Trends in sexually transmitted infection screening during COVID-19 and missed cases among adolescents.

OBJECTIVE: The COVID-19 pandemic disrupted sexual health services for young people, with potential consequences of decreasing preventive screening and increasing undiagnosed sexually transmitted infections (STIs). This study aimed to assess trends in asymptomatic screening among patients receiving STI testing and to estimate the number of STI cases that were missed during the early months of the pandemic. STUDY DESIGN: A cross-sectional study of electronic health records for chlamydia, gonorrhea, and trichomonas testing encounters from six pediatric primary care clinics in Philadelphia, July 2014 to November 2020. METHODS: A total of 35,548 testing encounters were analyzed, including 2958 during the pandemic. We assessed whether testing at each encounter was performed as asymptomatic screening, risk-based testing, or symptomatic testing. We evaluated screening trends over time and estimated the number of missed STI cases during the pandemic. RESULTS: The mean monthly testing encounters decreased from 479 per month prepandemic to 329 per month during the pandemic. The percent of tests performed as asymptomatic screening dropped from 72.5% prepandemic to a nadir of 54.5% in April 2020. We estimate that this decrease in asymptomatic screening would represent 159 missed cases (23.8% of expected cases) based on patient volume from the previous year. CONCLUSIONS: During the pandemic, the total volume of STI testing encounters and the proportion of tests performed as asymptomatic screening decreased, potentially resulting in missed diagnoses. Undiagnosed STIs can result in severe sequelae and contribute to community transmission of STIs. Efforts are needed to re-establish and sustain access to STI services for adolescents in response to disruptions caused by the pandemic.

Spontaneous emission from radiative chiral nematic liquid crystals at the photonic band-gap edge: an investigation into the role of the density of photon states near resonance.

In this article, we investigate the spontaneous emission properties of radiating molecules embedded in a chiral nematic liquid crystal, under the assumption that the electronic transition frequency is close to the photonic edge mode of the structure, i.e., at resonance. We take into account the transition broadening and the decay of electromagnetic field modes supported by the so-called "mirrorless"cavity. We employ the Jaynes-Cummings Hamiltonian to describe the electron interaction with the electromagnetic field, focusing on the mode with the diffracting polarization in the chiral nematic layer. As known in these structures, the density of photon states, calculated via the Wigner method, has distinct peaks on either side of the photonic band gap, which manifests itself as a considerable modification of the emission spectrum. We demonstrate that, near resonance, there are notable differences between the behavior of the density of states and the spontaneous emission profile of these structures. In addition, we examine in some detail the case of the logarithmic peak exhibited in the density of states in two-dimensional photonic structures and obtain analytic relations for the Lamb shift and the broadening of the atomic transition in the emission spectrum. The dynamical behavior of the atom-field system is described by a system of two first-order differential equations, solved using the Green's-function method and the Fourier transform. The emission spectra are then calculated and compared with experimental data.

The educational value of using cumulative sum charts.

Various workplace-based assessment tools are available, but none have been shown to improve performance in procedural skills. This study aimed to assess the impact of using one such tool, cumulative sum charts, on procedural skill ability. A single-blind randomised controlled trial was conducted on 82 final year medical students. Control group students received the usual teaching; in addition to this, intervention group students were provided with cumulative sum charts to log their cannulation attempts over a 7-month period. At the end of the year, students from both groups undertook a validated test of automaticity of cannulation skill. Students in the intervention group obtained median (IQR [range]) scores of 68.2 (60.5-74.3 [42.7-81.1]) vs 62.2 (52.2-68.8 [40.7-80.5]) for the control group (p = 0.013). The effect size was moderate (Cohen's d = 0.608). This study therefore provides support for the hypothesis that use of cumulative sum charts improves performance when learning procedural skills.

Spectrum, and clinical and functional implications of UNC13D mutations in familial haemophagocytic lymphohistiocytosis.

