A Brief Cognitive Analytic Therapy-Informed Approach for Young People That Have Self-Injured (CATCH-Y): A Case Series.

BACKGROUND: Non-suicidal self-injury (NSSI) presents an increasingly prevalent problem for young people; however, there remains a scarce evidence base for effective, scalable treatments for adolescents. This study aimed to assess the feasibility and acceptability of a brief, cognitive analytic therapy (CAT)-informed intervention for young people who engage in NSSI (CATCH-Y). METHODS: A case series design recruited 13 young people who met the inclusion and exclusion criteria to participate in the five-session intervention. Eligible participants were aged 13-17 years (M = 15.15, SD = 1.28) and had engaged in NSSI at least once in the previous 6 months. Feasibility and acceptability were measured via recruitment, retention, qualitative feedback and missing data. The secondary outcome measures of personal recovery and motivation were administered pre- and post-assessment, with measures of depressive symptoms and urges to self-injure. RESULTS: The intervention was found to be largely feasible and acceptable with high rates of recruitment, retention and pre-/post-assessment data completeness. Measures showed preliminary support for positive change in rates of NSSI, urges to self-harm, low mood and personal recovery, although results were mixed. Completion rates for remote assessments were low. CONCLUSIONS: The findings of this study support further evaluation of the CATCH-Y intervention on a larger scale. In-person assessments may be preferable to remote to ensure good completion rates.

IFITM3 restricts virus-induced inflammatory cytokine production by limiting Nogo-B mediated TLR responses.

Interferon-induced transmembrane protein 3 (IFITM3) is a restriction factor that limits viral pathogenesis and exerts poorly understood immunoregulatory functions. Here, using human and mouse models, we demonstrate that IFITM3 promotes MyD88-dependent, TLR-mediated IL-6 production following exposure to cytomegalovirus (CMV). IFITM3 also restricts IL-6 production in response to influenza and SARS-CoV-2. In dendritic cells, IFITM3 binds to the reticulon 4 isoform Nogo-B and promotes its proteasomal degradation. We reveal that Nogo-B mediates TLR-dependent pro-inflammatory cytokine production and promotes viral pathogenesis in vivo, and in the case of TLR2 responses, this process involves alteration of TLR2 cellular localization. Nogo-B deletion abrogates inflammatory cytokine responses and associated disease in virus-infected IFITM3-deficient mice. Thus, we uncover Nogo-B as a driver of viral pathogenesis and highlight an immunoregulatory pathway in which IFITM3 fine-tunes the responsiveness of myeloid cells to viral stimulation.

Occult tension pneumothorax discovered following imaging for adult trauma patients in the modern major trauma system: a multicentre observational study.

BACKGROUND: Tension pneumothorax following trauma is a life-threatening emergency and radiological investigation is normally discouraged prior to treatment in traditional trauma doctrines such as ATLS. Some trauma patients may be physiologically stable enough for diagnostic imaging and occult tension pneumothorax is discovered radiologically. We assessed the outcomes of these patients and compared them with those with clinical diagnosis of tension pneumothorax prior to imaging. METHODS: A multicentre civilian-military collaborative network of six major trauma centres in the UK collected observational data from adult patients who had a diagnosis of traumatic tension pneumothorax during a 33-month period. Patients were divided into 'radiological' (diagnosis following CT/CXR) or 'clinical' (no prior CT/CXR) groups. The effect of radiological diagnosis on survival was analysed using multivariable logistic regression that included the covariates of age, gender, comorbidities and Injury Severity Score. RESULTS: There were 133 patients, with a median age of 41 (IQR 24-61); 108 (81%) were male. Survivors included 49 of 59 (83%) in the radiological group and 59 of 74 (80%) in the clinical group (p=0.487). Multivariable logistic regression showed no significant association between radiological diagnosis and survival (OR 2.40, 95% CI 0.80 to 7.95; p=0.130). There was no significant difference in mortality between the groups. CONCLUSION: Radiological imaging may be appropriate for selected trauma patients at risk of tension pneumothorax if they are considered haemodynamically stable. Trauma patients may be physiologically stable enough for radiological imaging but have occult tension pneumothorax because they did not have the typical clinical presentation. The historical dogma of the 'forbidden scan' no longer applies to such patients.

