A Development and Implementation of a Preconception Counseling Program for Black Women and Men in the Southeastern United States: A Pilot Protocol.

Introduction: Racial/ethnic disparities in maternal mortality rates represent one of the most significant areas of disparities amongst all conventional population perinatal health measures in the U.S. The alarming trends and persistent disparities of outcomes by race/ethnicity and geographic location reinforce the need to focus on ensuring quality and safety of maternity care for all women. Despite complex multilevel factors impacting maternal mortality and morbidity, there are evidence-based interventions that, when facilitated consistently and properly, are known to improve the health of mothers before, during and after pregnancy. The objective of this project is to test implementation of pre-conception counseling with father involvement in community-based settings to improve cardiovascular health outcomes before and during pregnancy in southeastern United States. Methods and Analysis: This study has two components: a comprehensive needs and assets assessment and a small-scale pilot study. We will conduct a community informed needs and assets assessment with our diverse stakeholders to identify opportunities and barriers to preconception counseling as well as develop a stakeholder-informed implementation plan. Next, we will use the implementation plan to pilot preconception counseling with father involvement in community-based settings. Finally, we will critically assess the context, identify potential barriers and facilitators, and iteratively adapt the way preconception counseling can be implemented in diverse settings. Results of this research will support future research focused on identifying barriers and opportunities for scalable and sustainable public health approaches to implementing evidence-based strategies that reduce maternal morbidity and mortality in the southeastern United States' vulnerable communities. Discussion: Findings will demonstrate that preconception counseling can be implemented in community health settings in the southeastern United States. Furthermore, this study will build the capacity of community-based organizations in addressing the preconception health of their clients. We plan for this pilot to inform a larger scaled-up clinical trial across community health settings in multiple southeastern states.

C-terminal citrullinated peptide alters antigen-specific APC:T cell interactions leading to breach of immune tolerance.

In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide323-339 alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.

Serum angiotensin converting enzyme elevation in association with artificial stone silicosis.

BACKGROUND: Silicosis is a rapidly emerging major health concern for workers in the artificial stone benchtop industry. The association between serum angiotensin converting enzyme (sACE) levels and artificial stone silicosis is unknown. METHODS: We investigated 179 male workers (median age 40 years, interquartile range (IQR) 33-48 years) from the stone benchtop industry in Victoria, Australia. All had worked in an environment where dry processing of artificial stone had occurred and were registered with the Victorian Silica-associated Disease Registry between June 2019 and August 2020. Workers had undergone protocolised assessments including respiratory function testing, high resolution CT chest and blood tests panel, including sACE. FINDINGS: Sixty workers with artificial stone silicosis were identified and they had a higher median sACE level (64.1 U/L, IQR 51.5, 87.5), compared to 119 without silicosis (35.0 U/L, IQR 25.0, 47.0). Compared to those with a normal assessment, regression modelling noted significantly higher average differences in sACE levels for workers with lymphadenopathy alone (12.1 U/L, 95% confidence interval (CI): 1.3, 22.9), simple silicosis (28.7 U/L, 95% CI: 21.3, 36.0) and complicated silicosis (36.0 U/L, 95% CI 25.2, 46.9). There was a small negative association with gas transfer, but no associations with exposure duration or spirometry. CONCLUSION: sACE levels were noted to be higher in artificial stone workers with silicosis compared to those without disease and was highest in those with complicated silicosis. Longitudinal follow up is required to evaluate sACE as a prognostic biomarker for workers with this rapidly emerging occupational lung disease.

Novel therapeutic approaches to xeroderma pigmentosum.

