An outbreak of hepatitis A virus infection in a secondary school in England with no undetected asymptomatic transmission among students.

In June 2019 the Health Protection Team in Yorkshire and Humber, England, was notified of cases of hepatitis A virus (HAV) infection in staff at a secondary school. Investigation revealed that an earlier case worked as a food handler in the school kitchen. Indirect transmission through food from the canteen was considered the most likely route of transmission. Cases were described according to setting of exposure. Oral fluid was obtained from students for serological testing. Environmental investigations were undertaken at settings where food handling was considered a potential transmission risk. Thirty-three confirmed cases were linked to the outbreak. All of those tested (n = 31) shared the same sequence with a HAV IB genotype. The first three cases were a household cluster and included the index case for the school. A further 19 cases (16 students, 3 staff) were associated with the school and consistent with indirect exposure to the food handler. One late onset case could not be ruled out as a secondary case within the school and resulted in vaccination of the school population. Five cases were linked to a bakery where a case from the initial household cluster worked as a food server. No concerns about hygiene standards were noted at either the school or the bakery. Oral fluid samples taken at the time of vaccination from asymptomatic students (n = 219, 11-16 years-old) showed no evidence of recent or current infection. This outbreak included household and foodborne transmission but limited (and possibly zero) person-to-person transmission among secondary school students. Where adequate hygiene exists, secondary transmission within older students may not occur.

Hospitalisation and mortality risk of SARS-COV-2 variant omicron sub-lineage BA.2 compared to BA.1 in England.

The Omicron variant of SARS-CoV-2 became the globally dominant variant in early 2022. A sub-lineage of the Omicron variant (BA.2) was identified in England in January 2022. Here, we investigated hospitalisation and mortality risks of COVID-19 cases with the Omicron sub-lineage BA.2 (n = 258,875) compared to BA.1 (n = 984,337) in a large cohort study in England. We estimated the risk of hospital attendance, hospital admission or death using multivariable stratified proportional hazards regression models. After adjustment for confounders, BA.2 cases had lower or similar risks of death (HR = 0.80, 95% CI 0.71-0.90), hospital admission (HR = 0.88, 95% CI 0.83-0.94) and any hospital attendance (HR = 0.98, 95% CI 0.95-1.01). These findings that the risk of severe outcomes following infection with BA.2 SARS-CoV-2 was slightly lower or equivalent to the BA.1 sub-lineage can inform public health strategies in countries where BA.2 is spreading.

Association between knowledge, risk behaviours, and testing for sexually transmitted infections among men who have sex with men: findings from a large online survey in the United Kingdom.

OBJECTIVES: In the UK, men who have sex with men (MSM) bear a disproportionate sexually transmitted infection (STI) burden. We investigated MSM's STI knowledge; whether their STI testing behaviour met national guidelines (annually if sexually active; 3-monthly if engaging in STI risk behaviours); and the relationship between STI testing in the last 3 months, STI knowledge and STI risk behaviours by HIV status. METHODS: Sexually active (in the last year) men aged > 15 years who were UK residents and were recruited from gay-orientated online dating platforms completed an anonymous online survey about STI knowledge, STI risk behaviours, and STI testing (March-May 2017). This included 11 true statements about STIs. Respondents scored 1 for each statement they 'knew', with those scoring < 6 overall treated as having 'poor' STI knowledge. Descriptive and multivariable analyses were conducted, separately by HIV status, to test our hypothesis and calculate adjusted odds ratios (AORs) with 95% confidence intervals (CIs). RESULTS: Compared to HIV-positive men (n = 489), the proportion of HIV-negative/unknown-status men (n = 3157) with 'poor' STI knowledge was significantly higher (46.4% versus 22.9% for HIV-positive men) and the proportion with STI testing in the last 12 months was lower (71.6% versus 87.2%, respectively). In the last 3 months, 56.9% of HIV-negative/unknown-status and 74.1% of HIV-positive men reported STI risk behaviours, of whom 45.8% and 55.1%, respectively, had been tested for STIs during this time. Among HIV-negative/unknown-status men, those reporting STI risk behaviours were more likely (AOR 1.52; 95% CI 1.26-1.84) and those with poor STI knowledge less likely (AOR 0.73; 95% CI 0.61-0.89) to have been tested during the last 3 months. However, neither factor was independently associated with 3-monthly testing among HIV-positive men. CONCLUSIONS: Improving STI knowledge, especially among HIV-negative/unknown-status men, and promoting frequent STI testing among men engaging in STI risk behaviours are vital to address the poor sexual health of MSM.

