Evidence of striped electronic phases in a structurally modulated superlattice.

The electronic properties of crystals can be manipulated by superimposing spatially periodic electric, magnetic or structural modulations. Long-wavelength modulations incommensurate with the atomic lattice are particularly interesting1, exemplified by recent advances in two-dimensional (2D) moiré materials2,3. Bulk van der Waals (vdW) superlattices4-8 hosting 2D interfaces between minimally disordered layers represent scalable bulk analogues of artificial vdW heterostructures and present a complementary venue to explore incommensurately modulated 2D states. Here we report the bulk vdW superlattice SrTa2S5 realizing an incommensurate one-dimensional (1D) structural modulation of 2D transition metal dichalcogenide (TMD) H-TaS2 layers. High-quality electronic transport in the H-TaS2 layers, evidenced by quantum oscillations, is made anisotropic by the modulation and exhibits commensurability oscillations paralleling lithographically modulated 2D systems9-11. We also find unconventional, clean-limit superconductivity in SrTa2S5 with a pronounced suppression of interlayer relative to intralayer coherence. The in-plane magnetic field dependence of interlayer critical current, together with electron diffraction from the structural modulation, suggests superconductivity12-14 in SrTa2S5 is spatially modulated and mismatched between adjacent TMD layers. With phenomenology suggestive of pair-density wave superconductivity15-17, SrTa2S5 may present a pathway for microscopic evaluation of this unconventional order18-21. More broadly, SrTa2S5 establishes bulk vdW superlattices as versatile platforms to address long-standing predictions surrounding modulated electronic phases in the form of nanoscale vdW devices12,13 to macroscopic crystals22,23.

Guest Editorial - A personal journey in Acute Medicine.

This article describes my personal journey through Acute Medicine from the late 1980's and incorporates the development of Acute Medical Units (AMU's), co-establishing the Society for Acute Medicine (SAM), as well as involvement in the development of training curricula, research and audit. I am deeply indebted to a great number of professional colleagues over the last three decades, who have been pivotal to the development of the Acute Medicine specialism, and many of whom in turn became presidents of SAM.

Early prediction of respiratory disease in preweaning dairy calves using feeding and activity behaviors.

Bovine respiratory disease (BRD) represents one of the major disease challenges affecting preweaning dairy-bred calves. Previous studies have shown that differences in feeding and activity behaviors exist between healthy and diseased calves affected by BRD. The aim of this study was to develop and assess the accuracy of models designed to predict BRD from feeding and activity behaviors. Feeding and activity behaviors were recorded for 100 male preweaning calves between ~8 to 42 d of age. Calves were group housed with ad libitum access to milk via automatic milk feeders, water, starter diet, and straw. Activity was monitored via a leg-mounted accelerometer. Health status of individual calves was monitored daily using an adapted version of the Wisconsin Scoring System to identify BRD. Three models were created to predict disease: (1) deviation from normal lying time based on moving averages (MA); (2) random forest (RF), a machine learning technique based on feeding and activity variables; and (3) a combination of RF and MA output. For the MA model, lying time was predicted based on behavior over previous days (3- and 7-d MA) and the expected value for the current day (based on calf age; measured using accelerometers). Data were not split into training and test data sets. Occasions when the actual lying time increased >9% of predicted lying time were classified as a deviation from normal and a disease alert was provided. Both feeding and activity behaviors were included within the RF model. Data were split into training (70%) and test (30%) data sets based on disease events. Events were classified as 2 d before, the day(s) of the disease event, and 2 d after the event. Accuracy of models was assessed using sensitivity, specificity, balanced accuracy, and Matthews correlation coefficient (MCC). If a positive disease prediction agreed with an actual disease event within a 3-d rolling window, it was classified as a true positive. Stand-alone models (RF; MA) showed high specificity (0.95; 0.97), moderate sensitivity (0.35; 0.43), balanced accuracy (0.65; 0.64), and MCC (0.25; 0.29). Combining outputs increased accuracy (specificity = 0.95, sensitivity = 0.54, balanced accuracy = 0.75, MCC = 0.36). The work presented is the first to demonstrate the use of modeling data derived from precision livestock farming techniques that monitor feeding and activity behaviors for early detection of BRD in preweaning calves, offering a significant advance in health management of youngstock.