Torso body armour coverage defined according to feasibility of haemorrhage control within the prehospital environment: a new paradigm for combat trauma protection.

Developments in military personal armour have aimed to achieve a balance between anatomical coverage, protection and mobility. When death is likely to occur within 60 min of injury to anatomical structures without damage control surgery, then these anatomical structures are defined as 'essential'. However, the medical terminology used to describe coverage is challenging to convey in a Systems Requirements Document (SRD) for acquisition of new armour and to ultimately translate to the correct sizing and fitting of personal armour. Many of those with Ministry of Defence responsible for the procurement of personal armour and thereby using SRDs will likely have limited medical knowledge; therefore, the potentially complex medical terminology used to describe the anatomical boundaries must be translated into easily recognisable and measurable external landmarks. We now propose a complementary classification for ballistic protection coverage, termed threshold and objective, based on the feasibility of haemorrhage control within the prehospital environment.

Killed in action (KIA): an analysis of military personnel who died of their injuries before reaching a definitive medical treatment facility in Afghanistan (2004-2014).

INTRODUCTION: The majority of combat deaths occur before arrival at a medical treatment facility but no previous studies have comprehensively examined this phase of care. METHODS: The UK Joint Theatre Trauma Registry was used to identify all UK military personnel who died in Afghanistan (2004-2014). These data were linked to non-medical tactical and operational records to provide an accurate timeline of events. Cause of death was determined from records taken at postmortem review. The primary objective was to report time between injury and death in those killed in action (KIA); secondary objectives included: reporting mortality at key North Atlantic Treaty Organisation timelines (0, 10, 60, 120 min), comparison of temporal lethality for different anatomical injuries and analysing trends in the case fatality rate (CFR). RESULTS: 2413 UK personnel were injured in Afghanistan from 2004 to 2014; 448 died, with a CFR of 18.6%. 390 (87.1%) of these died prehospital (n=348 KIA, n=42 killed non-enemy action). Complete data were available for n=303 (87.1%) KIA: median Injury Severity Score 75.0 (IQR 55.5-75.0). The predominant mechanisms were improvised explosive device (n=166, 54.8%) and gunshot wound (n=96, 31.7%).In the KIA cohort, the median time to death was 0.0 (IQR 0.0-21.8) min; 173 (57.1%) died immediately (0 min). At 10, 60 and 120 min post injury, 205 (67.7%), 277 (91.4%) and 300 (99.0%) casualties were dead, respectively. Whole body primary injury had the fastest mortality. Overall prehospital CFR improved throughout the period while in-hospital CFR remained constant. CONCLUSION: Over two-thirds of KIA deaths occurred within 10 min of injury. Improvement in the CFR in Afghanistan was predominantly in the prehospital phase.

Suspected appendicitis and COVID-19, a change in investigation and management-a multicentre cohort study.

PURPOSE: The COVID-19 pandemic has reformed global healthcare delivery. On 25 March 2020, Intercollegiate guidelines were published in the UK to promote safe surgical provision during the COVID-19 outbreak advocating non-operative management or avoidance of laparoscopy when surgery is essential. The effects of this on the investigation and management of appendicitis remain unknown. METHODS: We performed a multicentre, prospective, observational study from the start of the new guidelines to the 6th of May 2020. We included all patients referred to surgical teams with suspected appendicitis. A recent historical cohort was identified for comparison. The primary outcome was the impact of the COVID-19 pandemic on the use of non-operative management in appendicitis. Secondary outcomes included imaging, negative appendicectomy rate (NAR), length of stay (LOS) and 30-day complications. RESULTS: A total of 63/164 (38%) patients compared to 79/191 (41%) were diagnosed with appendicitis before and after the guidelines were introduced (p = 0.589). CT scanning increased (71/164 vs 105/191; p = 0.033) while ultrasound scanning decreased (71/164 vs 62/191; p = 0.037). Appendicitis was more likely to be managed non-operatively (11/63 vs 51/79; p < 0.001) and, of those managed surgically, with an open approach (3/52 vs 26/28 p < 0.001). The NAR also reduced (5/52 vs 0/28; p = 0.157). LOS was shorter in non-operatively managed patients (1 day vs 3 days; p < 0.001) without a difference in complications (10/51 vs 4/28; p = 0.760). CONCLUSION: Introduction of the guidelines was associated with changes in practice. Despite these changes, short-term complications did not increase and LOS decreased. Questions remain on the longer-term complication rates in non-operatively managed patients.