BACKGROUND: The study of xeroderma pigmentosum has yielded unforeseen advances regarding how defects in the nucleotide excision repair pathway result in this devastating disease, but development of therapeutic strategies has trailed behind the mechanistic discoveries. OBJECTIVES: This review aims to cover clinical presentation, molecular mechanisms and current management, and highlights more recent insights into targeting the deficiencies secondary to the DNA repair defects to prevent skin cancer and/or neurological degeneration. METHODS: This review article discusses novel therapeutic approaches to xeroderma pigmentosum that focus on metabolic defects downstream of nucleotide excision repair. RESULTS: Current research demonstrates that specific sulfonylureas promote clearance of DNA damage and increase resistance to ultraviolet radiation in a cellular model of xeroderma pigmentosum. Moreover, nicotinamide attenuates the effects of ultraviolet radiation in cells, and caloric restriction decreases DNA damage burden in animal models of xeroderma pigmentosum. CONCLUSIONS: Clinical management of patients with xeroderma pigmentosum still focuses on preventative avoidance of sun exposure as opposed to therapies that would improve the patients' condition; thus, novel approaches to this disease are warranted.

Exposure to benzene in a pooled analysis of petroleum industry case-control studies.

Cases of lymphohematopoietic cancer from three petroleum industry cohorts, matched to controls from the respective cohort, were pooled into single study. Average benzene exposure was quantitatively estimated in ppm for each job based on measured data from the relevant country, adjusted for the specific time period, site and job exposure characteristics and the certainty of the exposure estimate scored. The probability of dermal exposure and of peak exposure was also assessed. Before risk was examined, an exposure estimate comparison and rationalisation exercise was performed across the studies to ensure accuracy and consistency of approach. This article evaluates the final exposure estimates and their use in the risk assessments. Overall benzene exposure estimates were low: 90% of participants accumulated less than 20 ppm-years. Mean cumulative exposure was estimated as 5.15 ppm-years, mean duration was 22 years, and mean exposure intensity was 0.2 ppm. 46% of participants were allocated a peak exposure (>3 ppm at least weekly). 40% of participants had a high probability of dermal exposure (based on the relative probability of at least weekly exposure). There were differences in mean intensity of exposure, probability of peak, and/or dermal exposure associated with job category, job site, and decade of exposure. Terminal Operators handling benzene-containing products were the most highly exposed group, followed by Tanker Drivers carrying gasoline. Exposures were higher around 1940-1950 and lower in more recent decades. Overall confidence in the exposure estimates was highest for recently held jobs and for white-collar jobs. We used sensitivity analyses, which included and excluded case-sets on the basis of exposure certainty scores, to inform the risk assessment. The above analyses demonstrated that the different patterns of exposure across the three studies are largely attributable to differences in jobs, site types, and time frames rather than study. This provides reassurance that the previous rationalisation of exposures achieved inter-study consistency and that the data could be confidently pooled.

Pregnancy and melanoma: a European-wide survey to assess current management and a critical literature overview.

BACKGROUND: Management of melanoma during pregnancy can be extremely challenging. The reported incidence of melanoma in pregnancy ranges from 2.8 to 5.0 per 100 000 pregnancies. There are no guidelines for the management of melanoma during pregnancy. METHODS: The survey was designed to investigate the opinions of melanoma physicians on decision making in relation to pregnancy and melanoma. A clinical scenario-based survey on management of pregnancy in melanoma was distributed all over Europe via the membership of the EORTC and other European melanoma societies. RESULTS: A total of 290 questionnaires were returned with a larger participation from southern Europe. A large heterogeneity was found for the answers given in the different clinical scenarios with 50% of the answers showing discordance, especially regarding sentinel lymph node biopsy during pregnancy. Discordant answers were also found for the counselling of women about a potential delay in getting pregnant after a high-risk melanoma (35% for a 2 year wait minimum vs. 57% no waiting needed), while for thin melanomas, as expected, there was more concordance with 70% of the physicians recommending no delay. Fifteen per cent of physicians recommended an abortion in stage II melanoma during the third month of pregnancy. Twenty per cent of the responders advised against hormonal replacement therapy in melanoma patients. CONCLUSIONS: The management of melanoma during pregnancy varies widely in Europe. At present, there is a lack of consensus in Europe, which may lead to very important decisions in women with melanoma, and guidelines are needed.

Mortality and cancer incidence in a cohort of male paid Australian firefighters.

