LINC01013 Is a Determinant of Fibroblast Activation and Encodes a Novel Fibroblast-Activating Micropeptide.

Myocardial fibrosis confers an almost threefold mortality risk in heart disease. There are no prognostic therapies and novel therapeutic targets are needed. Many thousands of unannotated small open reading frames (smORFs) have been identified across the genome with potential to produce micropeptides (< 100 amino acids). We sought to investigate the role of smORFs in myocardial fibroblast activation.Analysis of human cardiac atrial fibroblasts (HCFs) stimulated with profibrotic TGFß1 using RNA sequencing (RNA-Seq) and ribosome profiling (Ribo-Seq) identified long intergenic non-coding RNA LINC01013 as TGFß1 responsive and containing an actively translated smORF. Knockdown of LINC01013 using siRNA reduced expression of profibrotic markers at baseline and blunted their response to TGFß1. In contrast, overexpression of a codon-optimised smORF invoked a profibrotic response comparable to that seen with TGFß1 treatment, whilst FLAG-tagged peptide associated with the mitochondria.Together, these data support a novel LINC01013 smORF micropeptide-mediated mechanism of fibroblast activation. TGFß1 stimulation of atrial fibroblasts induces expression of LINC01013, whose knockdown reduces fibroblast activation. Overexpression of a smORF contained within LINC01013 localises to mitochondria and activates fibroblasts.

CXD101 and nivolumab in patients with metastatic microsatellite-stable colorectal cancer (CAROSELL): a multicentre, open-label, single-arm, phase II trial.

BACKGROUND: Patients with microsatellite stable (MSS) colorectal carcinoma (CRC) do not respond to immune checkpoint inhibitors. Preclinical models suggested synergistic anti-tumour activity combining CXD101 and anti-programmed cell death protein 1 treatment; therefore, we assessed the clinical combination of CXD101 and nivolumab in heavily pre-treated patients with MSS metastatic CRC (mCRC). PATIENTS AND METHODS: This single-arm, open-label study enrolled patients aged 18 years or older with biopsy-confirmed MSS CRC; at least two lines of systemic anticancer therapies (including oxaliplatin and irinotecan); at least one measurable lesion; Eastern Cooperative Oncology Group performance status of 0, 1 or 2; predicted life expectancy above 3 months; and adequate organ and bone marrow function. Nine patients were enrolled in a safety run-in study to define a tolerable combination schedule of CXD101 and nivolumab, followed by 46 patients in the efficacy assessment phase. Patients in the efficacy assessment cohort were treated orally with 20 mg CXD101 twice daily for 5 consecutive days every 3 weeks, and intravenously with 240 mg nivolumab every 2 weeks. The primary endpoint was immune disease control rate (iDCR). RESULTS: Between 2018 and 2020, 55 patients were treated with CXD101 and nivolumab. The combination therapy was well tolerated with the most frequent grade 3 or 4 adverse events being neutropenia (18%) and anaemia (7%). Immune-related adverse reactions commonly ascribed to checkpoint inhibitors were surprisingly rare although we did see single cases of pneumonitis, hypothyroidism and hypopituitarism. There were no treatment-related deaths. Of 46 patients assessable for efficacy, 4 (9%) achieved partial response and 18 (39%) achieved stable disease, translating to an immune disease control rate of 48%. The median overall survival (OS) was 7.0 months (95% confidence interval 5.13-10.22 months). CONCLUSIONS: The primary endpoint was met in this phase II study, which showed that the combination of CXD101 and nivolumab, at full individual doses in the treatment of advanced or metastatic MSS CRC, was both well tolerated and efficacious.

Changes in Body Composition in Older Adults after a Technology-Based Weight Loss Intervention.

We conducted a post-hoc analysis of a pre/post, single-arm, non-randomized, multicomponent weight loss intervention in older adults. Fifty-three older adults aged ≥65 with a body mass index ≥ 30 kg/m2 were recruited to participate in a six-month, remote monitoring and video-conferencing delivered, prescriptive intervention consisting of individual and group-led registered dietitian nutrition and physical therapy sessions. We assessed weight, height, and body composition using a SECA 514 bioelectrical impedance analyzer. Mean age was 72.9±3.9 years (70% female) and all had ≥2 chronic conditions. Of those with complete data (n=30), we observed a 4.6±3.5kg loss in weight, 6.1±14.3kg (1.9%) loss in fat mass, and 0.78±1.69L loss in visceral fat (all p<0.05). Fat-free mass (-3.4kg±6.8, p=0.19), appendicular lean mass (-0.25±1.83, p=0.22), and grip strength (+3.46±7.89, p=0.56) did not significantly change. These variables were preserved after stratifying by 5% weight loss. Our intervention led to significant body and visceral fat loss while maintaining fat-free and appendicular lean muscle mass.

