The independent and joint risks of alcohol consumption, smoking, and excess weight on morbidity and mortality: a systematic review and meta-analysis exploring synergistic associations.

OBJECTIVE: Alcohol consumption, smoking, and excess weight independently increase the risk of morbidity/mortality. Less is known about how they interact. This research aims to quantify the independent and joint associations of these exposures across health outcomes and identify whether these associations are synergistic. STUDY DESIGN: The protocol for this systematic review and meta-analysis was pre-registered (PROSPERO CRD42021231443). METHODS: Medline and Embase were searched between 1 January 2010 and 9 February 2022. Eligible peer-reviewed observational studies had to include adult participants from Organisation for Co-Operation and Development countries and report independent and joint associations between at least two eligible exposures (alcohol, smoking, and excess weight) and an ICD-10 outcome (or equivalent). For all estimates, we calculated the synergy index (SI) to identify whether joint associations were synergistic. Meta-analyses were conducted for outcomes with sufficiently homogenous data. RESULTS: The search returned 26,290 studies, of which 98 were included. Based on 138,130 participants, the combined effect (SI) of alcohol and smoking on head and neck cancer death/disease was 3.78 times greater than the additive effect of each exposure (95% confidence interval [CI] = 2.61, 5.48). Based on 2,603,939 participants, the combined effect of alcohol and excess weight on liver disease/death was 1.55 times greater than the additive effect of each exposure (95% CI = 1.33, 1.82). CONCLUSION: Synergistic associations suggest the true population-level risk may be underestimated. In the absence of bias, individuals with multiple risks would experience a greater absolute risk reduction from an intervention that targets a single exposure than individuals with a single risk.

Understanding SARS-CoV-2 Delta and Omicron variant transmission and vaccine impact in schools and child-care settings in Australia: a population-based study.

Background: Over 214 million students globally have been affected by school closures during the COVID-19 pandemic. To address knowledge gaps on transmission of SARS-CoV-2 delta (B.1.617.2) and omicron (B.1.1.529) variants in educational settings we examined virus transmission in schools and early childhood education and care settings (ECECs) in New South Wales (NSW), Australia in relation to mitigation measures, including COVID-19 vaccination. Methods: Secondary transmission from children and adults with laboratory-confirmed SARS-CoV-2 infection who attended a school (n = 3170) or ECECs (n = 5800) while infectious was investigated over two periods: 1) June 16 to September 18, 2021 (delta outbreak), and; 2) October 18 to December 18, 2021 (delta and omicron; schools only). Close contacts of cases underwent 14 days quarantine and SARS-CoV-2 nucleic acid testing. Secondary attack rates (SARs) were calculated and compared with state-wide notification data, school attendance, and vaccination status. Findings: 1187 schools and 300 ECECs had students (n = 1349) or staff (n = 440) attend while infectious. Of 24,277 contacts investigated, most (91.8%; 22,297/24,277) were tested and 912 secondary cases identified. The secondary attack rate (SAR) was 5.9% in 139 ECECs and 3.5% in 312 schools. The risk of becoming a secondary case was higher in unvaccinated school staff (OR 4.7; 95% CI: 1.7-13.3), particularly ECEC staff (OR 9.0; 95% CI: 3.6-22.7) and unvaccinated school students than in vaccinated school staff. SARs were similar for delta (4.9%) and omicron BA.1 (4.1%) in the unvaccinated and higher compared with vaccinated contacts (0.9% and 3.4%, respectively). Increasing school attendance rates raised case incursions and secondary case numbers, but not community-wide infection rates. Interpretation: Vaccination reduced SARS-CoV-2 transmission rates in schools, although less so for omicron than delta variants. Despite higher community-based transmission rates, in-school transmission remained low and stable with high attendance, suggesting that community restrictions, rather than school closures, best mitigated COVID-19 impacts. Funding: NSW Government Department of Health.

What is the evidence that advertising policies could have an impact on gambling-related harms? A systematic umbrella review of the literature.