T(3/2) dependence of the interlayer exchange coupling in ferromagnetic multilayers.

The temperature dependence of the interlayer exchange coupling in ferromagnetic films coupled across nonmagnetic spacers is determined via in situ ferromagnetic resonance experiments for various systems. Clear evidence for a T(3/2) law is found over a wide temperature regime.

Etiology of blindness in an urban community hospital setting.

OBJECTIVE: To determine the cause of monocular and binocular blindness in a predominantly nonwhite urban community hospital setting. DESIGN: Retrospective hospital-based cross-sectional study. PARTICIPANTS: All 3562 unique subjects examined in the New and General Ophthalmology clinic at Parkland Memorial Hospital, Dallas, Texas, from July 1 to September 30, 1998. METHODS: The EYEstation program by Datamedic was queried to conduct a detailed review of electronic medical records of the participants listed previously. MAIN OUTCOME MEASURES: Blindness was defined as visual acuity

Small tissue bites and wound strength: an experimental study.

HYPOTHESIS: Placing stitches close to the cut wound edge does not produce low wound bursting strength in midline laparotomy incisions closed with a suture length:wound length ratio of 4. DESIGN: Experimental study in rats. METHODS: Midline incisions were closed with a running suture in 51 Sprague-Dawley rats. A suture length:wound length ratio of 4 was used and stitches were placed at a distance of 3, 6, or 10 mm from the wound edge. Wound bursting strength was studied immediately after and 4 days after wound closure. RESULTS: Immediately after wound closure, bursting pressure was higher with stitches placed 10 mm from the wound edge than those at a distance of 3 mm. After 4 days, bursting pressure and bursting volume were lower with stitches placed 10 mm from the wound edge than those at a distance of 3 or 6 mm. The abdominal wall ruptured outside the suture line in 14 of 17 wounds closed with 21 stitches, in 11 of 17 wounds closed with 16 stitches, and in 6 of 17 wounds closed with 11 stitches (P=.02). CONCLUSIONS: Four days after closure of midline laparotomy incisions using a suture length-wound length ratio of 4, wound bursting strength is higher with stitches placed 3 to 6 mm from the wound edge than those at a distance of 10 mm. Wound bursting strength increases with the number of stitches used.

Functionally conserved xenobiotic responsive enhancer in cytochrome P450 3A7.

Nuclear receptors CAR and PXR play a key role in cytochrome P450 gene induction by xenobiotics. Human cytochrome P450 3A7 (CYP3A7) is expressed from early in gestation until the perinatal period, when there is a switch in expression to CYP3A4. Here we demonstrate that a PXR and CAR responsive enhancer is located approximately 8 kb upstream of the proximal CYP3A7 promoter. This distal xenobiotic responsive enhancer module (XREM) is conserved with the XREM of CYP3A4. Interestingly, not only the XREM, but also the entire promoters exhibit 90% sequence identity up to -8.8 kb, indicating a close evolutionary distance. We propose that the promoters have coevolved to functionally conserve P450 gene induction in response to xenobiotics through CAR and PXR. Thus, nuclear receptors for xenobiotics may not only play a role to provide a survival advantage during adulthood, but also to protect the embryo against endogenous and exogenous toxins.

Increased nuclear factor 1 binding to its nucleosomal site mediated by sequence-dependent DNA structure.