A 5-year retrospective review of skin adnexal tumours received at a tertiary dermatopathology service: implications for linked genetic diagnoses.

BACKGROUND: Skin adnexal tumours (SATs) comprise a diverse range of neoplasms, which are difficult to diagnose clinically. They present in paediatric and adult populations, and may be indicative of an underlying genetic syndrome. There is a lack of recent data on the presentation of these tumours in clinical practice in European populations. OBJECTIVES: To characterize the clinical and pathological features of SATs received at a single tertiary centre over a 5-year period. METHODS: A retrospective health record audit of SATs received at the Department of Cellular Pathology, Royal Victoria Infirmary, Newcastle upon Tyne Hospitals NHS Foundation Trust, during the period November 2012 to October 2017 was performed. RESULTS: In total, 107 144 skin cases were received during the audit period. A total of 1615 cases of SATs from 1359 patients were included; 1570 (97·2%) were benign and 45 (2·8%) were malignant. Overall, the average age at presentation was 55 years (range 11 months to 97 years) and the male to female ratio was 0·77 : 1. Sweat gland and hair follicle SATs were most frequently excised; in adults, the most frequent tumour was hidrocystoma, and in children, pilomatrixoma occurred most often. Prebiopsy diagnosis was correct in 28% of cases. Benign SATs are often markers of an associated genetic condition, which warrants improved discrimination of sporadic from genetically related SATs. CONCLUSIONS: SATs are difficult to diagnose clinically, and clinicopathological correlation may help enhance discrimination of genetically related SATs from sporadic cases. These data have implications for clinical and dermatopathological training provision, the development of reporting standards, and genetic assessment of selected patients.

Successful management of aspiration pneumopathy without antimicrobial agents: 14 dogs (2014-2021).

OBJECTIVES: To describe clinical cases of aspiration pneumonitis and pneumonia in dogs, which were successfully managed without antimicrobials. MATERIALS AND METHODS: Retrospective case review of dogs presenting to a referral teaching hospital between February 2014 and February 2021. Cases were included when a clinical diagnosis of aspiration pneumopathy was made (requiring one or more of the following: radiographic evidence of an aspiration pneumopathy, endotracheal airway sampling consistent with aspiration and/or a positive endotracheal airway sample culture) which was not treated with antimicrobial therapy. RESULTS: Fourteen cases were identified of which nine had respiratory signs including increased respiratory rate or effort (n=8), arterial hypoxaemia (n=2), or a clinician-determined requirement for oxygen therapy (n=4). Where haematology was performed, five of nine displayed a normal neutrophil count with toxic changes, three displayed neutrophilia and one displayed neutropenia with toxic changes. Endotracheal airway sample cytology in four cases revealed neutrophilic inflammation with bacteria, plant material, yeasts and unidentified foreign material. Where respiratory signs were present, these resolved within 12 to 36 hours. CLINICAL SIGNIFICANCE: In this case series, immunocompetent dogs sustaining aspiration events, even with classical evidence of pneumonitis or pneumonia, have been managed successfully without antimicrobials. Radiography alone cannot be used to determine the requirement for antimicrobials. Better characterisation of the pathogenesis and clinical trajectory of aspiration pneumopathy is required, which may enable a reduction in inappropriate antimicrobial prescriptions.

Safety and efficacy of subcutaneous alpha-tocopherol in healthy adult horses.

Vitamin E is essential for neuromuscular function. The primary treatment, oral supplementation with natural ('RRR') α-tocopherol, is not effective in all horses. The objectives of this pilot study were to evaluate the safety and efficacy of a subcutaneously administered RRR-α-tocopherol preparation. Horses were randomly assigned in a cross-over design to initially receive RRR-α-tocopherol (5000 IU/450 kg of 600 IU/mL) subcutaneously (n = 3) or orally (n = 3) or were untreated sentinels (n = 2). Tissue reactions following injection in Phase I of the study necessitated adjustment of the preparation with reduction of the RRR-α-tocopherol concentration to 500 IU/mL in Phase 2. Following an 8-week washout period, horses received the reciprocal treatment route with the new preparation (5000 IU/450 kg of 500 IU/mL). Serum, CSF and muscle α-tocopherol concentrations were determined by high-performance liquid chromatography over a 14-day period during each phase. Serum and CSF α-tocopherol concentrations increased significantly postinjection only when the 500 IU/mL product was administered (P<0.0001). There was no significant difference in the muscle concentration of α-tocopherol following either treatment. All eight horses had marked tissue reaction to subcutaneous injection, regardless of product concentration. Whilst we have demonstrated that this route may be a useful alternative to oral supplementation, the marked tissue reaction makes use of such products limited at this time to only the most refractory of cases.

