Outbreak of SARS-CoV-2 in a teenage discotheque in Northern Ireland-November 2021.

OBJECTIVES: To report key findings associated with an outbreak of SARS-CoV-2 following a teenage disco in Northern Ireland. STUDY DESIGN: Observational case series. METHODS: A case was defined as an individual who attended the event with a positive SARS-CoV-2 result between 6th and 20th November 2021. Demographic and clinical information, including symptom status, date of onset and school attended, were recorded during contact tracing. Vaccination status was derived from the COVID-19 Vaccine Management System. Forty-five samples associated with the outbreak were sequenced as part of the NI Whole Genome Sequencing (WGS) programme. RESULTS: Only 2.4% (5/205) of cases received a COVID-19 vaccine more than 14 days before the event. 84.9% (174/205) had received no vaccine at the time of the event and 12.7% (26/205) had been vaccinated within 14 days, offering only limited disease protection. The AY4.2.2 lineage of two cases who attended the event after symptom onset was found in 69% of sequenced outbreak cases. CONCLUSIONS: This study demonstrates extensive COVID-19 transmission in largely unvaccinated teenagers in an indoor venue with limited social distancing, close social contact and mixing, limited ventilation and singing and shouting. Public Health authorities developing COVID-19 entertainment regulations should consider congregations of teenagers in these settings, especially if vaccination rates are low in this group or they are not eligible for vaccination at that time. Public communications should be developed to ensure young people with COVID-19 symptoms follow public guidance regarding self-isolation and in particular avoid indoor events with larger numbers.

Efficacy and safety of autologous adipose-derived stromal vascular fraction enriched with platelet-rich plasma in flap repair of transsphincteric cryptoglandular fistulas.

BACKGROUND: Transanal advancement flap repair of transsphincteric fistulas is a sphincter-preserving procedure, which frequently fails, probably due to ongoing inflammation in the remaining fistula tract. Adipose-derived stromal vascular fraction (SVF) has immunomodulatory properties promoting wound healing and suppressing inflammation. Platelet-rich plasma (PRP) reinforces this biological effect. The aim of this study was to evaluate the efficacy and safety of autologous adipose-derived SVF enriched with PRP in flap repair of transsphincteric cryptoglandular fistulas. METHODS: A prospective cohort study was conducted including consecutive patients with transsphincteric cryptoglandular fistula in a tertiary referral center. During flap repair, SVF was obtained by lipoharvesting and mechanical fractionation of adipose tissue and combined with PRP was injected around the internal opening and into the fistulous wall. Endpoints were fistula healing at clinical examination and fistula closure on postoperative magnetic resonance imaging (MRI). Adverse events were documented. RESULTS: Forty-five patients with transsphincteric cryptoglandular fistula were included (29 males, median age 44 years [range 36-53 years]). In the total study population, primary fistula healing was observed in 38 patients (84%). Among the 42 patients with intestinal continuity at time of surgery, primary fistula healing was observed in 35 patients (84%). In one patient, the fistula recurred, resulting in a long-term healing rate of 82%. MRI, performed in 37 patients, revealed complete closure of the fistula tract in 33 (89.2%). In the other patients, the tract was almost completely obliterated by scar tissue. During follow-up, none of these patients showed clinical signs of recurrence. The postoperative course was uneventful, except for three cases; venous thromboembolism in one patient and bleeding under the flap, necessitating intervention in two patients. CONCLUSIONS: Addition of autologous SVF enriched with PRP during flap repair is feasible, safe and might improve outcomes in patients with a transsphincteric cryptoglandular fistula. TRIAL REGISTRATION: Dutch Trial Register, Trial Number: NL8416, https://www.trialregister.nl/.

Lateral Hooding of the Brow Revisited: Reverse Brow Lifting Versus the ROOF Lift.