OBJECTIVE: Familial haemophagocytic lymphohistiocytosis (FHL) is a fatal disorder of immune dysregulation with defective cytotoxic lymphocyte function. Disease-causing mutations have been identified in the genes encoding perforin (PRF1), syntaxin-11 (STX11), and Munc13-4 (UNC13D). We screened for UNC13D mutations and studied clinical and functional implications of such mutations in a well defined patient cohort. METHODS: Sequencing of UNC13D was performed in 38 FHL patients from 34 FHL families in which PRF1 and STX11 mutations had been excluded. RESULTS: We identified six different mutations affecting altogether 9/38 individuals (24%) in 6/34 (18%) unrelated PRF1/STX11-negative families. Four novel mutations were revealed; two homozygous nonsense mutations (R83X and W382X), one splice mutation (exon 28), and one missense mutation (R928P). In addition, two known mutations were identified (R214X and a deletion resulting in a frame-shift starting at codon 782). There was considerable variation in the age at diagnosis, ranging from time of birth to 14 years (median 69 days). Three of nine patients (33%) developed central nervous system (CNS) symptoms. Natural killer (NK) cell activity was impaired in all four patients studied. Defective cytotoxic lymphocyte degranulation was evident in the two patients investigated, more pronounced in the patient with onset during infancy than in the patient with adolescent onset. CONCLUSIONS: Biallelic UNC13D mutations were found in 18% of the PRF1/STX11-negative FHL families. Impairment of NK cell degranulation was less pronounced in a patient with adolescent onset. FHL should be considered not only in infants but also in adolescents, and possibly young adults, presenting with fever, splenomegaly, cytopenia, hyperferritinaemia, and/or CNS symptoms.

Use of nonprescription topical steroids: patients' experiences.

BACKGROUND: Topical steroids became available, without prescription, in the U.K. in 1987, with hydrocortisone 1% cream first being licensed for irritant contact dermatitis and reactions to insect bites. Since then the number of indications for nonprescription hydrocortisone use has increased and clobetasone has also become available as an over-the-counter (OTC) medicine. Little has been reported about how OTC steroids are used by community pharmacy clients. OBJECTIVES: We determined how OTC topical steroids are applied by patients, their demographic profile, the products used and the conditions treated, how frequently products were applied and how regularly purchased. The extent to which off-label use takes place was explored. METHODS: A patient-completed questionnaire study was used in 100 branches of a national pharmacy in Great Britain. RESULTS: Questionnaires were completed and returned by 315 clients (16%). Eczema (192 cases, 61%) and dermatitis (66 cases, 21%) were the conditions most frequently treated. Nottingham Eczema Severity Scores calculated for 228 eczema and dermatitis sufferers shows that 164 patients (72%) had mild eczema. Those with more severe eczema were more likely to use clobetasone than hydrocortisone. The use of topical steroids outside OTC marketing authorization guidelines was widespread; however, no patient reported any adverse effects or deterioration in condition following steroid use. CONCLUSIONS: OTC topical steroids are used mainly to treat eczema and dermatitis. Almost 50% of users treating these conditions exceed the limits of the rather restrictive OTC marketing authorization. Clinicians should be aware of the potential for adverse effects as a result of patients self-medicating with hydrocortisone or clobetasone for an extended period.

Agent-based computational modeling of wounded epithelial cell monolayers.

Computational modeling of biological systems, or in silico biology, is an emerging tool for understanding structure and order in biological tissues. Computational models of the behavior of epithelial cells in monolayer cell culture have been developed and used to predict the healing characteristics of scratch wounds made to urothelial cell cultures maintained in low- and physiological [Ca2+] environments. Both computational models and in vitro experiments demonstrated that in low exogenous [Ca2+], the closure of 500-microm scratch wounds was achieved primarily by cell migration into the denuded area. The wound healing rate in low (0.09 mM) [Ca2+] was approximately twice as rapid as in physiological (2 mM) [Ca2+]. Computational modeling predicted that in cell cultures that are actively proliferating, no increase in the fraction of cells in the S-phase would be expected, and this conclusion was supported experimentally in vitro by bromodeoxyuridine incorporation assay. We have demonstrated that a simple rule-based model of cell behavior, incorporating rules relating to contact inhibition of proliferation and migration, is sufficient to qualitatively predict the calcium-dependent pattern of wound closure observed in vitro. Differences between the in vitro and in silico models suggest a role for wound-induced signaling events in urothelial cell cultures.