OBJECTIVE: To summarise the evidence on the impacts of gambling-related advertising that could lead to gambling-related harm, including impacts on vulnerable individuals and inequalities in the distribution of harms. STUDY DESIGN: An umbrella review of studies investigating the impact of gambling advertising. METHODS: A review was undertaken of systematic reviews of qualitative, quantitative and mixed method studies reporting outcomes associated with gambling advertising and marketing. The search strategy included database searches (Web of Science, PsycInfo) and website searches. The quality of the included reviews was determined using A MeaSurement Tool to Assess systematic Reviews 2. RESULTS: 1024 papers were identified by database searches. Eight systematic reviews, including 74 unique studies, met inclusion criteria. Included studies, using quantitative and qualitative methods, consistently support the existence of a causal relationship between exposure to advertising of gambling products/brands and more positive attitudes to gambling, greater intentions to gamble and increased gambling activity at both individual and population level. There is evidence of a 'dose-response' effect; greater advertising exposure increases participation which leads to a greater risk of harm. There was more evidence for the impact on children and young people and for those already at risk from current gambling activity with those most vulnerable more likely to be influenced. CONCLUSION: Gambling advertising restrictions could reduce overall harm and mitigate the impact of advertising on gambling-related inequalities. Public health harm prevention strategies should include policies which limit exposure to advertising, particularly among children and vulnerable groups.

A sticky end for gastrointestinal helminths; the role of the mucus barrier.

Gastrointestinal (GI) nematodes are a group of successful multicellular parasites that have evolved to coexist within the intestinal niche of multiple species. It is estimated that over 10% of the world's population are chronically infected by GI nematodes, making this group of parasitic nematodes a major burden to global health. Despite the large number of affected individuals, there are few effective treatments to eradicate these infections. Research into GI nematode infections has primarily focused on defining the immunological and pathological consequences on host protection. One important but neglected aspect of host protection is mucus, and the concept that mucus is just a simple barrier is no longer tenable. In fact, mucus is a highly regulated and dynamic-secreted matrix, underpinned by a physical hydrated network of highly glycosylated mucins, which is increasingly recognized to have a key protective role against GI nematode infections. Unravelling the complex interplay between mucins, the underlying epithelium and immune cells during infection are a major challenge and are required to fully define the protective role of the mucus barrier. This review summarizes the current state of knowledge on mucins and the mucus barrier during GI nematode infections, with particular focus on murine models of infection.

Controlling alcohol availability through local policy: an observational study to evaluate Cumulative Impact Zones in a London borough.

Background: Cumulative impact zones (CIZs) are a discretionary policy lever available to local government, used to restrict the availability of alcohol in areas deemed already saturated. Despite little evidence of their effect, over 200 such zones have been introduced. This study explores the impact of three CIZs on the licensing of venues in the London Borough of Southwark. Methods: Using 10 years of licensing data, we examined changes in the issuing of licences on the introduction of three CIZs within Southwark, relative to control areas. The number of licence applications made (N = 1110), the number issued, and the proportion objected to, were analysed using negative binomial regression. Results: In one area tested, CIZ implementation was associated with 119% more licence applications than control areas (incidence rate ratios (IRR) = 2.19, 95% confidence intervals (CI): 1.29-3.73, P = 0.004) and 133% more licences granted (IRR = 2.33, 95% CI: 1.31-4.16, P = 0.004). No significant effect was found for the other two areas. CIZs were found to have no discernible effect on the relative proportion of licence applications receiving objections. Conclusions: CIZs are proposed as a key lever to limit alcohol availability in areas of high outlet density. We found no evidence that CIZ establishment reduced the number of successful applications in Southwark.

Fetal megacystis: A systematic review.

Fetal megacystis is variably defined and understood. The literature on fetal megacystis was systematically reviewed, focusing on prenatal diagnosis, associations and outcomes. This yielded a total of 18 primary references and eight secondary references. Fetal megacystis has an estimated first-trimester prevalence of between 1:330 and 1:1670, with a male to female ratio of 8:1. In the first trimester, megacystis is most commonly defined as a longitudinal bladder dimension of ≥7 mm. Later in pregnancy, a sagittal dimension (in mm) greater than gestational age (in weeks) + 12 is often accepted. Megacystis can be associated with a thickened bladder wall, which has been objectively defined as >3 mm. Oligohydramnios is present in approximately half of all cases. The most common underlying diagnosis is posterior urethral valves (57%), followed by urethral atresia/stenosis (7%), prune belly syndrome (4%), megacystis-microcolon-intestinal-hypoperistalsis syndrome (MMIHS) (1%), and cloacal anomalies (0.7%). Karyotype anomalies are found in 15%, and include trisomy 18, trisomy 13 and trisomy 21. Ultrasound imaging alone is often insufficient to enable a definitive diagnosis, although it may indicate that a specific diagnosis is more likely. Overall, about 50% of reported fetuses with megacystis are terminated, but this proportion varies considerably between countries and over time. Prognostic stratification is evolving, with the most important factors being oligohydramnios, gestational age at diagnosis, degree of bladder enlargement, renal hyperechogenicity, karyotype, and sex. CONCLUSIONS: This review demonstrated some consensus on the ultrasound criteria for defining fetal megacystis, and illustrated the spectrum of pathologies and their relative frequencies that can cause this condition. It also underlined important associated karyotype anomalies. To progress understanding of the natural history of enlarged fetal bladders, more accurate diagnostics are required, and risk stratification needs to be refined to facilitate prenatal counseling.