Is scan-negative cauda equina syndrome a functional neurological disorder? A pilot study.

BACKGROUND AND PURPOSE: Cauda equina syndrome (CES) is a neurosurgical emergency which warrants lumbar magnetic resonance imaging (MRI). Many patients with suggestive symptoms of CES have no radiological correlate. A functional (non-organic) aetiology has been proposed in some, but currently little is known about this patient group and their clinical outcomes. METHODS: At a tertiary referral centre, 155 adult patients underwent urgent lumbar MRI for suspected CES in 1 year from December 2014. Data regarding clinical symptoms and follow-up were obtained from records. Patients were divided into CES (n = 25), radiculopathy (n = 68) and scan-negative (SN) groups (n = 62) from scans. Up to 3 years post-discharge, postal questionnaires were sent to patients with Oswestry Disability Index, Pain Catastrophizing score, Patient Health Questionnaire (PHQ) 9, Generalized Anxiety Disorder (GAD) 7, PHQ 15 and Work and Social Adjustment Scale measures. RESULTS: No clinical symptoms were found to differentiate CES from SN patients. Functional comorbidities were significantly more common in SN patients but mental health diagnosis frequency did not differ. Follow-up was variable with no consistent referral pathways, particularly for the SN group. 33% (n = 47) responded to the postal questionnaires; high levels of pain, symptom chronicity and disability were ubiquitous but self-reported mental health diagnoses and PHQ 15 were higher for SN patients. CONCLUSIONS: Conflicting data suggest further research is needed to investigate the prevalence of mental illness and somatic symptoms in SN cases. SN patients have higher rates of comorbid functional disorders and inconsistent referral pathways. Self-report measures indicate impaired quality of life across all groups. The low response rate limits the generalizability of findings but neuropsychiatric assessment and care pathway optimization should be considered.

The ability of CNS vital signs to detect coached sandbagging performance during concussion baseline testing: a randomized control trial.

Objective: Despite widespread use of baseline neurocognitive testing in concussion management, suboptimal performance due to sandbagging still readily occurs without detection. The purpose of this study is to determine CNS Vital Signs validity indicator accuracy in detecting coached sandbagging compared to controls.Method: We compared rates of invalidity and domain composite scores for neurocognitive test performance between two groups of twenty-five college-aged students (age = 20.8 ± 1.1 years, range 18-25, 48% female) completing CNS Vital Signs instructed to either 1) give their best effort (control) or, 2) give suboptimal performance (sandbag). The sandbagging group was given standardized instructions on how to sandbag without detection. All participants rated their effort after completing on a Visual Analog Scale (0-100 mm).Results: Built in invalidity indicators successfully identified 68.0% of sandbaggers, while only 12% in the control group presented with invalid scores. Participants in the sandbagging group on average reported significantly lower effort (sandbag: 51.0 ± 21.0, control: 86.0 ± 12.0, p < .001)Conclusions: Built-in CNS Vital Signs validity indicators have an overall high accuracy in identifying those attempting to purposefully sandbag and are comparable to other computerized neurocognitive tests. Given that 32% of intentional sandbaggers went undetected, clinicians should consider additional safeguards to detect these individuals at baseline.

Implementing simple algorithms to improve glucose and lipid management in people with diabetes and acute coronary syndrome.

