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.

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.

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.

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.

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.

Four decades of conjoined twins at Red Cross Children's Hospital--lessons learned.

Conjoined twins represent a rare but fascinating congenital condition, the aetiology of which remains obscure. Over the past four decades, the paediatric surgeons at Red Cross Children's Hospital have been involved in the management of 46 pairs of conjoined twins, of which 33 have been symmetrical and 12 asymmetrical. Seventeen symmetrical twins have undergone separation with 22 children (65%) surviving; all of the live asymmetrical twins survived separation. We describe the important features of this unique cohort, outline our approach to management and present the results of this approach. We consider some of the ethical and moral dilemmas we have confronted, and discuss the prenatal diagnosis, obstetric implications and postnatal care of these children, including the relevant investigations and anaesthetic and surgical management. Specific aspects related to the cardiovascular system, hepatobiliary and gastrointestinal tracts, urogenital tract, central nervous system and musculoskeletal system are highlighted.

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.

Haemodynamic instability during thyroid surgery: a baroreflex-mediated neurogenic phenomenon?

We present a case of marked intra-operative blood pressure instability in a euthyroid, fit 33-year-old female undergoing elective hemithyroidectomy. This led to significant haemodynamic compromise, cardiac failure and end-organ damage. There was no evidence of a vasoactive endocrine cause, and the nature and timing of the event strongly pointed towards baroreflex-mediated neurogenic sympathetic dysfunction. This can occur during carotid surgery and neck dissection. Although haemodynamic fluctuations may happen during thyroid surgery, their severity in this case was unusual. We believe this could have been a rebound phenomenon in response to acute decompression of the carotid artery which had been compressed by an enlarging cyst. We suggest that in similar cases blockade of the carotid sinus could attenuate such responses.

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.

Guidelines for the successful treatment of lymphangioma with OK-432.

BACKGROUND/PURPOSE: Cystic hygroma or lymphangioma (LA) is a disfiguring benign lesion commonly seen in the neck and face regions in children. Extensive neck/face resectional surgery is frequently performed for this condition, often with disappointing results. An attractive alternative to surgery is injection, sclerosing therapy. OK-432 injection therapy has been characterised as a novel treatment of LA since 1987. Since this first report, there have been a number of articles from different institutions reporting variable success rates with its use. This has resulted in uncertainty and confusion among physicians, surgeons and parents alike as to in whom, when, and how to treat patients with this modality. METHOD: A prospective study over a five-year period. Thirty-five patients were injected with this agent, 1 to 4 times, depending on response. RESULT: In patients with macrocystic LA, complete regression was achieved in 96 %. Patients with microcystic LA responded poorly or not at all. CONCLUSION: The anatomical appearance of the malformation on computerised tomography (or sonar) scan is crucial in determining the treatment strategy taken; macrocystic lesions respond almost universally to OK-432 injections, whereas patients with microcystic disease generally do not respond and should therefore not be injected with this agent.

Pathophysiological mechanisms of vascular calcification in end-stage renal disease.

Vascular calcification has been clearly defined as a risk factor for cardiovascular mortality in the general population and is highly prevalent in end-stage renal disease (ESRD), where it is associated with a number of markers of increased mortality such as left ventricular hypertrophy. The pattern of calcification in ESRD is characterized by mineral deposition in the tunica media, in contrast to non-ESRD populations, where calcification of atheromatous plaque predominates. This difference may have important clinical implications. The pathophysiological mechanisms underlying both types of vascular calcification remain to be clarified; however, current evidence suggests that they are active processes rather than passive mineral precipitation, and the presence in the vasculature of cells expressing an osteoblastic phenotype may be of central importance. In ESRD, the presence of secondary and tertiary hyperparathyroidism, disordered calcium and phosphate homeostasis, and the use of vitamin D- and calcium-based treatments in its therapy may all contribute to vascular calcification. These issues and the impact on other current and future therapies have great importance for clinical nephrology, and a better understanding of vascular calcification through a focused research effort is essential.

The stigma of anxiety disorders.

People with genuine anxiety disorders can be misdiagnosed and mismanaged, because of negative public and professional attitudes to anxiety and the 'worried well'. Misdiagnosis includes not taking symptoms seriously and giving patients pejorative labels such as 'personality disorder' or 'inadequate'. This can lead to mismanagement such as reluctance to investigate symptoms fully, with regard to both physical and psychological aetiologies. Also, poor understanding of appropriate treatments can lead to mismanagement of these disorders. This paper reviews sources of stigma in dealing with anxiety disorders and ways in which this stigma might be avoided.

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.

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.