Body morphology differs in wild juvenile Chinook salmon Oncorhynchus tshawytscha that express different migratory phenotypes in the Willamette River, Oregon, U.S.A.

Body morphology of juvenile Chinook salmon Oncorhynchus tshawytscha in the upper Willamette River, Oregon, U.S.A., was analysed to determine if variation in body shape is correlated with migratory life-history tactics followed by juveniles. Body shape was compared between migrating juveniles that expressed different life-history tactics, i.e. autumn migrants and yearling smolts, and among parr sampled at three sites along a longitudinal river gradient. In the upper Willamette River, the expression of life-history tactics is associated with where juveniles rear in the basin with fish rearing in downstream locations generally completing ocean ward migrations earlier in life than fish rearing in upstream locations. The morphological differences that were apparent between autumn migrants and yearling smolts were similar to differences between parr rearing in downstream and upstream reaches, indicating that body morphology is correlated with life-history tactics. Autumn migrants and parr from downstream sampling sites had deeper bodies, shorter heads and deeper caudal peduncles compared with yearling smolts and parr from the upstream sampling site. This study did not distinguish between genetic and environmental effects on morphology; however, the results suggest that downstream movement of juveniles soon after emergence is associated with differentiation in morphology and with the expression of life-history variation.

Multi-center experience of 164 consecutive Hemodialysis Reliable Outflow [HeRO] graft implants for hemodialysis treatment.

OBJECTIVE: To report a multi-center experience with the novel Hemodialysis Reliable Outflow (HeRO) vascular access graft. MATERIALS AND METHODS: Four centers conducted a retrospective review of end stage renal disease patients who received the HeRO device from implant to last available follow-up. Data is available on 164 patients with an accumulated 2092.1 HeRO implant months. RESULTS: At 6 months, HeRO primary and secondary patency is 60% and 90.8%, respectively and at 12 months, 48.8% and 90.8%, respectively. At 24 months, HeRO had a primary patency of 42.9% and secondary patency was 86.7%. Interventions to maintain or re-establish patency have been required in 71.3% of patients (117/164) resulting in an intervention rate of 1.5/year. Access related infections have been reported in 4.3% patients resulting in a rate of 0.14/1000 implant days. CONCLUSIONS: In our experience the HeRO device has performed comparably to standard AVGs and has proven superior to TDCs in terms of patency, intervention, and infection rates when compared to the peer-reviewed literature. As an alternative to catheter dependence as a means for hemodialysis access, this graft could reduce the morbidity and mortality associated with TDCs and have a profound impact on the costs associated with catheter related infections and interventions.

Risk factors for transmission of foot-and-mouth disease during an outbreak in southern England in 2007.

During an outbreak of foot-and-mouth disease (FMD) in southern England in 2007, a case-control study was conducted to identify risk factors for infection and to investigate the relative impact of risk factors on transmission between the infected farms. Seven of the eight case farms in the outbreak and 22 control farms participated. Data were collected via questionnaires and subjected to comparative statistical analysis. Case farms were further classified as primary or secondary according to the likely source of infection during the study. On primary case farms, it was plausible that infection had been introduced directly from the original source. On secondary case farms, FMD infection was more likely to have originated from another infected premises. Calving occurred more frequently on case farms than on control farms during the risk period, and the two primary case farms had a larger proportion of youngstock than the other farms. Secondary case farms (n=5) had a higher composite environmental risk score and a lower biosecurity score than control farms.

Measurement of serum lanthanum in patients treated with lanthanum carbonate by inductively coupled plasma-mass spectrometry.

BACKGROUND: Lanthanum carbonate is used as a phosphate binder in patients with stage V chronic kidney disease (CKD). While well tolerated in clinical trials, with no toxicity reported as regards bone and liver metabolism, and cognitive function, concerns remain over possible toxicity. Published methods for the measurement of lanthanum ion in biological samples include aggressive and complicated sample preparation steps that are unsuitable for routine use. A simple method has been developed and validated for the measurement of serum lanthanum. METHOD: A ThermoFisher Scientific XSERIES-II inductively coupled plasma-mass spectrometer was used to monitor ¹³9La. Validation was undertaken using internal quality control solutions containing lanthanum ion (0.20, 0.70 and 4.00 µg/L). Lanthanum was measured in patients (number = 20) with CKD prescribed lanthanum carbonate (500-1500 mg/d) and patients undergoing haemodialysis not prescribed lanthanum carbonate (number = 20). RESULTS: Accuracy and imprecision were >95% and <5%, respectively. Calibration was linear (range 0.1-5 µg/L, R² = 0.99). The lower limit of quantification (LLoQ) was 0.1 µg/L lanthanum ion. In patients with CKD not prescribed lanthanum carbonate, serum lanthanum was below the LLoQ. Out of 20 CKD patients prescribed lanthanum carbonate, serum lanthanum was measurable in only 12 (range 0.11-0.60 µg/L lanthanum ion). There was no apparent relationship between dose and serum lanthanum in these patients. CONCLUSIONS: A lack of relationship between the dose of lanthanum carbonate and the serum lanthanum concentration may have been due to poor adherence to the treatment regimen. However the concentrations measured were close to the LLoQ.