AIM: Diabetes mellitus is associated with increased risk of adverse outcomes following acute coronary syndrome. Translating evidence-based recommendations into practice is necessary to improve outcomes. We evaluated whether implementing algorithms to guide inpatient care improved glycaemic control, and increased use of sodium-glucose co-transporter 2 (SGLT2) inhibitors and lipid-lowering medication in a tertiary cardiac unit. METHOD: A 3-month audit (phase 1) was conducted to evaluate hyperglycaemia and dyslipidaemia management, and medication prescriptions. Consecutive people with diabetes admitted for acute coronary syndrome were prospectively identified. Target blood glucose level was defined as 5-10 mmol/l. A multidisciplinary committee designed and implemented decision-support algorithms plus education. A 3-month post-implementation audit (phase 2) was conducted. RESULTS: There were 104 people in phase 1 and 101 in phase 2, with similar characteristics [HbA1c 64 ± 20 mmol/mol vs. 61 ± 21 mmol/mol (8.0 ± 1.8% vs. 7.8 ± 1.9%]. Post implementation, the incidence of blood glucose levels > 10 mmol/l was lower [phase 1: 46.4% vs. phase 2: 31.8%, rate ratio (RR) = 0.77, 95% confidence intervals (CI) 0.60-0.98; P = 0.031], without a difference in blood glucose levels < 5mmol/l (phase 1: 4.9% vs. phase 2: 4.5%, RR = 1.20, 95% CI 0.70-2.08; P = 0.506). SGLT2 inhibitor prescriptions increased significantly (baseline to discharge: 12.5% to 15.4% vs. 7.9% to 24.8%; P = 0.007) but high-intensity statin prescriptions did not (baseline to discharge: 35.6% to 72.1% vs. 40.6% to 85.1%; P = 0.074). Prescription rates of non-statin lipid-lowering medications were not significantly increased. CONCLUSIONS: Implementing decision-support algorithms was associated with improved inpatient glycaemic control and increased use of cardioprotective therapies at discharge in people with diabetes and acute coronary syndrome.

Salivary acinic cell carcinoma: reappraisal and update.

Epidemiologic and clinicopathologic features, therapeutic strategies, and prognosis for acinic cell carcinoma of the major and minor salivary glands are critically reviewed. We explore histopathologic, histochemical, electron microscopic and immunohistochemical aspects and discuss histologic grading, histogenesis, animal models, and genetic events. In the context of possible diagnostic difficulties, the relationship to mammary analog secretory carcinoma is probed and a classification is suggested. Areas of controversy or uncertainty, which may benefit from further investigations, are also highlighted.

A retrospective analysis of the cost of hospitalizations for sickle cell disease with crisis in England, 2010/11.

BACKGROUND: Sickle cell disease (SCD) is an inherited blood disorder which may result in a broad range of complications including recurring and severe episodes of pain--sickle 'crises'--which require frequent hospitalizations. We assessed the cost of hospitalizations associated with SCD with crisis in England. METHODS: Hospital Episodes Statistics data for all hospital episodes in England between 2010 and 2011 recording Sickle Cell Anaemia with Crisis as primary diagnosis were used. The total cost of admissions and exceeded length of stay due to SCD were assessed using Healthcare Resource Groups tariffs. The impact of patients' characteristics on SCD admissions costs and the likelihood of incurring extra bed days were also examined. RESULTS: In 2010-11, England had 6077 admissions associated with SCD with crisis as primary diagnosis. The total cost for these admissions for commissioners was £18,798 255. The cost of admissions increases with age (children admissions costs 50% less than adults). Patients between 10 and 19 years old are more likely to stay longer in hospital compared with others. CONCLUSION: SCD represents a significant cost for commissioners and the NHS. Further work is required to assess how best to manage patients in the community, which could potentially lead to a reduction in hospital admissions and length of stay, and their associated costs.

Deep vein thrombosis and pulmonary embolism in the military patient.

OBJECTIVES: Venous thromboembolism (VTE), encompassing deep vein thrombosis and pulmonary embolism, is a common, potentially lethal condition and a cause of long-term morbidity and functional limitation. This paper is a clinical review focused on military epidemiology, evidence-based recommendations for prevention, diagnosis and management of VTE and occupational considerations in a military population. METHODS: A literature review was conducted through Pubmed and Embase for systematic reviews, meta-analyses and clinical trials relating to VTE. Guidelines from the National Institute for Health and Care Excellence, British Thoracic Society and the American College of Chest Physicians were reviewed and recommendations considered. RESULTS: Acute morbidity from VTE can range from limb pain and swelling to life-threatening cardiovascular compromise. Long-term sequelae include postthrombotic syndrome, chronic thrombosis and pulmonary hypertension. Diagnosis should follow a validated pathway depending on the patient's prerest probability. The management of the condition should vary with attention to risk stratification. DISCUSSION: Prompt initiation of anticoagulation reduces symptoms, rates of recurrent VTE and death but treatment must be balanced against the risk of major haemorrhage. Military operations expose personnel to a unique combination of risk factors for VTE and operating in austere environments can increase the challenge of diagnosis, prognostication and management. Furthermore, there are implications for troop attrition, operational readiness and return to work.