The organization of DNA into chromatin is important in the regulation of transcription, by influencing the access of transcription factors to their DNA binding sites. Nuclear factor 1 (NF-1) is a transcription factor which binds to DNA constitutively and which interacts with its cognate DNA site with high affinity. However, this affinity is drastically reduced, approximately 100- to 300-fold, when the binding site is organized into a nucleosome. Here we demonstrate that the introduction of stretches of adenines of length 5 nt (A-tracts) on both sides of the NF-1 binding site has a distinct effect on NF-1 binding to a nucleosomal, but not to a free, NF-1 binding site. The position of the A-tracts, relative to the rotational phase of a synthetic DNA bending sequence, the TG-motif, decides whether the NF-1 affinity increases or decreases. The NF-1 binding affinity is seven times stronger when the flanking A-tracts are positioned out-of-phase with the TG-motif than it is when the A-tracts are positioned in-phase with the TG-motif. We demonstrate that this effect correlates with differences in DNA curvature and apparent histone octamer affinity. We conclude that DNA curvature influences the local histone-DNA contacts and hence the accessibility of the NF-1 site in a nucleosome context.

Identification of a human nuclear receptor defines a new signaling pathway for CYP3A induction.

Nuclear receptors regulate metabolic pathways in response to changes in the environment by appropriate alterations in gene expression of key metabolic enzymes. Here, a computational search approach based on iteratively built hidden Markov models of nuclear receptors was used to identify a human nuclear receptor, termed hPAR, that is expressed in liver and intestines. hPAR was found to be efficiently activated by pregnanes and by clinically used drugs including rifampicin, an antibiotic known to selectively induce human but not murine CYP3A expression. The CYP3A drug-metabolizing enzymes are expressed in gut and liver in response to environmental chemicals and clinically used drugs. Interestingly, hPAR is not activated by pregnenolone 16alpha-carbonitrile, which is a potent inducer of murine CYP3A genes and an activator of the mouse receptor PXR.1. Furthermore, hPAR was found to bind to and trans-activate through a conserved regulatory sequence present in human but not murine CYP3A genes. These results provide evidence that hPAR and PXR.1 may represent orthologous genes from different species that have evolved to regulate overlapping target genes in response to pharmacologically distinct CYP3A activators, and have potential implications for the in vitro identification of drug interactions important to humans.

Wound tissue oxygen tension predicts the risk of wound infection in surgical patients.

OBJECTIVE: To test the hypothesis that subcutaneous wound oxygen tension (PsqO2) has a predictive relation to the development of wound infection in surgical patients. DESIGN: A noninterventional, prospective study. SETTING: A university department of surgery. PATIENTS: One hundred thirty operative general surgical patients at notable risk of infection as predicted by an anticipated Study on the Effect of Nosocomial Infection Control (SENIC) score of 1 or greater. OUTCOME MEASURES: PsqO2 was measured perioperatively. Its relation to the subsequent incidence of surgical wound infection was then determined and compared with the SENIC score as a criterion standard. RESULTS: Although the SENIC score and PsqO2 are inversely correlated, PsqO2 is the stronger predictor of infection. Low PsqO2 identified patients at risk and concentrated them in a cohort that was about half the size of that identified by the SENIC score. CONCLUSIONS: Subcutaneous perfusion and oxygenation are important components of immunity to wound infections. The SENIC score identifies systemic physiological variables that are important to the development of wound infection. Nevertheless, PsqO2 is the more powerful predictor of wound infection. Moreover, PsqO2 can be manipulated by available clinical means, and thus may direct interventions to prevent infection.

Glucocorticoid receptor-glucocorticoid response element binding stimulates nucleosome disruption by the SWI/SNF complex.

