Subtype‐specific differences in transmission cluster dynamics of HIV‐1 B and CRF01_AE in New South Wales,Australia

IntroductionThe human immunodeficiency virus 1 (HIV‐1) pandemic is characterized by numerous distinct sub‐epidemics (clusters) that continually fuel local transmission. The aims of this study were to identify active growing clusters, to understand which factors most influence the transmission dynamics, how these vary between different subtypes and how this information might contribute to effective public health responses.MethodsWe used HIV‐1 genomic sequence data linked to demographic factors that accounted for approximately 70% of all new HIV‐1 notifications in New South Wales (NSW). We assessed differences in transmission cluster dynamics between subtype B and circulating recombinant form 01_AE (CRF01_AE). Separate phylogenetic trees were estimated using 2919 subtype B and 473 CRF01_AE sequences sampled between 2004 and 2018 in combination with global sequence data and NSW‐specific clades were classified as clusters, pairs or singletons. Significant differences in demographics between subtypes were assessed with Chi‐Square statistics.ResultsWe identified 104 subtype B and 11 CRF01_AE growing clusters containing a maximum of 29 and 11 sequences for subtype B and CRF01_AE respectively. We observed a > 2‐fold increase in the number of NSW‐specific CRF01_AE clades over time. Subtype B clusters were associated with individuals reporting men who have sex with men (MSM) as their transmission risk factor, being born in Australia, and being diagnosed during the early stage of infection (p < 0.01). CRF01_AE infections clusters were associated with infections among individuals diagnosed during the early stage of infection (p < 0.05) and CRF01_AE singletons were more likely to be from infections among individuals reporting heterosexual transmission (p < 0.05). We found six subtype B clusters with an above‐average growth rate (>1.5 sequences / 6‐months) and which consisted of a majority of infections among MSM. We also found four active growing CRF01_AE clusters containing only infections among MSM. Finally, we found 47 subtype B and seven CRF01_AE clusters that contained a large gap in time (>1 year) between infections and may be indicative of intermediate transmissions via undiagnosed individuals.ConclusionsThe large number of active and growing clusters among MSM are the driving force of the ongoing epidemic in NSW for subtype B and CRF01_AE.     

Disgusting disruptions: Capturing the everyday experience and burden of managing gastrointestinal infections in the home

Gastrointestinal (GI) infections exert a significant public health burden in the United Kingdom and the numbers of episodes are increasing. Younger children are considered particularly vulnerable to infection, and can experience 2–3 GI infections episodes per year, with consequences being more severe for more disadvantaged children, who are much more likely to be admitted to hospital. Few qualitative studies have explored the lived experience of GI infection in the community in the UK. The aim of the study reported here was to contribute to addressing this evidence gap, by examining the consequences of GI infection for ‘normal’ family life. Eighteen mothers with young children who had recently experienced a gastrointestinal infection were recruited from two socioeconomically contrasting neighbourhoods in North West of England. The findings demonstrated that GI infections were particularly disruptive: experienced as disgusting, laborious and stressful and significantly impacted normal family routines. Women felt burdened by the heavy physical and emotional demands of caring for a GI infection, resulting in feelings of isolation and insufficient support in their caring role from male partners. Tensions also arose from interactions with external community organisations, particularly in complying with their regulations on infection which often undermined caregivers knowledge and expertise of what was best for their children. This study challenges assumptions that managing GI infections in the home is unproblematic and experienced by caregivers as a ‘minor ailment.’ Infection control measures need to incorporate insights gleaned from the day-to-day realities of caring for sick children in the community.     

Working conditions and health behavior as causes of educational inequalities in self-rated health: an inverse odds weighting approach

Objective:Using a novel mediation method that presents unbiased results even in the presence of exposure–mediator interactions, this study estimated the extent to which working conditions and health behaviors contribute to educational inequalities in self-rated health in the workforce.Methods:Respondents of the longitudinal Survey of Health, Ageing, and Retirement in Europe (SHARE) in 16 countries were selected, aged 50–64 years, in paid employment at baseline and with information on education and self-rated health (N=15 028). Education, health behaviors [including body mass index (BMI)] and working conditions were measured at baseline and self-rated health at baseline and two-year follow-up. Causal mediation analysis with inverse odds weighting was used to estimate the total effect of education on self-rated health, decomposed into a natural direct effect (NDE) and natural indirect effect (NIE).Results:Lower educated workers were more likely to perceive their health as poor than higher educated workers [relative risk (RR) 1.48, 95% confidence interval (CI) 1.37–1.60]. They were also more likely to have unfavorable working conditions and unhealthy behaviors, except for alcohol consumption. When all working conditions were included, the remaining NDE was RR 1.30 (95% CI 1.15–1.44). When BMI and health behaviors were included, the remaining NDE was RR 1.40 (95% CI 1.27–1.54). Working conditions explained 38% and health behaviors and BMI explained 16% of educational inequalities in health. Including all mediators explained 64% of educational inequalities in self-rated health.Conclusions:Working conditions and health behaviors explain over half of the educational inequalities in self-rated health. To reduce health inequalities, improving working conditions seems to be more important than introducing health promotion programs in the workforce.     

Mendelian randomization analysis with survival outcomes

Mendelian randomization (MR) is an established approach for assessing the causal effects of heritable exposures on outcomes. Outcomes of interest often include binary clinical endpoints, but may also include censored survival times. We explore the implications of both the Cox proportional hazard model and the additive hazard model in the context of MR, with a specific emphasis on two‐stage methods. We show that naive application of standard MR approaches to censored survival times may induce significant bias. Through simulations and analysis of data from the Women's Health Initiative, we provide practical advice on modeling survival outcomes in MRs.     