Toenail onychomycosis: an important global disease burden.

Onychomycosis is a fungal infection of the nail plate or nail bed. It does not usually cure itself and it can trigger more infectious lesions in other parts of the body. The reported prevalence of onychomycosis is increasing in Western countries, presumably due to lifestyle changes and the ageing of the population. Approximately 10% of the general population, 20% of the population aged>60 years, up to 50% of people aged>70 years and up to one-third of diabetic individuals have onychomycosis. Care should be taken for the accurate diagnosis and timely treatment of toenail onychomycosis to prevent complications. Current treatment options have relatively limited therapeutic success, particularly long-term. Oral medications are associated with high recurrence rates and treatment failure, and are not suitable for many cases due to potential adverse effects. Topical medications are recommended only for mild to moderate cases. The cost of therapies may also be prohibitive in some cases. In the light of these issues, more research is warranted for the investigation and development of more effective and economical options for the treatment and prophylaxis of toenail onychomycosis. In patient populations such as diabetic individuals, where onychomycosis can provoke lower extremity complications, professional podiatry care of toenails and feet should be encouraged.

Outbreak of Newcastle disease due to pigeon paramyxovirus type 1 in grey partridges (Perdix perdix) in Scotland in October 2006.

In October 2006, following an initially non-statutory disease investigation affecting 12-week-old grey partridges (Perdix perdix), an outbreak of Newcastle disease due to infection with the avian paramyxovirus type 1 virus responsible for the current panzootic in pigeons (PPMV-1) was confirmed in Scotland. Two pens of partridges were affected by signs including loss of condition, diarrhoea, progressive neurological signs and mortality totalling approximately 24 per cent, and laboratory evidence of the infection was obtained only in these groups. The premises had approximately 17,000 poultry including a collection of 375 birds of rare breeds, containing endangered breeds of significant conservation value, which were not culled but subjected to a health monitoring and testing programme. Investigations suggested that a population of feral pigeons living above the affected pens of partridges was the likely source of the outbreak. Laboratory and genetic analyses confirmed that the isolate recovered from the clinically affected partridges was PPMV-1, belonging to genetic lineage 4b. However, the virus could not be isolated from or detected in dead pigeons collected from the affected buildings.

Hyperproliferation of PKD1 cystic cells is induced by insulin-like growth factor-1 activation of the Ras/Raf signalling system.

Autosomal dominant polycystic kidney disease (ADPKD) largely results from mutations in the PKD1 gene leading to hyperproliferation of renal tubular epithelial cells and consequent cyst formation. Rodent models of PKD suggest that the multifunctional hormone insulin-like growth factor-1 (IGF-1) could play a pathogenic role in renal cyst formation. In order to test this possibility, conditionally immortalized renal epithelial cells were prepared from normal individuals and from ADPKD patients with known germline mutations in PKD1. All patient cell lines had a decreased or absence of polycystin-1 but not polycystin-2. These cells had an increased sensitivity to IGF-1 and to cyclic AMP, which required phosphatidylinositol-3 (PI3)-kinase and the mitogen-activated protein kinase, extracellular signal-regulated protein kinase (ERK) for enhanced growth. Inhibition of Ras or Raf abolished the stimulated cell proliferation. Our results suggest that haploinsufficiency of polycystin-1 lowers the activation threshold of the Ras/Raf signalling system leading to growth factor-induced hyperproliferation. Inhibition of Ras or Raf activity may be a therapeutic option for decreasing tubular cell proliferation in ADPKD.

The role of geranylgeranylated proteins in human mesangial cell proliferation.