Small artificial waterbodies are widespread and persistent emitters of methane and carbon dioxide.

Inland waters play an active role in the global carbon cycle and emit large volumes of the greenhouse gases (GHGs), methane (CH4 ) and carbon dioxide (CO2 ). A considerable body of research has improved emissions estimates from lakes, reservoirs and rivers but recent attention has been drawn to the importance of small, artificial waterbodies as poorly quantified but potentially important emission hotspots. Of particular interest are emissions from drainage ditches and constructed ponds. These waterbody types are prevalent in many landscapes and their cumulative surface areas can be substantial. Furthermore, GHG emissions from constructed waterbodies are anthropogenic in origin and form part of national emissions reporting, whereas emissions from natural waterbodies do not (according to Intergovernmental Panel on Climate Change guidelines). Here, we present GHG data from two complementary studies covering a range of land uses. In the first, we measured emissions from nine ponds and seven ditches over a full year. Annual emissions varied considerably: 0.1-44.3 g CH4  m-2  year-1 and -36-4421 g CO2  m-2  year-1 . In the second, we measured GHG concentrations in 96 ponds and 64 ditches across seven countries, covering subtropical, temperate and sub-arctic biomes. When CH4 emissions were converted to CO2  equivalents, 93% of waterbodies were GHG sources. In both studies, GHGs were positively related to nutrient status (C, N, P), and pond GHG concentrations were highest in smallest waterbodies. Ditch and pond emissions were larger per unit area when compared to equivalent natural systems (streams, natural ponds). We show that GHG emissions from natural systems should not be used as proxies for those from artificial waterbodies, and that artificial waterbodies have the potential to make a substantial but largely unquantified contribution to emissions from the Agriculture, Forestry and Other Land Use sector, and the global carbon cycle.

A massive rock and ice avalanche caused the 2021 disaster at Chamoli, Indian Himalaya.

On 7 February 2021, a catastrophic mass flow descended the Ronti Gad, Rishiganga, and Dhauliganga valleys in Chamoli, Uttarakhand, India, causing widespread devastation and severely damaging two hydropower projects. More than 200 people were killed or are missing. Our analysis of satellite imagery, seismic records, numerical model results, and eyewitness videos reveals that ~27 × 106 cubic meters of rock and glacier ice collapsed from the steep north face of Ronti Peak. The rock and ice avalanche rapidly transformed into an extraordinarily large and mobile debris flow that transported boulders greater than 20 meters in diameter and scoured the valley walls up to 220 meters above the valley floor. The intersection of the hazard cascade with downvalley infrastructure resulted in a disaster, which highlights key questions about adequate monitoring and sustainable development in the Himalaya as well as other remote, high-mountain environments.

Homelessness, sex and a tale of two sexually transmitted infections.

The Young People's Health Service (YPHS) is a free, nurse-led Primary Health Care Clinic, in Melbourne, for young people aged 12-24 who are experiencing homelessness. Sexually transmitted infection (STI) screening is routinely offered as part of comprehensive psychosocial assessments. We wanted to determine the number of people positive for Chlamydia trachomatis (Ct) and Mycoplasma genitalium (Mg), amongst this asymptomatic high-risk population. We also wanted to review our screening practice. All asymptomatic sexually active clients seen by YPHS between 2014 and 2016 were offered a first pass urine polymerase chain reaction-based test for Ct and Mg. Urine samples were taken for men and women. Positivity for Ct and Mg out of those tested was determined and association with gender examined. Between 2014-2016, 272 males and 278 females (n = 550) were screened for Ct, and 72 infections were detected (13.1%. Chlamydia positivity did not differ between males (n = 35; 12.9%, 95% confidence interval [CI]: 8.8-16.8) and females (n = 37; 13.3%, 95%CI: 9.3-17.3). Over the same period 273 males and 284 females were screened for Mg (n = 557) and 55 infections were detected (9.9%). A higher proportion of females (n = 35; 12.3%, 95%CI: 8.5-16.1) tested positive compared to males (n = 20; 7.3%, 95%CI: 4.2-10.4), p = 0.048. Our study demonstrates both Ct and Mg are prevalent in the population, Mg being more common in young women than young men. Referral for specialist care for macrolide-resistant Mg increased and the updated Australian STI management guidelines led to a review of practice.