Combined ultrasound and Sestamibi scintigraphy provides accurate preoperative localisation for patients with primary hyperparathyroidism.

INTRODUCTION: Minimally invasive parathyroidectomy has advantages over the traditional bilateral neck exploration for the surgical treatment of primary hyperparathyroidism. It requires accurate localisation of the parathyroid pathology prior to surgery. The best method of preoperative localisation in a district general hospital setting is not well understood. METHODS: All patients who underwent parathyroidectomy for primary hyperparathyroidism from 2008 to 2016 were identified from a prospectively maintained database. Operative findings were correlated with radiological and histological results. Sensitivity and specificity of ultrasound, sestamibi scintigraphy and the two together were calculated for diagnostic precision and compared. RESULTS: One hundred and eighty-four patients met the inclusion criteria, of whom 81.5% had a histological diagnosis of a parathyroid adenoma. Ultrasound had higher sensitivity than sestamibi scintigraphy. Used together, ultrasound and sestamibi scintigraphy performed better than either ultrasound or sestamibi scintigraphy alone (P< 0.001). Twenty-two of 184 cases had no lesion located by either ultrasound or sestamibi scintigraphy preoperatively. Where neither ultrasound nor sestamibi scintigraphy located the lesion, additional computed tomography led to the excision of parathyroid pathology in one in ten patients. CONCLUSION: The combination of ultrasound and sestamibi scintigraphy provides the highest sensitivity of preoperative localisation. This approach led to a high success rate of minimally invasive parathyroidectomy. Where preoperative localisation is not achieved with ultrasound or sestamibi scintigraphy, computed tomography adds little additional benefit. In this setting other modalities of localisation such a selective venous sampling, intraoperative methylene blue or intraoperative parathyroid hormone levels could be considered.

Interferon-Induced Transmembrane Protein 1 Restricts Replication of Viruses That Enter Cells via the Plasma Membrane.

The acute antiviral response is mediated by a family of interferon-stimulated genes (ISGs), providing cell-intrinsic immunity. Mutations in genes encoding these proteins are often associated with increased susceptibility to viral infections. One family of ISGs with antiviral function is the interferon-inducible transmembrane proteins (IFITMs), of which IFITM3 has been studied extensively. In contrast, IFITM1 has not been studied in detail. Since IFITM1 can localize to the plasma membrane, we investigated its function with a range of enveloped viruses thought to infect cells by fusion with the plasma membrane. Overexpression of IFITM1 prevented infection by a number of Paramyxoviridae and Pneumoviridae, including respiratory syncytial virus (RSV), mumps virus, and human metapneumovirus (HMPV). IFITM1 also restricted infection with an enveloped DNA virus that can enter via the plasma membrane, herpes simplex virus 1 (HSV-1). To test the importance of plasma membrane localization for IFITM1 function, we identified blocks of amino acids in the conserved intracellular loop (CIL) domain that altered the subcellular localization of the protein and reduced antiviral activity. By screening reported data sets, 12 rare nonsynonymous single nucleotide polymorphisms (SNPs) were identified in human IFITM1, some of which are in the CIL domain. Using an Ifitm1-/- mouse, we show that RSV infection was more severe, thereby extending the range of viruses restricted in vivo by IFITM proteins and suggesting overall that IFITM1 is broadly antiviral and that this antiviral function is associated with cell surface localization.IMPORTANCE Host susceptibility to viral infection is multifactorial, but early control of viruses not previously encountered is predominantly mediated by the interferon-stimulated gene (ISG) family. There are upwards of 300 of these genes, the majority of which do not have a clearly defined function or mechanism of action. The cellular location of these proteins may have an important effect on their function. One ISG located at the plasma membrane is interferon-inducible transmembrane protein 1 (IFITM1). Here we demonstrate that IFITM1 can inhibit infection with a range of viruses that enter via the plasma membrane. Mutant IFITM1 proteins that were unable to localize to the plasma membrane did not restrict viral infection. We also observed for the first time that IFITM1 plays a role in vivo, and Ifitm1-/- mice were more susceptible to viral lung infection. These data contribute to our understanding of how ISGs prevent viral infections.