The Rho family of guanine 5'-triphosphatases (GTPases) play a key role in regulating cell proliferation, tubulointerstitial fibrosis, and glomerular hemodynamics. The post-translational prenylation of RhoGTPases by the addition of a geranylgeranyl moiety is critical for cellular localization and signaling activity. This study investigates the effects of (i) inhibiting geranylgeranylation (GG) in human mesangial cell (HMC) proliferation and apoptosis, using GGTI 298, a specific inhibitor of GG and (ii) lovastatin, an HMG-coacetyl A-reductase inhibitor, which depletes the availability of prenylation substrates. HMC proliferation was assessed using an assay of viable cell number and measuring bromodeoxyuridine (BrdU) incorporation. Hoechst 33342 staining was used to determine apoptosis. Extracellular signal-regulated protein kinase (Erk)1/2 and Akt activation were analysed by Western blotting. Rho activation was determined using the Rhotekin pull-down assay. Immunocytochemistry was performed to study the effects on the actin cytoskeleton and RhoA localization. GGTI 298 (10-20 muM) and lovastatin (5-10 muM) potently inhibited platelet-derived growth factor and serum-stimulated HMC proliferation and induced apoptosis. These effects of lovastatin were attenuated by co-incubation with geranylgeranylpyrophosphate. C3 exoenzyme, a clostridial toxin that specifically targets Rho also inhibited BrdU incorporation and promoted apoptosis. GGTI 298 increased cytosolic expression of RhoA, prevented RhoA activation, and inhibited the activation of Erk1/2 and the survival protein Akt. GGTI 298, lovastatin, and C3 exoenzyme inhibit HMC proliferation and promote apoptosis. Inhibiting GG increases cytosolic RhoA expression, disrupts the actin cytoskeleton, and inhibits RhoA activation. These results suggest that targeting geranylgeranylated proteins with statins or GGTI 298 is a promising therapeutic strategy in human mesangioproliferative renal disease.

Safety of telephone consultation for "non-serious" emergency ambulance service patients.

OBJECTIVE: To assess the safety of nurses and paramedics offering telephone assessment, triage, and advice as an alternative to immediate ambulance dispatch for emergency ambulance service callers classified by lay call takers as presenting with "non-serious" problems (category C calls). DESIGN: Data for this study were collected as part of a pragmatic randomised controlled trial reported elsewhere. The intervention arm of the trial comprised nurse or paramedic telephone consultation using a computerised decision support system to assess, triage, and advise patients whose calls to the emergency ambulance service had been classified as "non-serious" by call takers applying standard priority dispatch criteria. A multidisciplinary expert clinical panel reviewed data from ambulance service, accident and emergency department, hospital inpatient and general practice records, and call transcripts for patients triaged by nurses and paramedics into categories that indicated that dispatch of an emergency ambulance was unnecessary. All cases for which one or more members of the panel rated that an emergency ambulance should have been dispatched were re-reviewed by the entire panel for an assessment of the "life risk" that might have resulted. SETTING: Ambulance services in London and the West Midlands, UK. STUDY POPULATION: Of 635 category C patients assessed by nurses and paramedics, 330 (52%) cases that had been triaged as not requiring an emergency ambulance were identified. MAIN OUTCOME MEASURES: Assessment of safety of triage decisions. RESULTS: Sufficient data were available from the routine clinical records of 239 (72%) subjects to allow review by the specialist panel. For 231 (96.7%) sets of case notes reviewed, the majority of the panel concurred with the nurses' or paramedics' triage decision. Following secondary review of the records of the remaining eight patients, only two were rated by the majority as having required an emergency ambulance within 14 minutes. For neither of these did a majority of the panel consider that the patient would have been at "life risk" without an emergency ambulance being immediately dispatched. However, the transcripts of these two calls indicated that the correct triage decision had been communicated to the patient, which suggests that the triage decision had been incorrectly entered into the decision support system. CONCLUSIONS: Telephone advice may be a safe method of managing many category C callers to 999 ambulance services. A clinical trial of the full implementation of this intervention is needed, large enough to exclude the possibility of rare adverse events.

On-scene alternatives for emergency ambulance crews attending patients who do not need to travel to the accident and emergency department: a review of the literature.

With rising demand and recognition of the variety of cases attended by emergency ambulance crews, services have been considering alternative ways of providing non-urgent care. This paper describes and appraises the research literature concerning on-scene alternatives to conveyance to an emergency department, focusing on the: (1) profile and outcomes of patients attended but not conveyed by emergency crews; (2) triage ability of crews; (3) effectiveness and safety of protocols that allow crews to convey patients to alternative receiving units or to self care. The literature search was conducted through standard medical databases, supplemented with manual searches. Very few "live" studies were identified, and fewer still that included a control group. Findings indicated a complex area, with the introduction of protocols allowing crews to leave patients at scene carrying clinical risk. Robust research evidence concerning alternatives to current emergency care models is needed urgently to inform service and practice development.