Long-term safety data from the cladribine tablets clinical development program in multiple sclerosis.

BACKGROUND: Long-term safety data are of particular interest for any newly approved treatment in multiple sclerosis such as cladribine tablets 10 mg (MAVENCLAD®; 3.5 mg/kg cumulative dose over 2 years, referred to as cladribine tablets 3.5 mg/kg), which is approved in Europe and the USA. Here we provide the final report on the integrated analysis of the safety profile of cladribine tablets 3.5 mg/kg from the clinical development program, including final data from the PREMIERE registry. METHODS: Safety data for cladribine tablets 3.5 mg/kg from three previously reported Phase III studies (CLARITY, CLARITY Extension and ORACLE-MS), as well as the prospective, observational PREMIERE registry (which ran from November 2009 to October 2018; consisting of patients who had participated in at least one of the Phase III trials) were combined to provide the Monotherapy Oral cohort. Serious adverse events (SAEs) and predefined SAEs of special interest were recorded. Observation-adjusted incidence rates per 100 patient-years (Adj-AE per 100 PY) were used to assess adverse events (AEs). Standardized incidence ratios for malignancies were calculated in relation to a matched GLOBOCAN reference population, and risk differences (cladribine tablets versus placebo) were estimated. RESULTS: The Monotherapy Oral cohort comprised 923 patients who received cladribine tablets 3.5 mg/kg and 641 patients who received placebo. Overall, the reported number of SAEs was higher in the cladribine tablets 3.5 mg/kg group (133/923 [14.4%] patients with at least 1 SAE), versus the placebo group (68/641 [10.6%] patients with at least 1 SAE). Four patients in the cladribine tablets 3.5 mg/kg group had lymphopenia classified as a serious event (resulting in an Adj-AE of 0.10 per 100 PY) and 2 patients had serious herpes zoster (resulting in an Adj-AE of 0.05 per 100 PY). There were no cases in the corresponding placebo groups. There was no difference between the cladribine tablets 3.5 mg/kg group and placebo in the overall incidence of infections. However herpetic infection AEs occurred more frequently in the cladribine tablets 3.5 mg/kg group (driven primarily by herpes zoster, followed by oral herpes and herpes simplex). Overall, there was a numerical imbalance in malignancy incidence between cladribine tablets 3.5 mg/kg and placebo, with an Adj-AE of 0.26 and 0.12 per 100 PY, respectively; however the difference was not statistically significant. The rate of malignancies observed with cladribine tablets 3.5 mg/kg in the final integrated safety analysis was not different from the expected rate in the matched GLOBOCAN reference population (standardized incidence ratio, 0.88; 95% CI, 0.44-1.69). CONCLUSION: Additional patient-years of observation do not significantly alter the conclusions of earlier interim analyses, and no new major safety findings were identified in this consolidated analysis of safety data of cladribine tablets 3.5 mg/kg monotherapy in patients with relapsing-remitting multiple sclerosis.

Current fluid and blood product availability in veterinary setting: a survey of UK small animal practices.

OBJECTIVES: To investigate and discuss current fluid and blood products stocked in small animal practices in the UK. METHODS: An online survey was circulated to small animal veterinary practices across the UK. The survey included questions regarding the level of hospital care provided, the type of fluid and blood component products stocked, the most frequently restocked products, and the available options in the event that blood products were required but not stocked. RESULTS: There were 423 responses including 27 duplicates. The remaining 396 respondents represented a spectrum of practices including 19 referral practices. Crystalloids were stocked in all practices. Lactated Ringer's solution was the most frequently re-stocked product in 355 of 396 (90%) of practices. Where synthetic colloids were stocked, gelatin-based colloids (155/178 [87%]) were stocked in preference to hydroxyethyl starches (23/178 [13%]). Blood products were stocked by 81 of 396 (20%) of practices. If a blood product was required but not stocked, 31% of practices would use a pet blood banking service, 28% would use their own blood donors, and 21% would refer. CLINICAL SIGNIFICANCE: This study provides an insight into the fluid and blood products stocked and used by a selection of veterinary practices within the UK and serves as a baseline for ongoing research and decision-making in both veterinary practice and industry.

