Depression, anxiety and PTSD symptoms before and during the COVID-19 pandemic in the UK.

BACKGROUND: The impact of the coronavirus disease 2019 (COVID-19) pandemic on mental health is still being unravelled. It is important to identify which individuals are at greatest risk of worsening symptoms. This study aimed to examine changes in depression, anxiety and post-traumatic stress disorder (PTSD) symptoms using prospective and retrospective symptom change assessments, and to find and examine the effect of key risk factors. METHOD: Online questionnaires were administered to 34 465 individuals (aged 16 years or above) in April/May 2020 in the UK, recruited from existing cohorts or via social media. Around one-third (n = 12 718) of included participants had prior diagnoses of depression or anxiety and had completed pre-pandemic mental health assessments (between September 2018 and February 2020), allowing prospective investigation of symptom change. RESULTS: Prospective symptom analyses showed small decreases in depression (PHQ-9: -0.43 points) and anxiety [generalised anxiety disorder scale - 7 items (GAD)-7: -0.33 points] and increases in PTSD (PCL-6: 0.22 points). Conversely, retrospective symptom analyses demonstrated significant large increases (PHQ-9: 2.40; GAD-7 = 1.97), with 55% reported worsening mental health since the beginning of the pandemic on a global change rating. Across both prospective and retrospective measures of symptom change, worsening depression, anxiety and PTSD symptoms were associated with prior mental health diagnoses, female gender, young age and unemployed/student status. CONCLUSIONS: We highlight the effect of prior mental health diagnoses on worsening mental health during the pandemic and confirm previously reported sociodemographic risk factors. Discrepancies between prospective and retrospective measures of changes in mental health may be related to recall bias-related underestimation of prior symptom severity.

An in silico canine cardiac midmyocardial action potential duration model as a tool for early drug safety assessment.

Cell lines expressing ion channels (IC) and the advent of plate-based electrophysiology device have enabled a molecular understanding of the action potential (AP) as a means of early QT assessment. We sought to develop an in silico AP (isAP) model that provides an assessment of the effect of a compound on the myocyte AP duration (APD) using concentration-effect curve data from a panel of five ICs (hNav1.5, hCav1.2, hKv4.3/hKChIP2.2, hKv7.1/hminK, hKv11.1). A test set of 53 compounds was selected to cover a range of selective and mixed IC modulators that were tested for their effects on optically measured APD. A threshold of >10% change in APD at 90% repolarization (APD(90)) was used to signify an effect at the top test concentration. To capture the variations observed in left ventricular midmyocardial myocyte APD data from 19 different dogs, the isAP model was calibrated to produce an ensemble of 19 model variants that could capture the shape and form of the APs and also quantitatively replicate dofetilide- and diltiazem-induced APD(90) changes. Provided with IC panel data only, the isAP model was then used, blinded, to predict APD(90) changes greater than 10%. At a simulated concentration of 30 µM and based on a criterion that six of the variants had to agree, isAP prediction was scored as showing greater than 80% predictivity of compound activity. Thus, early in drug discovery, the isAP model allows integrating separate IC data and is amenable to the throughput required for use as a virtual screen.

Phase variation controls expression of Salmonella lipopolysaccharide modification genes by a DNA methylation-dependent mechanism.

The O-antigen of Salmonella lipopolysaccharide is a major antigenic determinant and its chemical composition forms the basis for Salmonella serotyping. Modifications of the O-antigen that can affect the serotype include those carried out by the products of glycosyltransferase operons (gtr), which are present on specific Salmonella and phage genomes. Here we show that expression of the gtr genes encoded by phage P22 that confers the O1 serotype is under the control of phase variation. This phase variation occurs by a novel epigenetic mechanism requiring OxyR in conjunction with the DNA methyltransferase Dam. OxyR is an activator or a repressor of the system depending on which of its two binding sites in the gtr regulatory region is occupied. Binding is decreased by methylation at Dam target sequences in either site, and this confers heritability of the expression state to the system. Most Salmonella gtr operons share the key regulatory elements that are identified here as essential for this epigenetic phase variation.