OBJECTIVES: To investigate mortality and cancer incidence of paid male Australian firefighters and of subgroups of firefighters by era of first employment, duration of employment and number and type of incidents attended. METHODS: Participating fire agencies supplied records of individual firefighters including their job histories and incidents attended. The cohort was linked to the Australian National Death Index and Australian Cancer Database. SMRs and SIRs were calculated. Firefighters were grouped into tertiles by duration of employment and by number of incidents attended and relative mortality ratios and relative incidence ratios calculated. Analyses were carried out separately for full-time and part-time male firefighters. RESULTS: Compared to the Australian population, there were significant increases in overall risk of cancer, for all paid firefighters SIR 1.09 (95% CI 1.03 to 1.14), in prostate cancer, full-time firefighters 1.23 (95% CI 1.10 to 1.37), part-time 1.51 (1.28 to 1.77), and melanoma full-time 1.45 (95% CI 1.26 to 1.66), part-time firefighters 1.43 (95% CI 1.15 to 1.76). Kidney cancer was associated with longer service in internal analyses for paid firefighters. Prostate cancer was associated with longer service and increased attendance at fires, particularly structural fires for full-time firefighters.The overall risk of mortality was significantly decreased and almost all major causes of death were significantly reduced for paid firefighters. CONCLUSIONS: Male paid firefighters have an increased risk of cancer. They have reduced mortality compared with the general population, which is likely to be a result of a strong healthy worker effect and likely lower smoking rates among firefighters compared with the Australian population.

Mortality and cancer incidence at a fire training college.

BACKGROUND: An investigation into concerns about possible health effects of fire training practices at an Australian training facility recommended a study to investigate the risk of cancer and mortality of those with risk of chronic occupational exposure to several chemicals. AIMS: To investigate mortality and cancer incidence in firefighters at the Country Fire Authority (CFA) Fiskville training facility, Victoria, Australia, between 1971 and 1999. METHODS: CFA supplied human resources records, supplemented by self-reported information for a retrospective cohort, and allocated firefighters to low, medium or high groups based on probability of exposure. We linked the cohort to state and national cancer and mortality data. We calculated standardized mortality ratios and standardized cancer incidence ratios (SIRs). RESULTS: The high group (n = 95) had a clearly increased risk of overall cancers SIR = 1.85 (95% CI 1.20-2.73), testicular cancer SIR = 11.9 (1.44-42.9) and melanoma SIR = 4.59 (1.68-9.99) relative to the population of Victoria. Brain cancer was significantly increased for the medium group (n = 256): SIR = 5.74 (1.56-14.7). Mortality was significantly reduced for all groups. CONCLUSIONS: Dealing with supplied records can be problematic but despite the small numbers, we identified an increased risk of cancer for the high group. The mortality data suggested that there was under-ascertainment for the medium and low groups which underestimated risk and a possible reporting bias for brain cancer. Small cohorts can still provide statistically significant findings when investigating locations for cancer risk.

Prediction of high naevus count in a healthy U.K. population to estimate melanoma risk.

BACKGROUND: Despite recent discoveries of germline and somatic mutations in melanoma, naevus count remains the most important risk factor for melanoma. Counting naevi on the whole body is time consuming. In order to identify patients at risk for melanoma, many studies have used naevus count on selected body sites as a proxy for total body naevus count (TBNC). OBJECTIVES: The main aim of this study was to assess the predictive value of naevus count on 17 different body sites in estimating TBNC in a large cohort of healthy U.K. Caucasian female subjects. Once the site with the best predictive value for TBNC was determined, a second aim was to estimate the cut-off values of naevus counts at this anatomical site that best predict the presence of 50 or 100 naevi, respectively. METHODS: The most predictive body site for TBNC was assessed in a cohort of healthy female twins. This finding was replicated on a control group from a U.K. case-control study and a prediction model was performed afterwards. The area under the receiver operating characteristics curve was used to evaluate the best cut-off for the prediction of having a TBNC of more than 50 or 100. RESULTS: There were 3694 female twins included. The TBNC showed a steady decline after the age of 30 years (P < 0·001). The most predictive sites for TBNC were the arms and legs: the adjusted correlation coefficients were 0·50 and 0·51 (P < 0·001) for the right and left arm, respectively, and 0·49 and 0·48 for the right and left legs, respectively (P < 0·001). The arm remained the most predictive site for TBNC when replicated in a control population including both sexes. In the twin study, women with more than 11 naevi on the right arm were approximately nine times more likely to have more than 100 naevi (odds ratio = 9·38, 95% confidence interval 6·71-13·11). CONCLUSIONS: The ability to estimate TBNC quickly by counting naevi on one arm could be a very useful tool in assessing melanoma risk in primary care.