Does higher quality of primary healthcare reduce hospital admissions for diabetes complications? A national observational study.

AIM: To determine if hospital admission rates for diabetes complications (acute complications, chronic complications, no complications and hypoglycaemia) were associated with primary care diabetes management. METHODS: We performed an observational study in the population in England during the period 2004-2009 (54 741 278 people registered with 8140 general practices). We used multivariable negative binomial regression to model the associations between indirectly standardized hospital admission rates for complications and primary healthcare quality, supply and access indicators, diabetes prevalence and population factors. RESULTS: In multivariate regression models, increasing deprivation (incidence rate ratio: 1.0154; P < 0.001, 95% CI 1.0141-1.0166) and diabetes prevalence (incidence rate ratio: 1.0956; P < 0.001, 95% CI 1.0677-1.1241) were risk factors for admission, while most healthcare covariates, i.e. a larger practice population (incidence rate ratio 0.9999, P = 0.013, 95% CI 0.9999-0.9999), better patient-perceived urgent and non-urgent access to primary care (incidence rate ratio: 0.9989, P = 0.023; 95% CI 0.9979-0.9998 and incidence rate ratio: 0.9988; P = 0.003, 95% CI 0.9980-0.9996, respectively) and better HbA1c target achievement (incidence rate ratio: 0.9971; P < 0.001, 95% CI 0.9958-0.9984), were protective. Diabetes admissions decreased significantly during the period 2004-2009. CONCLUSIONS: After controlling for population factors, better scheduled primary care access and glycaemic control were associated with lower hospital admission rates across most complications. There is little rationale to restrict primary care-sensitive condition definitions to acute complications. They should be revised to improve the usefulness of hospital admission data as an outcome measure, and to facilitate international comparisons. The risk of emergency hospital admission should be monitored routinely.

Is statin-induced diabetes clinically relevant? A comprehensive review of the literature.

In those predisposed to the development of diabetes (the insulin resistant, obese and older patients) statins may increase the risk of developing diabetes. Despite the fact that the conversion to diabetes is generated from post hoc analyses, it seems to be a class effect with a dose-response relationship. However, statins have not been clearly shown to increase diabetic microvascular complications (retinopathy, nephropathy and neuropathy). Thus, the clinical significance of increased glucose levels in patients treated on statins is uncertain. While the exact mechanism for how statins increase the risk of diabetes is unknown, a possible explanation is through a reduction in adiponectin levels. Despite the fact that higher statin doses are more likely to lead to new-onset diabetes, for every case of diabetes caused, there are approximately three cardiovascular events reduced with high dose versus moderate dose statin therapy. Overall, the small risk of developing type 2 diabetes with statin therapy is far outweighed by the potential of statins to decrease cardiac events.

Randomised clinical trial: study of escalating doses of NRL001 given in rectal suppositories of different weights.

AIMS: The application of α-adrenoceptor agonists can improve faecal incontinence symptoms. The aim of this study was to investigate the pharmacokinetic and systemic effects of NRL001 administered as different strengths in 1 or 2 g suppositories. METHODS: This randomised, double-blind, placebo controlled study included 48 healthy subjects. Group 1 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 5, 7.5 or 10 mg NRL001, or matching placebo. Group 2 consisted of two cohorts of 12 subjects administered either four single doses of 1 or 2 g rectal suppository with either 10, 12.5 or 15 mg NRL001, or matching placebo. Doses were given in an escalating manner with placebo at a random position within the sequence. RESULTS: Tmax was at ~4.5 h post-dose for all NRL001 doses. Median AUC0-tz , AUC0-∞ and Cmax increased with increasing dose for both suppository sizes. The estimate of ratios of geometric means comparing 2 g with 1 g suppository, and regression analysis for dose proportionality, was close to 1 for the variables AUC0-tz , AUC0-∞ and Cmax (P > 0.05). For both suppository sizes, 20-min mean pulse rate was significantly decreased compared with placebo with all doses (P < 0.05). Blood pressure decreased overall. There were 144 adverse events (AEs) and no serious AEs reported during the study. All AEs were mild in severity. CONCLUSIONS: The regression analysis concluded that the doses were dose proportional.