Role of age, gender and marital status in prognosis for adults with depression: An individual patient data meta-analysis.

AIMS: To determine whether age, gender and marital status are associated with prognosis for adults with depression who sought treatment in primary care. METHODS: Medline, Embase, PsycINFO and Cochrane Central were searched from inception to 1st December 2020 for randomised controlled trials (RCTs) of adults seeking treatment for depression from their general practitioners, that used the Revised Clinical Interview Schedule so that there was uniformity in the measurement of clinical prognostic factors, and that reported on age, gender and marital status. Individual participant data were gathered from all nine eligible RCTs (N = 4864). Two-stage random-effects meta-analyses were conducted to ascertain the independent association between: (i) age, (ii) gender and (iii) marital status, and depressive symptoms at 3-4, 6-8, and 9-12 months post-baseline and remission at 3-4 months. Risk of bias was evaluated using QUIPS and quality was assessed using GRADE. PROSPERO registration: CRD42019129512. Pre-registered protocol https://osf.io/e5zup/. RESULTS: There was no evidence of an association between age and prognosis before or after adjusting for depressive 'disorder characteristics' that are associated with prognosis (symptom severity, durations of depression and anxiety, comorbid panic disorderand a history of antidepressant treatment). Difference in mean depressive symptom score at 3-4 months post-baseline per-5-year increase in age = 0(95% CI: -0.02 to 0.02). There was no evidence for a difference in prognoses for men and women at 3-4 months or 9-12 months post-baseline, but men had worse prognoses at 6-8 months (percentage difference in depressive symptoms for men compared to women: 15.08% (95% CI: 4.82 to 26.35)). However, this was largely driven by a single study that contributed data at 6-8 months and not the other time points. Further, there was little evidence for an association after adjusting for depressive 'disorder characteristics' and employment status (12.23% (-1.69 to 28.12)). Participants that were either single (percentage difference in depressive symptoms for single participants: 9.25% (95% CI: 2.78 to 16.13) or no longer married (8.02% (95% CI: 1.31 to 15.18)) had worse prognoses than those that were married, even after adjusting for depressive 'disorder characteristics' and all available confounders. CONCLUSION: Clinicians and researchers will continue to routinely record age and gender, but despite their importance for incidence and prevalence of depression, they appear to offer little information regarding prognosis. Patients that are single or no longer married may be expected to have slightly worse prognoses than those that are married. Ensuring this is recorded routinely alongside depressive 'disorder characteristics' in clinic may be important.

Updated emm-typing protocol for Streptococcus pyogenes.

OBJECTIVES: PCR-based typing of the emm gene Streptococcus pyogenes often results in the amplification of multiple bands. This has resulted in the misclassification of strains into types based on non-emm gene sequences. We aimed to improve the specificity of the emm typing PCR reaction using a primer called CDC3, the sequence for which has been previously used to identify emm genes in silico. METHODS: The proposed primer CDC3 was validated in silico from a global database of 1688 GAS genomes and in vitro with 32 isolates. PCR reactions were performed on genomic DNA from each isolate, using the published CDC1 forward primer with the CDC2 reverse primer or the new CDC3 reverse primer. The products were examined by gel electrophoresis, and representative PCR products were sequenced. RESULTS: In 1688 S. pyogenes genomes, the previous CDC2 reverse primer annealed in silico in 1671 emm genes and also in 2109 non emm genes in close proximity, whereas the new CDC3 primer annealed in 1669 emm genes only. The remaining 19 genes without a CDC3 binding site were chimeric emm genes. The PCR pair CDC1+CDC3 produced a single band at appropriate molecular weight in all 32 isolates tested, while the CDC1+CDC2 pair produced more than one band in 13 of 32 isolates (40%). CONCLUSIONS: The new CDC3 primer is more specific for emm genes than the previous CDC2 primer and represents a simple solution to reduce the potential for mistyping S. pyogenes strains.