Cranial burst fracture in infants: acute recognition and management

In the past, the diagnosis of growing skull fracture or diastatic fracture has included a subset of injuries better referred to as cranial burst fracture. Cranial burst fracture, typically associated with severe injury in infants less than 1 year of age, is a closed, widely diastatic skull fracture accompanied by acute cerebral extrusion outside the calvarium. We treated 11 such infants at the LeBonheur Children's Medical Center and 2 at the Children's National Medical Center from January 1986 through December 1994. Infants ranged in age from 1 to 17 months, with an average age of 5.7 months. All presented with marked scalp swelling and a Glasgow Coma Scale score of 10 or less. Twelve had a history consistent with severe injury (motor vehicle accident, 7, abuse 5). The cause of injury in one patient remains unproven. Surgery (reduction of herniated cerebral tissue, repair of large dural laceration, and cranioplasty) was usually performed within 10 days of injury, a time period long enough to assure hemodynamic stability and resolution of acute cerebral swelling, yet sufficiently brief to avoid the chronic changes (scarring, parasitization of scalp vessels by damaged cortex) associated with a growing skull fracture. Prompt repair of cranial burst fracture may prevent ongoing brain injury such as has been neuropathologically demonstrated in patients with growing skull fracture. Magnetic resonance imaging establishes the diagnosis of cranial burst fracture in equivocal cases, rendering unnecessary a waiting period to see if scalp swelling resolves. Our experience, together with information in the neuropathological and neurosurgicla literature, suggests that cranial burst fracture is associated with severe trauma, requires expeditious treatment, and has been underdiagnosed in the past, leading to growing skull fracture, a condition requiring more extensive surgery.     

Carbon dioxide analysers: accuracy,alarm limits and effects of interfering gases

Six mainstream and twelve sidestream infrared carbon dioxide (CO₂) analysers were tested for accuracy of the CO₂ display value, alarm activation and the effects of nitrous oxide (N₂O), oxygen (O₂) and water vapour according to the ISO Draft International Standard (DIS) #9918. Mainstream analysers (M-type): Novametrix Capnogard 1265; Hewlett Packard HP M1166A (CO₂module HP M1016A); Datascope Passport; Marquette Tramscope 12; Nellcor Ultra Cap N-6000; Heilige Vicom-sm SMU 611/612 ETC. Sidestream analysers: Brüel &; Kjaer Type 1304; Datex Capnomac II; Marquette MGA-AS; Datascope Multinex; Ohmeda 4700 OxiCap (all type S1: respiratory cycles not demanded); Biochem BCI 9000; Bruker BCI 9100; Dräger Capnodig and PM 8020; Criticare Poet II; Heilige Vicom-sm SMU 611/612 A-GAS (all type S2: respiratory cycles demanded). The investigations were performed with premixed test gases (2.5, 5, 10 vol%, error ?1% rel.). Humidification (37° C) of gases were generated by a Dräger Aquapor. Respiratory cycles were simulated by manually activated valves. All monitors complied with the tolerated accuracy bias in CO₂ reading (≤ 12% or 4 mmHg of actual test gas value) for wet and dry test gases at all concentrations, except that the Marquette MGA-AS exceeded this accuracy limit with wet gases at 5 and 10 vol% CO₂. Water condensed in the metal airway adapter of the HP M1166A at 37° C gas temperature but not at 3(P C. The Servomex 2500 (nonclinical reference monitor), Passport (M-type), Multinex (S1-type) and Poet II (S2-type) showed the least bias for dry and wet gases. Nitrous oxide and O₂ had practically no effect on the Capnodig and the errors in the others were max. 3.4 mmHg, still within the tolerated bias in the DIS (same as above). The difference between the display reading at alarm activation and the set point was in all monitors (except in the Capnodig: bias 1.75 mmHg at 5 vol% CO₂) below the tolerated limit of the DIS (difference ≤ 0.2 vol%). The authors conclude that the tested monitors are safe for clinical use (except those failing the DIS limits). The accuracy of the CO₂-reading (average of mean absolute bias) is better in the M-type than in the S1- or S2- type analysers although no statistical (nor clinical) significant differences could be detected. Most manufacturers work with stricter limits than those proposed by the DIS.     

Clozapine as a drug of dependence

Rationale: In schizophrenics, clozapine has been reported to induce various withdrawal signs and rapid onset relapse to psychosis on cessation of chronic treatment. Objective: The study was designed to develop an animal model of one aspect of clozapine tolerance and withdrawal using core body temperature measures. Methods: Two groups of 15 female Wistar rats were treated chronically (b.i.d.) with clozapine at 6 or 12 mg/kg per injection for 21 days prior to cessation of drug treatment, withdrawal being studied over 4 consecutive days. Body temperatures were assessed daily throughout the study. Results: Acutely, clozapine induced dose-related hypothermia, to which complete tolerance developed in both groups, the development of tolerance being more rapid in the group treated with 6 mg/kg per injection of clozapine. During withdrawal only the group treated chronically with 12 mg/kg per injection of clozapine showed rapid onset significant hyperthermia. This dissipated progressively over days, and was completely absent after 4 days of withdrawal. Conclusions: Clozapine induced a clear somatic withdrawal sign after chronic treatment. It is suggested that, in future research in both humans and animals, it is important to attempt to differentiate between clozapine withdrawal and clozapine withdrawal-induced relapse to psychosis. It is also important to characterise the clozapine withdrawal syndrome fully in animals; to establish the neurochemical mechanisms involved in such withdrawal; and to determine which novel antipsychotics are most efficacious in inducing clozapine-like withdrawal effects, in suppressing clozapine withdrawal, and in preventing relapse to psychosis in patients being transferred from clozapine to novel atypical antipsychotic drugs. Received: 14 May 1998/Final version: 14 September 1998