The epitheliome: agent-based modelling of the social behaviour of cells.

We have developed a new computational modelling paradigm for predicting the emergent behaviour resulting from the interaction of cells in epithelial tissue. As proof-of-concept, an agent-based model, in which there is a one-to-one correspondence between biological cells and software agents, has been coupled to a simple physical model. Behaviour of the computational model is compared with the growth characteristics of epithelial cells in monolayer culture, using growth media with low and physiological calcium concentrations. Results show a qualitative fit between the growth characteristics produced by the simulation and the in vitro cell models.

Selection of mutant CHO cells with constitutive activation of the HIF system and inactivation of the von Hippel-Lindau tumor suppressor.

Hypoxia-inducible factor (HIF) mediates a widespread transcriptional response to hypoxia through binding to cis-acting DNA sequences termed hypoxia response elements (HREs). Activity of the transcriptional complex is suppressed in the presence of oxygen by processes that include the targeting of HIF-alpha subunits for ubiquitin-mediated proteolysis. To provide further insights into these processes we constructed Chinese hamster ovary (CHO) cells bearing stably integrated plasmids that expressed HRE-linked surface antigens and used these cells in genetic screens for mutants that demonstrated constitutive up-regulation of HRE activity. From mutagenized cultures, clones were isolated that demonstrated up-regulation of HRE activity and increased HIF-1alpha protein levels in normoxic culture. Transfection and cell fusion studies suggested that these cells possess recessive defects that affect one or more pathways involved in HIF-alpha proteolysis. Two lines were demonstrated to harbor truncating mutations in the von Hippel-Lindau (VHL) tumor suppressor gene. In these cells, defects in ubiquitylation of exogenous human HIF-1alpha in vitro could be complemented by wild type pVHL, and re-expression of a wild type VHL gene restored a normal pattern of HIF/HRE activity, demonstrating the critical dependence of HIF regulation on pVHL in CHO cells. In contrast, other mutant cells had no demonstrable mutation in the VHL gene, and ubiquitylated exogenous HIF-1alpha normally, suggesting that they contain defects at other points in the oxygen-regulated processing of HIF-alpha subunits.

Surface electromyography using electrode arrays: a study of motor neuron disease.

The use of electromyography (EMG) is limited, particularly in the investigation of children, by the invasive nature of needle electrodes. Surface electrode techniques are an attractive alternative but the detected signals are greatly influenced by volume conductor effects, thus making their interpretation problematic. Using finite element analysis we investigated the relationship between surface potential distribution and motor unit depth, incorporating anisotropic conductivity to model muscle tissue and a range of subcutaneous fat thicknesses. The modeling results were used to analyze data recorded with a 16-channel surface electrode array, from 10 normals subjects and 12 patients with motor neuron disease. Differences in the motor units between the two groups were statistically significant (P < 0.01) and are consistent with reinnervation and increased motor unit territory in the patient group. This noninvasive technique shows promise as a more acceptable alternative to the use of conventional needle electrodes for neurophysiological investigations.

CYP2D6 and CYP2C19 genotypes of patients with terodiline cardiotoxicity identified through the yellow card system.