The organization of DNA in chromatin is involved in repressing basal transcription of a number of inducible genes. Biochemically defined multiprotein complexes such as SWI/SNF (J. Côté, J. Quinn, J. L. Workman, and C. L. Peterson, Science 265:53-60, 1994) and nucleosome remodeling factor (T. Tsukiyama and C. Wu, Cell 83:1011-1020, 1995) disrupt nucleosomes in vitro and are thus candidates for complexes which cause chromatin decondensation during gene induction. In this study we show that the glucocorticoid receptor (GR), a hormone-inducible transcription factor, stimulates the nucleosome-disrupting activity of the SWI/SNF complex partially purified either from HeLa cells or from rat liver tissue. This GR-mediated stimulation of SWI/SNF nucleosome disruption depended on the presence of a glucocorticoid response element. The in vitro-reconstituted nucleosome probes used in these experiments harbored 95 bp of synthetic DNA-bending sequence in order to rotationally position the DNA. The GR-dependent stimulation of SWI/SNF-mediated nucleosome disruption, as evaluated by DNase I footprinting, was 2.7- to 3.8-fold for the human SWI/SNF complex and 2.5- to 3.2-fold for the rat SWI/SNF complex. When nuclear factor 1 (NF1) was used instead of GR, there was no stimulation of SWI/SNF activity in the presence of a mononucleosome containing an NF1 binding site. On the other hand, the SWI/SNF nucleosome disruption activity increased the access of NF1 for its nucleosomal binding site. No such effect was seen on binding of GR to its response element. Our results suggest that GR, but not NF1, is able to target the nucleosome-disrupting activity of the SWI/SNF complex.

The affinity of nuclear factor 1 for its DNA site is drastically reduced by nucleosome organization irrespective of its rotational or translational position.

A DNA-bending sequence has been used for in vitro reconstitution of nucleosomes in order to direct a nuclear factor 1 (NF-1) binding site into different nucleosome positions. By this strategy nucleosomes were obtained that had one of two rotational positions of the NF-1 binding site, one oriented toward the periphery and the other toward the histone octamer, translationally positioned 50 and 45 base pairs, respectively, from the nucleosome dyad. The affinity of partially purified NF-1 for these nucleosomal targets was compared with its affinity for free DNA by dimethylsulfate methylation protection and DNase I footprinting assays. The binding affinity of NF-1 to all nucleosomal targets was reduced 100-300-fold compared with its affinity for free DNA. The two rotational settings of the NF-1 site showed the same binding affinity for NF-1 as did other nucleosome constructs in which the NF-1 binding site was translationally positioned from 10 to 40 base pairs from the nucleosome dyad. We conclude that the nucleosomal inhibition of NF-1 binding is an inherent characteristic of NF-1 since another transcription factor, the glucocorticoid receptor, is able to bind to its DNA site in a nucleosome.

Triple helix DNA alters nucleosomal histone-DNA interactions and acts as a nucleosome barrier.

Oligonucleotides which form triple helical complexes on double-stranded DNA have been previously reported to selectively inhibit transcription both in vitro and in vivo by physically blocking RNA polymerase or transcription factor access to the DNA template. Here we show that a 16mer oligonucleotide, which forms triple helix DNA by binding to a 16 bp homopurine segment, alters the formation of histone-DNA contacts during in vitro nucleosome reconstitution. This effect was DNA sequence-specific and required the oligonucleotide to be present during in vitro nucleosome reconstitution. Binding of the triple helix oligonucleotide on a 199 bp mouse mammary tumour virus promoter DNA fragment with a centrally located triplex DNA resulted in interruption of histone-DNA contacts flanking the triplex DNA segment. When nucleosome reconstitution is carried out on a longer, 279 bp DNA fragment with an asymmetrically located triplex site, nucleosome formation occurred at the border of the triple helical DNA. In this case the triplex DNA functioned as a nucleosome barrier. We conclude that triplex DNA cannot be accommodated within a nucleosome context and thus may be used to site-specifically manipulate nucleosome organization.

The effect of diverting colostomy on anastomotic healing after resection of left colon obstruction. An experimental study in the rat.