Nuclear hormone receptor-dependent regulation of hepatic transporters and their role in the adaptive response in cholestasis.

1. Hepatobiliary transport systems are essential for the uptake and excretion of a variety of organic anions including bile acids and bilirubin. Perturbation of this vital liver function can result in pathological conditions such as cholestasis, where the formation of bile at the canaliculus is impaired resulting in the intrahepatic accumulation of toxic bile constituents. 2. Members of the nuclear hormone receptor superfamily are important mediators of the adaptive response during cholestasis controlling the expression of transporters and other proteins with the aim to limit tissue damage. Bile acids are the endogenous ligands for these nuclear hormone receptors and therefore directly participate in the control of their own transport and metabolism. 3. Adaptive events include repression of bile acid uptake and de novo bile acid synthesis as well as a concomitant induction of alternative efflux routes and bile acid detoxification. Importantly, the adaptation also extends to other organs such as intestine and kidney to facilitate elimination of bile acids from the body. 4. This review provides an overview of the transcriptional regulation of bile acid transporting proteins and metabolizing enzymes mediated by nuclear hormone receptors. Furthermore, the complex networks between nuclear hormone receptors and regulated genes are illustrated and implications of targeting these receptors for the treatment of cholestasis are discussed.

Methodologies for Quantitative Systems Pharmacology (QSP) Models: Design and Estimation.

With the increased interest in the application of quantitative systems pharmacology (QSP) models within medicine research and development, there is an increasing need to formalize model development and verification aspects. In February 2016, a workshop was held at Roche Pharma Research and Early Development to focus discussions on two critical methodological aspects of QSP model development: optimal structural granularity and parameter estimation. We here report in a perspective article a summary of presentations and discussions.

Respiratory pressure monitoring as an indirect method of intra-abdominal pressure measurement in gastroschisis closure.

AIM OF STUDY: Abdominal compartment syndrome (ACS) is a rare but potentially fatal complication of gastroschisis closure. The liberal use of a staged reduction technique has become a well-established method of avoiding this problem. Unfortunately the use of silos is associated with a high rate of sepsis, prolonged ileus, and ventilation. A method of predicting an impending ACS would help surgeons to decide more objectively which patients would benefit from a staged reduction. A new simple method is presented here which predicts intra-abdominal pressure based on airway pressure readings. METHOD: Over a four-year period, 34 neonates with gastroschisis underwent measurement of Pplateau respiratory pressures and simultaneous intra-vesical pressures. RESULT: The Pplateau pressures were approximately 10 cmH2O higher than any concurrent intra-vesical pressure readings. ACS occurred, in one patient, when pressure measurements were above 15 cmH2O (intra-vesical) or 25 cmH2O (Pplateau). CONCLUSION: By measuring Pplateau pressures, it is possible to predict the intra-abdominal pressure and hence avoid the development of an abdominal compartment syndrome on closing the abdominal wall in gastroschisis.

Enhancement of the activity of asparaginyl-tRNA synthetase by an activator from rabbit liver.

Asparaginyl-tRNA synthetase has been partially purified from acetone powders of rabbit liver. (NH-4)-2SO-4 fractionation was followed by chromatography of the enzyme on DEAE-cellulose. An activator separated from the enzyme. Further chromatography on Sephadex G-100 and G-200 showed that the latter consisted of two components. The smaller of these (mol wt is approximately equal to 35 000) possessed enzyme transfer activity but the larger one (mol wt 80 000-90 000) required the addition of activator before any enzyme transfer activity was demonstrable. The activator itself was devoid of transfer activity. After chromatography of crude extracts of asparaginyl-tRNA synthetase on Sepharose 4B the activity in the enzyme peak, which was of considerably larger molecular weight than any of the fractions found after purification could be enhanced by addition of the activator. None of the fractions of the enzyme or of activator catalysed any extensive asparagine-dependent ATP-PP-i exchange, either in the presence or the absence of added tRNA.