AIMS: Terodiline has concentration dependent QT prolonging effects and thus the potential for cardiotoxicity. Pharmacogenetic variation in terodiline metabolism could be responsible for cardiotoxicity. We sought to determine whether CYP2D6 (debrisoquine hydroxylase) or CYP2C19 (S-mephenytoin hydroxylase) status is a risk factor for terodiline cardiotoxicity. METHODS: Using the UK Yellow Card scheme to identify patients, blood samples were obtained from eight patients who survived ventricular tachycardia or torsades de pointes suspected to be due to terodiline, for determination of CYP2D6 and CYP2C19 genotypes. Genotype prevalence was compared with that in published general population groups. RESULTS: One patient was a CYP2D6 poor metaboliser (CYP2D6*4 homozygous) and a second was heterozygous for CYP2D6*4, a slightly lower frequency for these genotypes compared with the general population (P = 0.31). In the case of CYP2C19, one patient was a poor metaboliser and four were heterozygous for the variant CYP2C19*2 allele, compared with general population frequencies of 2% and 23%, respectively (P = 0.035). CONCLUSIONS: These findings suggest that debrisoquine poor metaboliser status is not primarily responsible for terodiline cardiotoxicity. However, possession of the CYP2C19*2 allele appears to contribute to adverse cardiac reactions to terodiline. The present study demonstrates the feasibility of using spontaneous adverse drug reaction reporting schemes to determine the contribution of genotype for metabolizing enzymes to uncommon adverse drug reactions.

Oxidative stress in humans during work at moderate altitude.

Increased oxidative stress has been associated with work at high altitude; however, it is not known whether oxidative stress is a significant problem at moderate altitudes. The oxidative stress indicators, breath pentane (BP), 8-hydroxydeoxyguanosine (8-OHdG), oxygen radical absorption capacity (ORAC), 4-hydroxynonenal (4-HNE), malondialdehyde (MDA), and lipid peroxides (LPO) were measured in breath, blood and urine samples of U.S. Marines engaged in moderate altitude ( approximately 3000 m) cold weather field training. The test subjects were divided into a placebo and four antioxidant supplement groups (n = 15/group) and received the following supplements for 28 d: 1) vitamin E, 440 alpha-tocopherol equivalents (alpha-TE); 2) vitamin A, 2000 retinol equivalents (RE) of beta-carotene; 3) vitamin C, 500 mg ascorbic acid; 4) a mixture of 440 alpha-TE, 2000 RE of beta-carotene, 500 mg ascorbic acid, 100 microg selenium and 30 mg zinc daily. Strenuous work ( approximately 23 MJ/d) in cold weather at moderate altitude was accompanied by increases in several indicators of oxidative stress that were not effectively controlled by conventional antioxidant supplements. The group receiving the antioxidant mixture exhibited lower BP (P < 0. 05) compared with those receiving single antioxidant supplements; however, not all markers of oxidative stress responded like BP. Because these markers did not respond in the same manner, it is important to include markers from more than one source to assess the effect of supplemental dietary antioxidants.

Effect of antioxidant supplementation on urine and blood markers of oxidative stress during extended moderate-altitude training.

OBJECTIVE: To investigate the increase in oxidative stress during work at moderate altitudes due to additional energy expenditure, tissue anoxia, and UV light exposure. METHODS: Thirty US Marine Corps volunteers were divided into placebo (P) and antioxidant supplement (S) groups and tested for markers of oxidative stress before (t0), at the midpoint of (t1), and after (t2) 14 days of winter training at a moderate altitude (approximately 2700 m). The antioxidant supplement consisted of a daily dose of 20,000 IU beta-carotene, 400 IU vitamin E, 500 mg vitamin C, 100 micrograms selenium, and 30 mg zinc. The following markers of oxidative stress were measured: urine thiobarbituric acid reactive substances (TBARSs), urine hydroxynonenal (HNE), urine 8-hydrodeoxyguanosine (8-OHdG), plasma total peroxyl radical trapping potential (TRAP), and plasma lipid hydroperoxides (LPOs). Urine was collected on a 24-hr basis at t0, t1, and t2; blood samples were collected at t0 and t2. RESULTS: P group LPOs increased 30% (p < 0.05) between t0 and t2, whereas S group LPOs did not increase. Both groups exhibited significant increases in urine TBARSs, HNE, and 8-OHdG by t2. Urine TBARSs, HNE, and 8-OHdG increased between t0 and t1 in both groups, with the greater increase in the S group. The conflicting results between the plasma and urine markers of oxidative stress may be due to a time-phase relationship. CONCLUSIONS: The results of this study suggest that work in a moderate-altitude cold-weather environment is accompanied by increased oxidative stress, despite relatively high intakes of dietary and supplemental antioxidants.