We read with great interest the article titled "Anatomical Study and Clinical Observation of Retro-orbicularis Oculi Fat (ROOF)" by Xian Wang and Haiping Wang. Our aim with this comment is to contribute to a more precise nomenclature of any correction of lateral hooding of the brow. We believe both a ROOF lift and reverse browpexy or transblepharoplasty browpexy are not just two different techniques for the same purpose, they are also techniques based on two different concepts. As treatments should be cause-based, each of these procedures could be performed independently, or in combination, depending on the specific anatomical requirements for an optimal result.Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.

Allen: A High-Level Trigger on GPUs for LHCb.

We describe a fully GPU-based implementation of the first level trigger for the upgrade of the LHCb detector, due to start data taking in 2021. We demonstrate that our implementation, named Allen, can process the 40 Tbit/s data rate of the upgraded LHCb detector and perform a wide variety of pattern recognition tasks. These include finding the trajectories of charged particles, finding proton-proton collision points, identifying particles as hadrons or muons, and finding the displaced decay vertices of long-lived particles. We further demonstrate that Allen can be implemented in around 500 scientific or consumer GPU cards, that it is not I/O bound, and can be operated at the full LHC collision rate of 30 MHz. Allen is the first complete high-throughput GPU trigger proposed for a HEP experiment.

Regional gene expression analysis of multiple tissues in an experimental animal model of post-traumatic osteoarthritis.

OBJECTIVE: To characterize local disease progression of the medial meniscus transection (MMT) model of post-traumatic osteoarthritis (OA) at the molecular level, in order to establish a baseline for therapeutic testing at the preclinical stage. DESIGN: Weight-matched male Lewis rats underwent MMT or sham surgery on the left limb with the right leg as contralateral control. At 1 and 3 weeks post-surgery, tissues were harvested from different areas of the articular cartilage (medial and lateral tibial plateaus, and medial osteophyte region) and synovium (medial and lateral), and analyzed separately. RNA was extracted and used for microarray (RT-PCR) analysis. RESULTS: Gene expression changes due to surgery were isolated to the medial side of the joint. Gene changes in chondrocyte phenotype of the medial tibial plateau cartilage preceded changes in tissue composition genes. Differences in inflammatory markers were only observed at the osteophyte region at 3 weeks post-surgery. There was surgical noise in the synovium at week 1, which dissipated at week 3. At this later timepoint, meniscal instability resulted in elevated expression of matrix degradation proteins and osteogenic markers in the synovium and cartilage. CONCLUSION: These results suggest feedback interactions between joint tissues during disease progression. Regional tissue expression differences found in MMT joints indicated similar pathophysiology to human OA, and provided novel insights about this degeneration model. The examination of gene expression at a localized level in multiple tissues provides a well-characterized baseline to evaluate mechanistic effects of potential therapeutic agents on OA disease progression in the MMT model.

The Addition of Platelet-Rich Plasma to Facial Lipofilling: A Double-Blind, Placebo-Controlled, Randomized Trial.

BACKGROUND: Lipofilling is a treatment modality to restore tissue volume, but it may also rejuvenate the aging skin. Platelet-rich plasma has been reported to augment the efficacy of lipofilling, both on graft take and rejuvenation, by altering the adipose-derived stem cells. The authors hypothesized that addition of platelet-rich plasma would increase the rejuvenating effect and shorten recovery time. METHODS: The study conducted was a single-center, double-blind, placebo-controlled, randomized trial (2012 to 2015). In total, a well-defined cohort of 32 healthy female patients enrolled in the study, with 25 completing the follow-up. All patients underwent aesthetic facial lipofilling with either saline or platelet-rich plasma added. Outcome was determined by changes in skin elasticity, volumetric changes of the nasolabial fold, recovery time, and patient satisfaction during follow-up (1 year). RESULTS: Platelet-rich plasma did not improve the outcome of facial lipofilling when looking at skin elasticity improvement, graft volume maintenance in the nasolabial fold. Reversal of the correlation between age and elasticity, however, might suggest a small effect size, and thus might not be significant with our small study population. CONCLUSIONS: This randomized, double-blind, placebo-controlled study clearly has shown that platelet-rich plasma significantly reduces postoperative recovery time but does not improve patient outcome when looking at skin elasticity, improvement of the nasolabial fold, or patient satisfaction. The reversal of the correlation between age and elasticity might indicate some effect on skin but requires more power in future studies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Current Status of Companion and Complementary Diagnostics: Strategic Considerations for Development and Launch.