In vitro agonist effects of nociceptin and [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in the mouse and rat colon and the mouse vas deferens.

Nociceptin is an endogenous ligand of the opioid receptor-like (ORL1) receptor, a G-protein coupled receptor with sequence similarities to the opioid receptors. ORL1 receptors are present at both central and peripheral sites in several mammalian species but their functions are as yet poorly understood. The main aim of this investigation was to study the effects of nociceptin and the putative ORL1 receptor antagonist [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) in two peripheral tissues, the isolated proximal colon of the mouse and the distal colon of the rat. Nociceptin, [D-Ala(2), MePhe(4), Gly-ol(5)]enkephalin (DAMGO; mu-opioid receptor selective) and [D-Pen(2), D-Pen(5)]enkephalin (DPDPE; delta-opioid receptor selective) caused concentration-dependent contractions of mouse and rat isolated colon preparations (nociceptin EC(50)=1.20 and 0.28 nM in the mouse and rat, respectively). Des[Phe(1)]nociceptin (250 nM) had no contractile effect. Naloxone (300 nM) antagonised the effects of DAMGO and DPDPE but had no effect in either preparation on contractions seen in response to nociceptin. [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) also caused contractions in the colonic preparations (EC(50)=6.0 and 3.1 nM in the mouse and rat, respectively); there was no evidence of any antagonist activity. Tetrodotoxin (1 microM) abolished the contractile effects of nociceptin in the mouse colon but had no effect in the rat. In the vas deferens preparation isolated from DBA/2 mice, nociceptin caused concentration-dependent inhibitions of electrically-evoked contractions which were antagonised by [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (apparent pK(B)=6. 31). However, [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) (0.3-10 microM) also possessed agonist activity in this preparation, as it inhibited the electrically-evoked contractions in a concentration-dependent manner. These observations do not support the proposal that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) has agonist activity at central ORL1 receptors but is an antagonist in the periphery and that these differences in efficacy point to differences in the receptors. Rather, these data along with those of others suggest that [Phe(1)psi(CH(2)-NH)Gly(2)]nociceptin(1-13)NH(2) is a partial agonist and that differences in receptor reserve can account for the varied pharmacological actions of this pseudopeptide at central and peripheral sites.

Prospecting for new group A streptococcal vaccine candidates.

BACKGROUND & OBJECTIVES: Most group A streptococcal (GAS) vaccine strategies focused on the surface M protein of the GAS. However, vaccine based on M protein have some drawbacks. In the present study, we used two approaches to identify new proteins and peptides that may have utility as vaccine candidates. METHODS: A whole gel elution procedure was used to separate GAS surface antigens into 9 size fractionated pools. Mice were vaccinated with each pool and antibody titre, opsonic ability and protective capacity measured. In an alternative approach BioInformatics was used to identify putative GAS surface proteins. Peptides from within these proteins were then selected on the basis of predicted antigenicity or location. These peptides were conjugated to keyhole lymphocyanin (KLH) and immunogenicity measured in a mouse model. RESULTS: One pool of GAS surface proteins (approximately 29kDa) induced antibodies that were both opsonic and potentially protective. Immunoflourescent microscopy demonstrated that these antibodies bound to the surface of M1 GAS. Amino acid sequencing subsequently identified superoxide dismutase as the major antigen in this pool. A BioInformatic search of the M1 GAS genome and subsequent analysis identified several peptides that fulfilled criteria as potential vaccine candidates. Each peptide when conjugated to KLH was able to induce a strong antibody response. INTERPRETATION & CONCLUSION: Several new antigens were identified that may have potential as vaccine targets. A future GAS vaccine may have multiple peptide epitopes, providing protection against multiple GAS strains.

Burns in Madras, India: an analysis of 1368 patients in 1 year.