Secondary heterotypic versus homotypic infection by Coxsackie B group viruses: impact on early and late histopathological lesions and virus genome prominence.

The impact of prior exposure to a different or identical strain of Coxsackievirus B (CVB) on murine CVB myocarditis was studied using a susceptible murine host (A/J[H-2a]) and myocarditic CVB3 or avirulent CVB2 as primary or secondary infectants. The effects of secondary heterotypic infection (CVB2 followed by CVB3) and homotypic infection (CVB3 followed by CVB3) 28 days after primary inoculation, versus CVB2 or CVB3 alone, on injury and viral genomic replication, both early (day 7) and late (days 28 and 56), were evaluated. After the primary infection by CVB2, trivial viral RNA was present in the heart and other organs, and a substantial positivity was observed with CVB3 infection. Seven days after secondary heterotypic (CVB2-CVB3) infection, the quantity of CVB genome in heart, pancreas, liver, and spleen was increased compared with the virus genome in the CVB3-CVB3 group and in the group with primary CVB3 infection alone. This phenomenon was seen in the heart and spleen up to day 28 postsecondary infection. Tissue inflammation and necrosis in heart and pancreas were prominent 7 days postsecondary infection with CVB2-CVB3 and correlated well with an increased quantity of CVB genome. Virus genome was present in heart and spleen 28 days after CVB3 infection alone. Serum CVB3 neutralization titer was increased to 1:128 in CVB2-CVB3 group at days 7 and 28 postsecondary infection, and serum completely neutralized cytopathological effects of CVB3 in the CVB3-CVB3 group at day 7 and 28 postsecondary infection. Our results indicate that secondary heterotypic infection by CVB causes increased injury, inflammation, and CVB replication in target organs such as the heart and pancreas, as well as in immune compartments like the spleen. Compared with CVB3 alone, the intense inflammatory infiltriate in the CVB2-CVB3 group is as not due solely to postviral sensitization of the immune system, but rather to the inability of the host to eradicate the virus.

Induction of endothelial PAS domain protein-1 by hypoxia: characterization and comparison with hypoxia-inducible factor-1alpha.

Hypoxia results in adaptive changes in the transcription of a range of genes including erythropoietin. An important mediator is hypoxia-inducible factor-1 (HIF-1), a DNA binding complex shown to contain at least two basic helix-loop-helix PAS-domain (bHLH-PAS) proteins, HIF-1alpha and aryl hydrocarbon nuclear receptor translocator (ARNT). In response to hypoxia, HIF-1alpha is activated and accumulates rapidly in the cell. Endothelial PAS domain protein 1 (EPAS-1) is a recently identified bHLH-PAS protein with 48% identity to HIF-1alpha, raising the question of its role in responses to hypoxia. We developed specific antibodies and studied expression and regulation of EPAS-1 mRNA and protein across a range of human cell lines. EPAS-1 was widely expressed, and strongly induced by hypoxia at the level of protein but not mRNA. Comparison of the effect of a range of activating and inhibitory stimuli showed striking similarities in the EPAS-1 and HIF-1alpha responses. Although major differences were observed in the abundance of EPAS-1 and HIF-1alpha in different cell types, differences in the inducible response were subtle with EPAS-1 protein being slightly more evident in normoxic and mildly hypoxic cells. Functional studies in a mutant cell line (Ka13) expressing neither HIF-1alpha nor EPAS-1 confirmed that both proteins interact with hypoxically responsive targets, but suggest target specificity with greater EPAS-1 transactivation (relative to HIF-1alpha transactivation) of the VEGF promoter than the LDH-A promoter.

Mortality and morbidity of workers exposed to acrylonitrile in fiber production.