Cost-effectiveness of routine imaging of suspected appendicitis.

Introduction The misdiagnosis of appendicitis and consequent removal of a normal appendix occurs in one in five patients in the UK. On the contrary, in healthcare systems with routine cross-sectional imaging of suspected appendicitis, the negative appendicectomy rate is around 5%. If we could reduce the rate in the UK to similar numbers, would this be cost effective? This study aimed to calculate the financial impact of negative appendicectomy at the Queen Alexandra Hospital and to explore whether a policy of routine imaging of such patients could reduce hospital costs. Materials and methods We performed a retrospective analysis of all appendicectomies over a 1-year period at our institution. Data were extracted on outcomes including appendix histology, operative time and length of stay to calculate the negative appendicectomy rate and to analyse costs. Results A total of 531 patients over 5 years of age had an appendicectomy. The negative appendicectomy rate was 22% (115/531). The additional financial costs of negative appendicectomy to the hospital during this period were £270,861. Universal imaging of all patients with right iliac fossa pain that could result in a 5% negative appendicectomy rate would cost between £67,200 and £165,600 per year but could save £33,896 (magnetic resonance imaging), £105,896 (computed tomography) or £132,296 (ultrasound) depending on imaging modality used. Conclusions Negative appendicectomy is still too frequent and results in additional financial burden to the health service. Routine imaging of patients with suspected appendicitis would not only reduce the negative appendicectomy rate but could lead to cost savings and a better service for our patients.

Mitochondrial genetic diversity, selection and recombination in a canine transmissible cancer.

Canine transmissible venereal tumour (CTVT) is a clonally transmissible cancer that originated approximately 11,000 years ago and affects dogs worldwide. Despite the clonal origin of the CTVT nuclear genome, CTVT mitochondrial genomes (mtDNAs) have been acquired by periodic capture from transient hosts. We sequenced 449 complete mtDNAs from a global population of CTVTs, and show that mtDNA horizontal transfer has occurred at least five times, delineating five tumour clades whose distributions track two millennia of dog global migration. Negative selection has operated to prevent accumulation of deleterious mutations in captured mtDNA, and recombination has caused occasional mtDNA re-assortment. These findings implicate functional mtDNA as a driver of CTVT global metastatic spread, further highlighting the important role of mtDNA in cancer evolution.

Defining our destiny: trainee working group consensus statement on the future of emergency surgery training in the United Kingdom.

The United Kingdom National Health Service treats both elective and emergency patients and seeks to provide high quality care, free at the point of delivery. Equal numbers of emergency and elective general surgical procedures are performed, yet surgical training prioritisation and organisation of NHS institutions is predicated upon elective care. The increasing ratio of emergency general surgery consultant posts compared to traditional sub-specialities has yet to be addressed. How should the capability gap be bridged to equip motivated, skilled surgeons of the future to deliver a high standard of emergency surgical care? The aim was to address both training requirements for the acquisition of necessary emergency general surgery skills, and the formation of job plans for trainee and consultant posts to meet the current and future requirements of the NHS. Twenty nine trainees and a consultant emergency general surgeon convened as a Working Group at The Association of Surgeons in Training Conference, 2015, to generate a united consensus statement to the training requirement and delivery of emergency general surgery provision by future general surgeons. Unscheduled general surgical care provision, emergency general surgery, trauma competence, training to meet NHS requirements, consultant job planning and future training challenges arose as key themes. Recommendations have been made from these themes in light of published evidence. Careful workforce planning, education, training and fellowship opportunities will provide well-trained enthusiastic individuals to meet public and societal need.

The selective use of splenic flexure mobilization is safe in both laparoscopic and open anterior resections.