A standardized stenosis of the left colon was created in the rat model. After four days the stenosis was resected and a primary anastomosis made. Half of the animals (n = 21) were randomized to a proximal diverting colostomy and the other half to a non-colostomy control group. On postoperative days two and seven anastomotic complications were recorded and anastomotic strength was determined. Collagen content in the anastomotic area was measured. In the colostomy group no anastomotic complications occurred, while 6/21 (29%) animals in the non-colostomy group had complications. On day two there was no difference between the groups as regards anastomotic strength and collagen content. After a week, however, the control group showed a significant increase in both anastomotic strength and collagen content which was not observed in the colostomy group. The absence of increase in anastomotic strength in the colostomy group had no adverse effect on anastomotic healing, as judged by complications. Thus, a diverting colostomy may be of value in reducing anastomotic complications after resection of a left colon obstruction.

Impact of bacteria on metabolism of collagen in colonic obstruction in rats.

The influence of bacteria on metabolism of collagen in the colonic wall under normal conditions and after obstruction was evaluated by using germ-free and conventionally bred rats. Under normal conditions, no differences in synthesis and content of collagen or tissue dry weight in the colonic wall were found between germ-free and conventionally bred rats. After obstruction, both groups reacted similarly with an equally increased collagen synthesis. The findings imply that bacteria do not play any major role in the regulation of collagen metabolism in the colonic wall, neither under normal conditions nor in the strained situation with colonic obstruction and fecal impaction.

Effect of transscleral neodymium: YAG cyclophotocoagulation on intraocular lenses.

A neodymium: YAG laser operating in the thermal mode was used to irradiate isolated intraocular lenses (IOLs) and to perform transscleral cyclophotocoagulation on pseudophakic autopsy eyes to investigate the potential damage to IOL haptics such irradiation may cause. In the isolated IOLs, 70 mJ of energy deformed and partially melted both polymethylmethacrylate (PMMA) and polypropylene haptics. One of the capsular-fixated PC-IOL haptics in an autopsy eye partially melted when irradiated with the maximum energy level (8.8 J), with the aiming beam focused 1 mm posterior to the limbus and maximal posterior focus offset.

Anastomotic healing after resection of left-colon stenosis: effect on collagen metabolism and anastomotic strength. An experimental study in the rat.

Anastomotic breaking strength and collagen metabolism in the colonic wall were studied after resection of a standardized left-colon stenosis in the rat. An increased complication rate was found in the stenosis group compared with the control group (27 percent vs. 2 percent) and the complications arise soon after surgery. The collagen turnover in the anastomotic area, as well as the changes of breaking strength, were equal between the groups in the early healing course, implying that the stenosis group, as an entity, did not show impairment in the studied parameters predisposing for complications. Other factors such as mechanical strain by the increased fecal bulk and increased bacterial load may contribute to occurrence of the anastomotic complications.

Influence of long-term relative bowel rest on the healing of a left colon anastomosis.

The influence of long-term relative bowel rest, using a low residue diet, on healing of a left colon anastomosis was experimentally studied. Retarded and diminished gain of postoperative anastomotic collagen and strength was found. The healing of the anastomosis was uncomplicated, however, and it is concluded that anastomotic integrity after surgery in this condition is safe.

Impact of long-term relative bowel rest on conditions for colonic surgery.

Collagen content, bursting wall tension, and suture-holding capacity in the proximal and distal colon of the rat were studied after long-term treatment with a low-residue or a standard laboratory chow diet. Collagen content decreased uniformly in both the proximal and distal colon of the low-residue diet group. In addition, the bursting wall tension of the nonoperated proximal colon was reduced, whereas the breaking strength of a newly constructed anastomosis at three different colonic sites was unaffected.

The effect of stenosis on collagen metabolism in the colonic wall. Studies in the rat.

The influence of colonic stenosis resulting in faecal loading was investigated in regard to collagen metabolism in the intact colonic wall. The collagen content was increased in the left colon proximal to the stenosis, due to enhanced collagen synthesis. The collagen concentration fell significantly, however, as noncollagenous substances increased more than collagen. Collagen concentration clearly can be misleading as an indication of the actual amount of collagen. The enhanced rate of collagen turnover with collagen accumulation proximal to stenosis requires further analysis in regard to its importance for healing capacity.