This study assessed the risk of cancer mortality and incidence among 2559 employees exposed to acrylonitrile in the production of Orlon at 2 plants in 1944-1991. Latency, duration of exposure, highest level of exposure ever experienced, and cumulative exposure were used as indicators of exposure. The average duration of exposure for the workers was 7.6 years with an average cumulative exposure of 57.6 ppm-years. Overall mortality was lower than expected in a comparison with the United States population and all DuPont employees [454 deaths, standardized mortality ratios (SMR) of 69 and 91, respectively)]. All the cancer death ratios were lower than expected in a similar comparison. The SMR values for specific sites did not differ significantly from the expected values. Mortality from all cancers and from prostate, respiratory, and digestive cancer did not show any significantly associated increases or a consistent pattern suggestive of a dose-response. The cancer morbidity patterns were similarly unremarkable.

Selection and analysis of a mutant cell line defective in the hypoxia-inducible factor-1 alpha-subunit (HIF-1alpha). Characterization of hif-1alpha-dependent and -independent hypoxia-inducible gene expression.

Hypoxia-inducible expression has been demonstrated for many groups of mammalian genes, and studies of transcriptional control have revealed the existence of hypoxia-responsive elements (HREs) in the cis-acting sequences of several of these genes. These sequences generally contain one or more binding sites for a heterodimeric DNA binding complex termed hypoxia-inducible factor-1 (HIF-1). To analyze this response further, Chinese hamster ovary cells were stably transfected with plasmids bearing HREs linked to genes encoding immunoselectable cell surface markers, and clones that showed reduced or absent hypoxia-inducible marker expression were selected from a mutagenized culture of cells. Analysis of these cells revealed several clones with transacting defects in HRE activation, and in one the defect was identified as a failure to express the alpha-subunit of HIF-1. Comparison of hypoxia-inducible gene expression in wild type, HIF-1alpha-defective, and HIF-1alpha-complemented cells revealed two types of response. For some genes (e.g. glucose transporter-1), hypoxia-inducible expression was critically dependent on HIF-1alpha, whereas for other genes (e.g. heme oxygenase-1) hypoxia-inducible expression appeared largely independent of the expression of HIF-1alpha. These experiments show the utility of mutagenesis and selection of mutant cells in the analysis of mammalian transcriptional responses to hypoxia and demonstrate the operation of HIF-1alpha-dependent and HIF-1alpha-independent pathways of hypoxia-inducible gene expression in Chinese hamster ovary cells.

Severe cystitis associated with tiaprofenic acid.

OBJECTIVE: To review the UK spontaneous reports of urinary disorders associated with tiaprofenic acid and other non-steroidal anti-inflammatory drugs (NSAIDs) and put them into context of the usage of these preparations in the UK. METHODS: Suspected adverse drug reaction (ADR) reports of urinary disorders associated with tiaprofenic acid and other NSAIDs received by the UKs spontaneous ADR reporting scheme were analysed. RESULTS: Between 1982, when tiaprofenic acid was introduced in the UK, and August 1994, 69 cases of cystitis were reported, with a further 32 reports describing related urinary symptoms including frequency, dysuria and haematuria. Only eight cases of cystitis were reported for all other NSAIDs. The duration of treatment with tiaprofenic acid before the onset of urinary symptoms varied markedly (range 2 days to > 3 years). In patients in whom a drug-induced cause was suspected and the drug was stopped promptly, recovery usually occurred within weeks. However, many patients continued on long-term treatment with tiaprofenic acid and underwent extensive investigations to determine the cause of their urinary symptoms. On cystoscopy and biopsy, the findings were similar to interstitial cystitis. Most patients with chronic cystitis recovered after withdrawal of tiaprofenic acid, but some patients had surgery before the drug was stopped. CONCLUSION: Tiaprofenic acid can cause severe cystitis. These reports highlight the importance of taking a full drug history in patients with unexplained chronic cystitis. Tiaprofenic acid should be stopped immediately in all patients developing urinary symptoms.