AIM: Splenic flexure mobilization (SFM) is standard practice in anterior resections. No previous studies have compared outcomes with and without SFM in laparoscopic and open colorectal cancer surgery. This study aimed to determine whether routine or selective SFM should be advised. METHOD: Data were collected prospectively on all elective anterior resections for cancer in our unit between October 2006 and November 2009. RESULTS: Of 263 resections, SFM data were recorded in 216; 138 were laparoscopic (32% with SFM, 3.6% converted) and 78 open (68% with SFM). Eighty-eight were low anterior resections (LARs) for mid-low rectal cancers, with 54 laparoscopic (50% with SFM) and 34 open (91% with SFM). Comparing laparoscopic with SFM to without, differences were found in the proportion of LARs (61%vs 29%, P<0.001), defunctioning ileostomy rates (75%vs 46%, P=0.001) and operative time (median 255 vs 185 min, P<0.001), with no differences in age, gender, body mass index, American Society of Anesthesiology score, preoperative treatment, length of stay, lymph node yield, conversion rate, mortality, anastomotic leakage, reoperation, readmission and R0 resection. No differences in outcomes were seen between laparoscopic LARs with and without SFM or between open resections with and without SFM. CONCLUSION: Our results show no disadvantage in short-term clinical or oncological outcomes when SFM was avoided. Laparoscopic anterior resections with SFM take longer. A selective approach to SFM is safe during anterior resection (open or laparoscopic), including mid-low rectal cancers.

Nutrition, metabolism, and fertility in dairy cows: 3. Amino acids and ovarian function.

Plasma insulin concentrations influence resumption of ovarian activity in postpartum dairy cows, and plasma insulin can be manipulated by changing dietary starch and fat supply. The objective of this experiment was to investigate the role of dietary amino acids in altering peripheral metabolic hormones and ovarian function. Thirty-two cows were fed a standard diet from calving until 40 d in milk (DIM), and then 8 cows were transferred to each of 4 dietary treatments until 70 DIM. The 4 diets were designed to supply either low (diets 1 and 2) or high (diets 3 and 4) levels of metabolizable protein (MP), containing either low (diet 1 and 3) or high (diets 2 and 4) proportions of Leu. Leucine was manipulated with heat-treated lupins and corn gluten meal. Estrus was synchronized at 60 DIM. Between 60 and 70 DIM, energy intake and energy balance were similar among diet groups, although cows receiving high MP containing high Leu had a greater milk yield than other groups (means: 37.8, 37.1, 37.4, 39.4 +/- standard error 0.85 kg/d for diets 1 to 4, respectively). Interactions between MP and Leu were found for insulin, glucagon, and the ratio between them. Insulin was not affected by Leu in diets with low MP but was decreased by greater Leu in diets with high MP (means: 0.37, 0.32, 0.46, 0.39 +/- SE 0.031 ng/mL for diets 1 to 4, respectively). Glucagon was not affected by MP in diets with low Leu but was increased by greater MP in diets with high Leu (means: 92, 81, 88, 95 +/- SE 6.0 pg/mL for diets 1 to 4, respectively). For the low-MP treatments, the insulin-to-glucagon ratio was greater with high Leu; for the high-MP treatments, the insulin-to-glucagon ratio was greater with low Leu (means: 4.28, 5.42, 5.16, 4.22 +/- SE 0.456 for diets 1 to 4, respectively). There was no effect of MP or Leu on ovarian follicle numbers or reproductive hormones. Based on hormonal and ovarian responses, we conclude that altering metabolic hormones through manipulation of amino acid supply and balance is unlikely to have a significant effect on ovarian function in dairy cows.

An immune control model for viral replication in the CNS during presymptomatic HIV infection.