US Food and Drug Administration (FDA)-approved diagnostic assays play an increasingly common role in managing patients to prolong lifespan while also enhancing quality of life. Diagnostic assays can be essential for the safe and effective use of therapeutics (companion diagnostic), or may inform on improving the benefit/risk ratio without restricting drug access (complementary diagnostic). This tutorial reviews strategic considerations for drug and assay development resulting in FDA-approved companion or complementary diagnostic status.

Childhood adverse life events and parental psychopathology as risk factors for bipolar disorder.

Childhood adverse events are risk factors for later bipolar disorder. We quantified the risks for a later diagnosis of bipolar disorder after exposure to adverse life events in children with and without parental psychopathology. This register-based population cohort study included all persons born in Denmark from 1980 to 1998 (980 554 persons). Adversities before age 15 years were: familial disruption; parental somatic illness; any parental psychopathology; parental labour market exclusion; parental imprisonment; placement in out-of-home care; and parental natural and unnatural death. We calculated risk estimates of each of these eight life events as single exposure and risk estimates for exposure to multiple life events. Main outcome variable was a diagnosis of bipolar disorder after the age of 15 years, analysed with Cox proportional hazard regression. Single exposure to most of the investigated adversities were associated with increased risk for bipolar disorder, exceptions were parental somatic illness and parental natural death. By far the strongest risk factor for bipolar disorder in our study was any mental disorder in the parent (hazard ratio 3.53; 95% confidence interval 2.73-4.53) and the additional effects of life events on bipolar risk were limited. An effect of early adverse life events on bipolar risk later in life was mainly observed in children without parental psychopathology. Our findings do not exclude early-life events as possible risk factors, but challenge the concept of adversities as important independent determinants of bipolar disorder in genetically vulnerable individuals.

Platelet-Rich Plasma Influences Expansion and Paracrine Function of Adipose-Derived Stromal Cells in a Dose-Dependent Fashion.

BACKGROUND: Lipofilling is a treatment modality to restore tissue volume. Both platelet-rich plasma and adipose-derived stromal cells have been reported to augment the efficacy of lipofilling, yet results are not conclusive. The authors hypothesized that the variation reported in literature is caused by a dose-dependent influence of platelet-rich plasma on adipose-derived stromal cells. METHODS: Whole blood (n = 3) was used to generate platelet-rich plasma, which was diluted with Dulbecco's Modified Eagle Medium to 15%, 5%, and 1.7%, with 15% platelet-poor plasma and 10% fetal calf serum as controls. Pooled adipose-derived stromal cells (n = 3) were cultured in these media. Gene expression was assessed, along with angiogenic sprouting of endothelial cells by conditioned medium and platelet-rich plasma. RESULTS: platelet-rich plasma in culture medium affected the expression of genes in a dose-dependent manner. The 15% concentration stimulated proliferation almost eightfold. Mesenchymal markers were unaffected. Interestingly, expression of collagens type 1 and 3 increased at lower concentrations, whereas transforming growth factor-ß showed reduced expression in lower concentrations. Proangiogenic gene expression was unaltered or strongly reduced in a dose-dependent manner. platelet-rich plasma promoted endothelial sprouting and survival in a dose-dependent manner; however, conditioned medium from adipose-derived stromal cells exposed to platelet-rich plasma blocked endothelial sprouting capabilities. CONCLUSION: The dose-dependent influence of platelet-rich plasma on the therapeutic capacity of adipose-derived stromal cells conditioned medium in vitro warrants caution in clinical trials.

Influence of scaffold properties on the inter-relationship between human bone marrow derived stromal cells and endothelial cells in pro-osteogenic conditions.

