization resistance conferred by a diverse microflora. Thus, therapies that minimize perturbations to the gut microbiome should be more effective at reducing CDIs and their recurrence, the main source of disease complications. Given that spore germination is essential for C. difficile to initiate infection and that C. difficile uses a unique pathway to initiate germination, methods that inhibit distinct elements of germination could selectively prevent C. difficile disease recurrence. Here, we identify GerG as a C. difficile-specific protein that controls the incorporation of germinant signaling proteins into spores. Since gerG mutant spores exhibit germination defects and are less responsive to germinant, GerG may represent a promising target for developing therapeutics against CDI.

Acute liver failure in Scotland: changes in aetiology and outcomes over time (the Scottish Look-Back Study).

BACKGROUND: Acute liver failure is a rare and devastating clinical condition resulting from sudden loss of hepatic parenchyma and metabolic function. The Scottish Liver Transplant Unit (SLTU) offers specialist management and emergency liver transplantation to patients with acute liver failure from across Scotland. AIM: To describe temporal changes in number of admissions, aetiology of acute liver failure, severity of disease at presentation and outcomes over a 22-year period. METHODS: Retrospective analysis of the SLTU database, including all patients admitted with acute liver injury or acute liver failure between November 1992 and March 2014. RESULTS: There has been no change in the number of patients presenting with acute liver injury or failure secondary to paracetamol overdose, but a reduction in the number of admissions with acute liver injury or failure secondary to non paracetamol causes. Over time, disease severity at presentation has not changed in the paracetamol cohort; those with a non paracetamol aetiology have latterly presented with milder hepatic encephalopathy. Spontaneous survival rates improved significantly over time for those patients with acute liver failure due to paracetamol and non paracetamol aetiologies. The most marked improvement in survival is observed in the sickest patients meeting Kings College Hospital poor prognostic criteria. CONCLUSIONS: The number of admissions to the SLTU with acute liver failure is decreasing, due to reduced numbers of non paracetamol cases. Outcomes in this condition are improving, due to improvements in intensive care management and use of liver transplantation, and the increase in survival is most marked in patients meeting Kings College Hospital poor prognostic criteria.