The brain is targeted by human immunodeficiency virus type 1 (HIV-1) during the course of untreated infection, leading to cognitive impairment, neurological damage and HIV encephalitis (HIVE). To study early dynamics of HIV entry into the brain, we examined a unique autopsy series of samples obtained from 15 untreated individuals who died in the presymptomatic stages of infection from non-HIV causes. HIV was detected and quantified by limiting dilution PCR and genetically characterized in the V3 region of env. Limiting dilution was shown to be essential for correct estimation of genetic partitioning between brain- and lymphoid-associated HIV populations. While no actively expressing HIV-infected cells were detected by immunohistochemistry, variable and generally extremely low levels of proviral DNA were detected in presymptomatic brain samples. V3 region sequences were frequently genetically distinct from lymphoid-associated HIV variants, with association index (AI) values similar to those observed in cases of HIVE. Infiltration of CD8 lymphocytes in the brain was strongly associated with expression of activation markers (MHCII; R = 0.619; P < 0.05), the presence of HIV-infected cells (proviral load; R = 0.608; P < 0.05) and genetic segregation of brain variants from populations in lymphoid tissue (AI value, R = -0.528; P approximately 0.05). CD8 lymphocytes may thus limit replication of HIV seeded into the brain in early stages of infection. Neurological complications in AIDS occur when this control breaks down, due to systemic immunosuppression from HIV that destroys CD8 lymphocyte function and/or through the evolution of more aggressive neuropathogenic variants.

Intra-articular hyaluronate in experimental rabbit osteoarthritis can prevent changes in cartilage proteoglycan content.

OBJECTIVE: The purpose of this study was to determine the effects of intra-articular injections of high molecular weight (2000 kDa) sodium hyaluronate (HA) on the progression of articular cartilage degeneration in a rabbit partial medial meniscectomy model of osteoarthritis. DESIGN: Six experimental groups included normal, sham operated, and operated and injected animals, the latter injected once-weekly (for two weeks or twelve weeks, beginning four weeks after surgery) with either 1% (w/v) HA or phosphate buffered saline (PBS). Following assessment of gross morphology, serial adjacent blocks of full-depth articular cartilage were prepared from the tibial condyle for analysis of total water, hydroxyproline, DNA and proteoglycan (uronic acid) content, as well as the ratio of galactosamine to glucosamine. Samples were sub-divided into inner (medial) and outer (lateral) regions. RESULTS: No morphological differences were recognized between joints injected with PBS and those receiving HA. When analysed biochemically, there were no significant differences in hydration, hydroxyproline or DNA content between the experimental groups. In contrast, HA injection did affect changes in proteoglycan content. Expressed per tissue dry weight, uronic acid content in the operated group injected with PBS for two weeks was lower than normal (P<0.02), a result not seen in the corresponding HA injected group. After 12 weeks of PBS injections, uronic acid content (per dry weight) was higher than normal (P<0.01), an effect again not observed in the corresponding HA injected group. Results for the galactosamine: glucosamine ratio showed a reduction after 12 weeks of injections, but no differences between PBS and HA injected groups. CONCLUSIONS: Once-weekly, intra-articular injection of high molecular weight HA can prevent changes in proteoglycan content in tibial condylar articular cartilage, compared to PBS injected controls, in the rabbit partial meniscectomy model of osteoarthritis.

Regulation of cell polarity, radial intercalation and epiboly in Xenopus: novel roles for integrin and fibronectin.

Fibronectin (FN) is reported to be important for early morphogenetic movements in a variety of vertebrate embryos, but the cellular basis for this requirement is unclear. We have used confocal and digital time-lapse microscopy to analyze cell behaviors in Xenopus gastrulae injected with monoclonal antibodies directed against the central cell-binding domain of fibronectin. Among the defects observed is a disruption of fibronectin matrix assembly, resulting in a failure of radial intercalation movements, which are required for blastocoel roof thinning and epiboly. We identified two phases of FN-dependent cellular rearrangements in the blastocoel roof. The first involves maintenance of early roof thinning in the animal cap, and the second is required for the initiation of radial intercalation movements in the marginal zone. A novel explant system was used to establish that radial intercalation in the blastocoel roof requires integrin-dependent contact of deep cells with fibronectin. Deep cell adhesion to fibronectin is sufficient to initiate intercalation behavior in cell layers some distance from the substrate. Expression of a dominant-negative beta1 integrin construct in embryos results in localized depletion of the fibronectin matrix and thickening of the blastocoel roof. Lack of fibronectin fibrils in vivo is correlated with blastocoel roof thickening and a loss of deep cell polarity. The integrin-dependent binding of deep cells to fibronectin is sufficient to drive membrane localization of Dishevelled-GFP, suggesting that a convergence of integrin and Wnt signaling pathways acts to regulate radial intercalation in Xenopus embryos.