One of the significant challenges in bone tissue engineering is the integration of biomaterials designed to facilitate and stimulate mineralization with a simultaneously rapid rate of angiogenesis and vascularization of the tissue construct, a challenge complicated by our lack of knowledge of the interactions among key cell types and scaffold properties. This study compared functional activity of human bone marrow-derived stromal cells (hMSC) seeded onto a porous salt-leached poly(D,L-lactic acid) (PDLLA) scaffolds, with and without the incorporation of silk fibroin fibers and then further investigated their co-culture with human umbilical vein endothelial cells (HUVECs). Cell viability, proliferation, and alkaline phosphatase activity were measured for a range of time points in culture, with osteogenic and angiogenic marker immunolocalization and gene expression at selected stages. Our findings suggest that, despite similar porosity and pore size distribution exhibited by the PDLLA and PDLLA plus silk fibroin scaffolds, there were marked differences in cell distribution and function. In the absence of fibers, a highly osteogenic response was observed in hMSCs in the scaffolds co-cultured with endothelial cells, greater than that observed with hMSCs alone or in either of the scaffolds with fibers added. However, fiber presence clearly better supported endothelial cell cultures, as determined by greater levels of endothelial marker expression at both the gene and protein level after 3 weeks of culture. The design of composite scaffolds integrating beneficial components of differing structures and materials to facilitate appropriate biological responses appears a promising yet challenging avenue of research. STATEMENT OF SIGNIFICANCE: A significant challenge in bone tissue engineering is to promote a rapid vascularization of the tissue construct in parallel to the extracellular matrix mineralization. The design of composite scaffolds integrating beneficial components of differing structures and materials to facilitate appropriate biological responses appears a promising yet challenging avenue of research. Here we investigated cultures of hMSCs and HUVECs on a silk fibroin enhanced PDLLA scaffold, showing that the final output of this in vitro system is not the linear sum of the effects of the single variables. These results are of interest as they demonstrate how the addition of endothelial cells can affect hMSC phenotype and that the output can be further modulated by the introduction of silk fibroin fibers.

Post-illness-onset risk of offending across the full spectrum of psychiatric disorders.

BACKGROUND: The link between psychotic disorders and violent offending is well established; knowledge about risk of post-illness-onset offending across the full spectrum of psychiatric disorders is lacking. We aimed to compare rates of any offending and violent offending committed after the onset of illness, according to diagnostic group, with population controls. METHOD: A 25% random sample of the Danish population (n = 521 340) was followed from their 15th birthday until offending occurred. Mental health status was considered as a time-varying exposure in a Poisson regression model used to examine the duration from service contact to the offence. RESULTS: Males with any psychiatric contact had an incidence rate ratio (IRR) of 2.91 [95% confidence interval (CI) 2.80-3.02] for any offending; 4.18 (95% CI 3.99-4.38) for violent offending. Associations were stronger for women (IRR 4.17, 95% CI 3.95-4.40 for any offending; 8.02, 95% CI 7.20-8.94 for violent offending). Risk was similar across diagnostic groups for any offending in males, while variation between diagnostic groups was seen for male violent and female offending, both any and violent. CONCLUSIONS: Risk of offending, particularly violent offending, was elevated across a range of mental disorders following first contact with mental health services. The extent of variation in strength of effect across diagnoses differed by gender.

Prenatal stress and inhibitory neuron systems: implications for neuropsychiatric disorders.

Prenatal stress is a risk factor for several psychiatric disorders in which inhibitory neuron pathology is implicated. A growing body of research demonstrates that inhibitory circuitry in the brain is directly and persistently affected by prenatal stress. This review synthesizes research that explores how this early developmental risk factor impacts inhibitory neurons and how these findings intersect with research on risk factors and inhibitory neuron pathophysiology in schizophrenia, anxiety, autism and Tourette syndrome. The specific impact of prenatal stress on inhibitory neurons, particularly developmental mechanisms, may elucidate further the pathophysiology of these disorders.