SNP-based heritability and genetic architecture of cranial cruciate ligament rupture in Labrador Retrievers.

Cranial cruciate ligament rupture (CCLR) is one of the leading causes of pelvic limb lameness in dogs. About 6% of Labrador Retrievers suffer from this orthopedic problem. The aim of this study was to determine the heritability of CCLR in this breed using SNP array genotyping data. DNA samples were collected from CCLR-affected dogs (n = 190) and unaffected dogs over the age of 8 years (n = 143). All 333 dogs were genotyped directly or imputed up to approximately 710k SNPs on the Affymetrix Axiom CanineHD SNP array. Heritability of CCLR was calculated using multiple methodologies, including linear mixed models, Bayesian models and a model that incorporates LD. The covariates of sex and sterilization status were added to each analysis to assess their impact. Across the algorithms of these models, heritability ranged from 0.550 to 0.886, depending on covariate inclusion. The relatively high heritability for this disease indicates that a substantial genetic component contributes to CCLR in the Labrador Retriever.

Sustaining better care for patients undergoing emergency laparotomy.

Emergency laparotomy is associated with high mortality. Implementation of an evidence-based care bundle has been shown to improve patient outcomes. A quality improvement project to implement a six-component care bundle was undertaken between July 2015 and May 2018. As part of this project, we worked with 27 hospitals in the Emergency Laparotomy Collaborative. Previous pilot implementation of the same bundle in our hospital between December 2012 and July 2013 had shown marked improvement, maintained until April 2014, but then deterioration. Understanding the reasons for this deterioration informed our work to re-implement the bundle and sustain improvement. A cohort of 930 consecutive patients requiring emergency laparotomy between October 2014 and April 2019 were included. Baseline data were collected between October 2014 and June 2015, and the bundle was re-implemented in July 2015. Thirty-day mortality decreased from 11% in the baseline group to 7.3% after bundle implementation. Hospital length of stay decreased from 19.5 to 17.9 days. Full bundle compliance improved from < 60% to > 80% for all patients, with improvement in application of all individual bundle components. This study provides further evidence that outcomes for high-risk surgical patients can be improved with an evidence-based care bundle, but attention must be paid to maintaining bundle compliance. Issues around sustaining improvement must be considered from project initiation.

Reported Weight Change in Older Adults and Presence of Frailty.

OBJECTIVE: A 5% change in weight is a significant predictor for frailty and obesity. We ascertained how self-reported weight change over the lifespan impacts rates of frailty in older adults. METHODS: We identified 4,984 subjects ≥60 years with body composition measures from the National Health and Nutrition Examination Survey. An adapted version of Fried's frailty criteria was used as the primary outcome. Self-reported weight was assessed at time current,1 and 10 years earlier and at age 25. Weight changes between each time point were categorized as ≥ 5%, ≤5% or neutral. Logistic regression assessed the impact of weight change on the outcome of frailty. RESULTS: Among 4,984 participants, 56.5% were female, mean age was 71.1 years, and mean BMI was 28.2kg/m2. A weight loss of ≥ 5% had a higher association with frailty compared to current weight, age 25 (OR 2.94 [1.72,5.02]), 10 years ago (OR 1.68 [1.05,2.69]), and 1 year ago (OR 1.55 [1.02,2.36]). Weight gain in the last year was associated with increased rate of frailty (1.59 [1.09,2.32]). CONCLUSION: There is an association between frailty and reported weight loss over time while only weight gain in the last year has an association with frailty.

Carbon monoxide concentration in mainstream E-cigarette emissions measured with diode laser spectroscopy.

The e-fluid heated in electronic cigarettes (e-cigarettes) is largely composed of organic compounds, specifically propylene glycol, vegetable glycerin and flavouring compounds. When heated, as it is in an e-cigarette, the chemical species in this fluid have the potential to oxidise into carbon monoxide (CO) and other species. Using diode laser spectroscopy, the concentration of CO in e-cigarette mainstream effluent as a function of e-cigarette power and flavour was measured. Carbon monoxide concentration was found to be a direct function of the power of the resistive heating. At the highest powers testable using commercial e-cigarette components, the maximum CO concentration measured was over 180 ppm. The flavouring compounds in the e-fluid also had an effect on the concentration of carbon monoxide present in the effluent.