Analyses were made of 1368 patients who attended Kilpauk Medical College Hospital, Madras with burns between 1 May 1987 and 30 April 1988. Nine hundred and sixty-five patients were admitted, of whom 505 died. The peak age incidence was in young adults (11-30 years; 58.9 per cent of all burns). Three quarters of the patients came from the low family income group, 39.5 per cent were illiterate and 86.2 per cent of burns occurred in the home. Of those admitted 81 per cent of the injuries were flame burns; in 31.3 per cent the burn affected more than half of the body surface. Of the 505 deaths 94.8 per cent were the result of flame burns (at least 323 being caused by kerosene), and 20.4 per cent were suicide. Most of the deaths (91 per cent) occurred in the first 5 days. The urgent need for burn prevention in the Madras area is discussed.

Facilitating the operative exposure of the portal plate in cases of biliary atresia by dislocating the whole liver onto the abdominal wall.

Obtaining adequate exposure of the portal plate in cases with biliary atresia can tax the ingenuity of the surgeon. The successful completion of a hepatic portoenterostomy depends on it. Mobilising the liver and dislocating it into an ex vivo-like position on the anterior abdominal wall simplifies this step of the operation. It achieves maximal visualisation and access to the anatomy of the liver port. When used correctly by the surgeon this technique is not complicated by hepatic or caval blood flow occlusion. Its use in over 40 clinical cases has not resulted in any major mishap.

Anatomy of the nerve supply of the rectum, bladder, and internal genitalia in anorectal dysgenesis in the male.

Using a posterior sagittal approach to expose retroperitoneal viscera and nerves, the anatomy of the pelvic autonomic nerve plexus was studied in normal and abnormal male cadaver specimens. This plexus is found on the anterolateral surface of the lower rectum surrounded by endopelvic fascia. The autonomic nerves that supply the plexus reach it from posterior, lateral to the midline by passing over the surface of the rectum. The nerves of this plexus are distributed with the terminal branches of the internal iliac arteries, mainly with the vessels of the inferior vesical plexus. The rectum receives its autonomic nerves with its arterial blood supply, the superior rectal artery. The nerves of the pelvic plexus supply the genitourinary viscera that lie anterior to the rectum and in front of the fascia of Denonvilliers. The named fascial layers of the pelvis play a major role in determining the anatomic plane of these structures. In anorectal agenesis the plexus becomes a more midline structure. Because the pelvic fascia is often deficient in these cases these nerves lie vulnerable to inappropriate midline dissection.

Iatrogenic hepatic rupture in the newborn and its management by pack tamponade.

BACKGROUND/PURPOSE: This report compares the ultrastructure of the newborn and adult liver and emphasizes that the newborn liver is very prone to iatrogenic rupture resulting in a high morbidity and mortality. This study describes the methods used to treat this condition and suggests that pack tamponade may be the method of choice to control hemorrhage. METHODS: latrogenic liver rupture with blood loss greater than 35% estimated blood volume occurred in seven patients. Cause of rupture included perihepatic dissection (left lobe mobilization [n = 2], capsule breached surgically [n = 1]), and retraction (n = 3) or prosthetic silo manipulation (n = 1). RESULTS: Initial attempts to control the hemorrhage were unsuccessful in six of seven patients. The only secure method to obtain long-term control of the bleeding was perihepatic pack tamponade. Control was incomplete in one patient who had an associated coagulopathy. Transfusion-induced clotting defects were present in four cases. Pack removal at 24 to 96 hours was successful in five of six patients where the bleeding was stopped, the patient fully stabilized and coagulopathy was corrected. Pack removal caused renewed bleeding in one patient, and repacking was unsuccessful. Ultrastructural differences between newborn and adult livers were investigated. The newborn liver contains little fibrous stroma and has a very thin capsule. Suture hepatorraphy therefore is an inappropriate technique in most instances and contraindicated if a coagulopathy is present. Surface coagulation and pack tamponade may be the only options available. A single patient in this series survived this complication. CONCLUSIONS: This review documents the serious nature of iatrogenic liver injury. Blood loss must be strictly limited by obtaining immediate control of the hemorrhage. If surface control is unsuccessful, pack tamponade should be used. Suturing the newborn liver (especially premature) produces unpredictable results. These observations suggest that pack tamponade is an effective method of controlling bleeding from the liver surface.