A randomised, controlled, crossover study to investigate the pharmacodynamics, pharmacokinetics and safety of 1R,2S-methoxamine hydrochloride (NRL001) in healthy elderly subjects.

AIMS: This study aimed to assess the effects of a single dose of 10 mg NRL001 (the 1R,2S stereoisomer of methoxamine hydrochloride) in a 2 g suppository on pharmacodynamic and pharmacokinetic (PK) variables, and safety, in a healthy elderly population. METHODS: This was a Phase I, single-centre, randomised, double-blind, placebo-controlled crossover study during which subjects received a single 2 g suppository of 10 mg NRL001 and a matching placebo in two separate treatment periods. The main outcome measures were Holter-, vital signs- and electrocardiogram-derived cardiovascular variables; plasma PK analysis; and safety assessments. RESULTS: Twenty-six subjects were dosed with study medication. Statistically significant reductions in Holter-derived heart rate (HR), vital signs-derived HR and diastolic blood pressure (BP) were observed comparing NRL001 with placebo treatment, and also with increasing NRL001 plasma concentration. No statistically significant relationships were observed between NRL001 concentration and systolic BP, mean arterial pressure or QTC interval (both Bazett's and Fridericia's correction). Thirty-nine adverse events were reported in 20 (76.9%) subjects, mostly after dosing with NRL001. CONCLUSION: Administration of NRL001 suppositories led to decreases in HR when compared with placebo data. NRL001 was well tolerated with a good safety profile during the study. Healthy elderly subjects did not show significantly different biological responses to NRL001 suppositories compared with younger healthy volunteers in previous studies.

A double-blind, placebo-controlled, randomised, parallel-group, dose-escalating, repeat dose study in healthy volunteers to evaluate the safety, tolerability, pharmacodynamic effects and pharmacokinetics of the once daily rectal application of NRL001 suppositories for 14 days.

AIMS: The 1R,2S stereoisomer of methoxamine hydrochloride, NRL001, is a highly selective α1-adrenoceptor agonist being developed for the local treatment of non-structural faecal incontinence caused by weak internal anal sphincter tone. This study investigated the steady state pharmacokinetics (PK) and safety of 2 g rectal suppositories containing NRL001 in different strengths (7.5, 10, 12.5 or 15 mg). METHODS: Healthy volunteers aged 18-45 years received 14 daily doses of NRL001 2 g suppositories or matching placebo. In each dose group nine participants received NRL001 and three received placebo. Blood samples to determine NRL001 concentrations were taken on Days 1, 7 and 14. Cardiovascular parameters were collected via electrocardiograms, Holter monitoring (three lead Holter monitor) and vital signs. RESULTS: Forty-eight volunteers were enrolled; 43 completed the study and were included in the PK analysis population. AUC and Cmax broadly increased with increasing dose, Tmax generally occurred between 4.0 and 5.0 h. Although the data did not appear strongly dose proportional, dose proportionality analysis did not provide evidence against dose proportionality as the log(dose) coefficients were not significantly < 1. NRL001 did not accumulate over time for any dose. Increasing NRL001 concentrations were related to changes in vital sign variables, most notably decreased heart rate. The most commonly reported adverse events (AEs) in the active treatment groups were paraesthesia and piloerection. CONCLUSIONS: Treatment with NRL001 was generally well tolerated over 14 days once daily dosing and plasma NRL001 did not accumulate over time. Treatment was associated with changes in vital sign variables, most notably decreased heart rate. AEs commonly reported with NRL001 treatment were events indicative of a systemic α-adrenergic effect.

Obesity and abdominal hernia in ambulatory patients, 2018-2023.