The delayed addition of human mesenchymal stem cells to pre-formed endothelial cell networks results in functional vascularization of a collagen-glycosaminoglycan scaffold in vivo.

This paper demonstrates a method to engineer, in vitro, a nascent microvasculature within a collagen-glycosaminoglycan scaffold with a view to overcoming the major issue of graft failure due to avascular necrosis of tissue-engineered constructs. Human umbilical vein endothelial cells (ECs) were cultured alone and in various co-culture combinations with human mesenchymal stem cells (MSCs) to determine their vasculogenic abilities in vitro. Results demonstrated that the delayed addition of MSCs to pre-formed EC networks, whereby MSCs act as pericytes to the nascent vessels, resulted in the best developed vasculature. The results also demonstrate that the crosstalk between ECs and MSCs during microvessel formation occurs in a highly regulated, spatio-temporal fashion, whereby the initial seeding of ECs results in platelet derived growth factor (PDGF) release; the subsequent addition of MSCs 3 days later leads to a cessation in PDGF production, coinciding with increased vascular endothelial cell growth factor expression and enhanced vessel formation. Functional assessment of these pre-engineered constructs in a subcutaneous rat implant model demonstrated anastomosis between the in vitro engineered vessels and the host vasculature, with significantly increased vascularization occurring in the co-culture group. This study has thus provided new information on the process of in vitro vasculogenesis within a three-dimensional porous scaffold for tissue engineering and demonstrates the potential for using these vascularized scaffolds in the repair of critical sized bone defects.

Pharmacoscintigraphy confirms consistent tamsulosin release from a novel triple-layered tablet.

Conventional modified release preparations of tamsulosin HCl have been linked to increased incidence of cardiovascular adverse events, possibly due to rapid drug peaks soon after ingestion. A 'flattened' absorption profile has been shown to reduce the occurrence of these unwanted effects while improving symptom control. The potential of a novel triple-layered tablet to effect prolonged release and continuous absorption of tamsulosin HCl in the gastrointestinal tract was investigated in this clinical study. Gastrointestinal (GI) transit behaviour was monitored by scintigraphic imaging of technetium-labelled tablets. Drug absorption levels were simultaneously determined through pharmacokinetic analysis of blood samples. A mean Cmax of 6 ± 3 ng/nL was achieved after 324 ± 184 min (mean tmax). The mean AUC0-24 was noted as 4,359 ± 1,880 ng/mL min. The mean gastric emptying and colon arrival times of the tablets were 105.2 ± 68.9 and 270.1 ± 32.0 min post-dose; giving a mean small intestine transit time of 164.9 ± 83.6 min. Variations in gastrointestinal transit did not appear to influence drug absorption. Correlation of scintigraphic and PK data indicated that tamsulosin HCl is released steadily throughout the entire GI tract, suggesting that the mechanism of drug release is independent of GI site allowing drug release even in the low moisture environment of the colon.

Localized 3D analysis of cartilage composition and morphology in small animal models of joint degeneration.

OBJECTIVE: Current histological scoring methods to evaluate efficacy of potential therapeutics for slowing or preventing joint degeneration are time-consuming and semi-quantitative in nature. Hence, there is a need to develop and standardize quantitative outcome measures to define sensitive metrics for studying potential therapeutics. The objectives of this study were to use equilibrium partitioning of an ionic contrast agent via Equilibrium Partitioning of an Ionic Contrast-Microcomputed tomography (EPIC-µCT) to quantitatively characterize morphological and compositional changes in the tibial articular cartilage in two distinct models of joint degeneration and define localized regions of interest to detect degenerative cartilage changes. MATERIALS AND METHODS: The monosodium iodoacetate (MIA) and medial meniscal transection (MMT) rat models were used in this study. Three weeks post-surgery, tibiae were analyzed using EPIC-µCT and histology. EPIC-µCT allowed measurement of 3D morphological changes in cartilage thickness, volume and composition. RESULTS: Extensive cartilage degeneration was observed throughout the joint in the MIA model after 3 weeks. In contrast, the MMT model showed more localized degeneration with regional thickening of the medial tibial plateau and a decrease in attenuation consistent with proteoglycan (PG) depletion. Focal lesions were also observed and 3D volume calculated as an additional outcome metric. CONCLUSIONS: EPIC-µCT was used to quantitatively assess joint degeneration in two distinct preclinical models. The MMT model showed similar features to human Osteoarthritis (OA), including localized lesion formation and PG loss, while the MIA model displayed extensive cartilage degeneration throughout the joint. EPIC-µCT imaging provides a rapid and quantitative screening tool for preclinical evaluation of OA therapeutics.