Inadequate pouch emptying following Martin's pull-through procedure for intestinal aganglionosis.

Diarrhea is an expected problem following Martin's operation. Its cause is obvious. With medical management, the phase of intolerance to enteral feeding can be bridged. Adaptation is usually reached within 3-6 mo of surgery. This is confirmed by our experience with five patients treated in this manner. In two further patients, episodic bouts of diarrhea continued to mar their recovery. It was then appreciated that this was related to pouch content stasis. The nonoperative management of this complication proved unsuccessful. A death at 20 mo post-pull-through due to "enterocolitis" and an operation 13 mo post-pull-through to repair an acute pouch perforation followed. Attention is drawn to this complication. The following points aimed at preventing stasis, which in our series has been the most difficult problem to treat, are made: a low anal anastomosis--0.5 cm above dentate line; limit pouch size; and use normally innervated bowel. With the use of these changes, early postoperative diarrhea may be difficult to control. For this reason it is proposed that parenteral feeding be used routinely in the immediate postoperative period, and, as rapid fluid loss is better tolerated, surgery be deferred until the patient is 8 mo or more of age.

Antegrade continence enema and its application in Africa.

BACKGROUND: Antegrade continent enema (ACE) procedure has been accepted worldwide as the salvage procedure for intractable constipation and faecal incontinence after anorectal malformation surgery. Its application only has been reported from the developed countries. METHODS: The authors performed four such operations on incontinent children in a poor socioeconomic group in South Africa. RESULTS: Three patients had previous surgery for anorectal malformation, and one had intractable encopresis. The patients kept clean with water washouts only, starting 1 week after the operation. CONCLUSIONS: The ACE procedure can be used easily by patients in disadvantaged communities of Africa, and its use requires minimal but sympathetic supervision only. The authors recommend that all pediatric surgeons dealing with these unfortunate children should perform this procedure after a trial period of medical treatment. This is also the first report of the ACE procedure performed for an encopretic child.

The use of a lateral skin-flap perineoplasty in congenital anorectal malformations.

A lateral skin-flap perineoplasty has been used in 15 patients born with an absent anal canal. The aim behind the introduction of this modification was the prevention of mucosal prolapse. On early assessment, this has been achieved in 11 of the cases. This represents a 50% improvement on our previous results.

The flaccid trachea and tracheoesophageal congenital anomalies.

The patient with an esophageal atresia associated with a distal tracheoesophageal fistula, is often found to have an abnormally soft trachea. The use of contrast material as an aid in the diagnosis of this congenital anomaly demonstrates radiologically the compressive effect that a dilated and hypertrophied proximal esophageal pouch has on the trachea of the newborn. It is postulated that this chronic compressive force plays a part in retarding the development of the trachea during fetal life. The important decompressive effect of a distal tracheoesophageal fistula allowing nonphysiologic escape of lung fluid, supplements this effect. Attention is drawn to the fact that tracheal compression plays an important part in the respiratory distress seen in these patients, both before and after surgical correction of the tracheoesophageal anomaly.

Life-threatening respiratory distress caused by a mediastinal teratoma in a newborn.

Mediastinal teratomas rarely cause symptoms in newborns. Case reports drawing attention to this presentation have appeared in the literature. A 2-day-old baby with respiratory distress treated by intubation and mechanical ventilation underwent an urgent thoracotomy to alleviate tracheal compression that was caused by a teratoma. The clinical, radiological, and surgical features related to this case are reported.