PURPOSE: To determine the relationship between abdominal hernia and obesity. Although obesity is frequently cited as a risk factor for abdominal hernia, few studies have confirmed this association (Menzo et al. Surg Obes Relat Dis 14:1221-1232. 10.1016/j.soard.2018.07.005, 2018). METHODS: A cross-sectional study of primary care ambulatory patients aged older than 16 years treated at UCLA Health from 01/01/2018 to 06/06/2023. Abdominal hernia was identified by clinic encounter ICD-10 codes (K40-K46). RESULTS: There were 41,703 hernias identified among 1,362,440 patients (306.1 per10,000) with a mean age of 62.5 ± 16.1 years, and 57.6% were men. Nearly half (44.7%) of all abdominal hernias were diaphragmatic. There was an approximately equal distribution of the ventral (28.7%) and inguinal (24.3%) hernia. Each hernia type had a different relationship with obesity: The odds of having a ventral hernia increased with BMI in both sexes: BMI 25-29.9 kg/m2 odds ratio (OR) = 1.65, (CI 1.56-1.74); BMI 30-39.9 kg/m2 OR = 2.42 (CI 2.29-2.56), BMI 40-49.9 kg/m2 OR = 2.28 (CI 2.05-2.54) and BMI > = 50 kg/m2 OR = 2.54 (CI 2.03-3.17) all relative to normal BMI. In contrast, the odds of having an inguinal hernia decreased with obesity relative to normal weight [obesity (BMI 30-39.9 kg/m2): OR = 0.60 (CI 0.56-0.65)], morbid obesity (BMI 40-49.9 kg/m2): OR = 0.29 (CI 0.23-0.37). The OR for diaphragmatic hernia peaks with obesity in women and overweight status in men but was found to decrease with morbid obesity [OR = 1.18 (CI 1.07-1.30)]. There was no significant difference between men and women in the prevalence of femoral hernia (men: 0.7/per10,000, women: 0.9/per10,000, p = 0.19). CONCLUSIONS: The relationship between hernia and obesity is complex with some hernias decreasing in prevalence as obesity increases. Further research is needed to better understand this paradoxical relationship.

Combine and conquer: advantages and disadvantages of fixed-dose combination therapy.

The majority of patients with type 2 diabetes mellitus (T2DM) do not achieve the glycaemic goals recommended by leading diabetes organizations using monotherapy alone, and often require multiple antihyperglycaemic agents to achieve glycaemic control. Fixed-dose combination (FDC) therapies offer a means to simplify complex treatment regimens, and have several advantages that help patients reach their glycaemic goals. In this review, four key benefits are identified and discussed in support of FDCs for treatment of patients with T2DM: (i) Greater efficacy compared with higher dose monotherapy, (ii) Reduced risk of adverse reactions relative to higher dose monotherapy, (iii) Lower overall costs and (iv) Improved medication concordance. Given these advantages, the place of fixed combination therapy in the course of treatment is discussed. Establishing a therapeutic strategy that incorporates fixed combination therapy (including combinations with insulin) will simplify the treatment of diabetes, ideally resulting in improved medication concordance, clinical outcomes and quality of life for patients with T2DM.

Prolonged vitamin D intoxication: presentation, pathogenesis and progress.

Vitamin D toxicity from unactivated vitamin D (calciferol) therapy is currently a rare cause of hypercalcaemia. However, the frequency of this event may increase as high-dose unactivated vitamin D preparations become available. Prolonged vitamin D toxicity can cause reversible hypercalcaemia and partially reversible renal impairment. Parathyroid hormone may not be suppressed with unactivated vitamin D toxicity, especially if renal disease coexists.

SOX9 directly regulates the type-II collagen gene.

Mutations in human SOX9 are associated with campomelic dysplasia (CD), characterised by skeletal malformation and XY sex reversal. During chondrogenesis in the mouse, Sox9 is co-expressed with Col2a1, the gene encoding type-II collagen, the major cartilage matrix protein. Col2a1 is therefore a candidate regulatory target of SOX9. Regulatory sequences required for chondrocyte-specific expression of the type-II collagen gene have been localized to conserved sequences in the first intron in rats, mice and humans. We show here that SOX9 protein binds specifically to sequences in the first intron of human COL2A1. Mutation of these sequences abolishes SOX9 binding and chondrocyte-specific expression of a COL2A1-driven reporter gene (COL2A1-lacZ) in transgenic mice. Furthermore, ectopic expression of Sox9 trans-activates both a COL2A1-driven reporter gene and the endogenous Col2a1 gene in transgenic mice. These results demonstrate that COL2A1 expression is directly regulated by SOX9 protein in vivo and implicate abnormal regulation of COL2A1 during, chondrogenesis as a cause of the skeletal abnormalities associated with campomelic dysplasia.