National study of suicide method in violent criminal offenders.

BACKGROUND: Gaining a greater knowledge of the mechanisms and means by which violent offenders die by suicide can inform tailored preventive strategies. METHODS: Using interlinked national Danish registry data we constructed a nested case-control study dataset of all adult suicides during 1994-2006: N=9708 cases and N=188,134 age and gender matched living controls. Completely ascertained International Classification of Diseases 10th revision cause-specific mortality codes were examined, with all criminal charges since 1980, and covariate information on psychiatric treatment and socio-demographics. Self-poisonings were classified as 'nonviolent' suicide and all other methods as being 'violent' ones. RESULTS: Compared with the general population, risk among male and female violent offenders was strongly and significantly elevated for suicide by either a violent or a nonviolent method, although the relative risk was greater for nonviolent suicide. These patterns were also observed among nonviolent offenders, albeit with smaller effect sizes. Risk was especially raised for self-poisoning with narcotics & hallucinogens. We could only examine the full range of suicide methods in male violent offenders. In these men, hanging was the most frequently used method, although risk was markedly and significantly elevated virtually across the entire range of regularly used suicide methods. LIMITATIONS: We lacked sufficient statistical power for undertaking a detailed profiling of specific suicide methods among female violent offenders. CONCLUSIONS: Our findings indicate that comprehensive and broadly-based preventive approaches are needed for tackling the markedly raised risk of suicide by both violent and nonviolent means in this population. Their high relative risk for self-poisoning by illicit or illegal drugs underlines the importance of access to means and of prevailing subculture.

HLA class II gene associations in African American type 1 diabetes reveal a protective HLA-DRB1*03 haplotype.

AIMS: Owing to strong linkage disequilibrium between markers, pinpointing disease associations within genetic regions is difficult in European ancestral populations, most notably the very strong association of the HLA-DRB1*03-DQA1*05:01-DQB1*02:01 haplotype with Type 1 diabetes risk, which is assumed to be because of a combination of HLA-DRB1 and HLA-DQB1. In contrast, populations of African ancestry have greater haplotype diversity, offering the possibility of narrowing down regions and strengthening support for a particular gene in a region being causal. We aimed to study the human leukocyte antigen (HLA) region in African American Type 1 diabetes. METHODS: Two hundred and twenty-seven African American patients with Type 1 diabetes and 471 African American control subjects were tested for association at the HLA class II genes, HLA-DRB1, HLA-DQA1, HLA-DQB1 and 5147 single nucleotide polymorphisms across the major histocompatibility complex region using logistic regression models. Population admixture was accounted for with principal components analysis. RESULTS: Single nucleotide polymorphism marker associations were explained by the HLA associations, with the major peak over the class II loci. The HLA association overall was extremely strong, as expected for Type 1 diabetes, even in African Americans in whom diabetes diagnosis is heterogeneous. In addition, there were unique features: the HLA-DRB1*03 haplotype was split into HLA-DRB1*03:01, which confers greatest susceptibility in these samples (odds ratio 3.17, 95% CI 1.72-5.83) and HLA-DRB1*03:02, an allele rarely observed in Europeans, which confers the greatest protection in these African American samples (odds ratio 0.22, 95% CI 0.09-0.55). CONCLUSIONS: The unique diversity of the African HLA region we have uncovered supports a specific and major role for HLA-DRB1 in HLA-DRB1*03 haplotype-associated Type 1 diabetes risk.