A telephone survey of factors affecting willingness to participate in health research surveys.

BACKGROUND: In recent years, reduced participation has been encountered across all epidemiological study designs, both in terms of non-response as well as refusal. A low response rate may reduce the statistical power but, more importantly, results may not be generalizable to the wider community. METHODS: In a telephone survey of 1413 randomly selected members of the Australian general population and of 690 participants sourced from previous studies, we examined factors affecting people's stated willingness to participate in health research. RESULTS: The majority of participants (61 %) expressed willingness to participate in health research in general but the percentage increased when provided with more specific information about the research. People were more willing if they have personal experience of the disease under study, and if the study was funded by government or charity rather than pharmaceutical companies. Participants from previous studies, older people and women were the groups most willing to participate. Younger men preferred online surveys, older people a written questionnaire, and few participants in any age and sex groups preferred a telephone questionnaire. CONCLUSION: Despite a trend toward reduced participation rates, most participants expressed their willingness to participate in health research. However, when seeking participants, researchers should be concrete and specific about the nature of the research they want to carry out. The preferred method of recommended contact varies with the demographic characteristics.

Global abnormalities in lymphatic function following systemic therapy in patients with breast cancer.

BACKGROUND: Breast cancer-related lymphoedema (BCRL) is a result of interaction between several pathophysiological processes, and is not simply a 'stopcock' effect resulting from removal of axillary lymph nodes. The aim of this study was to test the hypothesis that there is a constitutional 'global' lymphatic dysfunction in patients who develop BCRL. METHODS: Lower-limb lymphoscintigraphy was performed in 30 women who had undergone axillary lymph node dissection at least 3 years previously, of whom 15 had BCRL and 15 did not. No patient had any clinical abnormality of the lower limb. The control group comprised 24 women with no history of cancer or lower-limb lymphoedema. (99m) Tc-Nanocoll was injected subcutaneously into the first webspace of each foot, followed by whole-body imaging. Scans were reported as abnormal if there was delay in lymph transport or rerouting through skin or deep system. Quantification was expressed as the percentage injected activity accumulating in ilioinguinal nodes. RESULTS: Mean(s.d.) ilioinguinal nodal accumulation at 150 min was significantly lower in women with BCRL than in those without (2·7(2·5) versus 5·9(4·8) per cent respectively; P = 0·006). Abnormal findings on lower-limb lymphoscintigraphy were observed in 17 of the 30 patients: ten of the 15 women who had BCRL and seven of the 15 who did not. None of the 24 control subjects had abnormal scan findings. CONCLUSION: Women with BCRL had reduced lower-limb lymph drainage, supporting the hypothesis of a predisposition to BCRL. A surprisingly high proportion of patients with breast cancer also demonstrated lymphatic dysfunction, despite clinically normal lower limbs. Possible explanations could be a systemic effect of breast cancer or its treatment, or an unidentified association between breast cancer and lymphatic dysfunction. REGISTRATION NUMBER: ISRCTN84866416 ( http://www.isrctn.com).

Childhood brain tumours: associations with parental occupational exposure to solvents.

BACKGROUND: Parental occupational exposures have been associated with childhood brain tumours (CBT), but results are inconsistent. Few studies have studied CBT risk and parental solvent exposure, suggesting a possible association. We examined the association between CBT and parental occupational exposure to solvents in a case-control study. METHODS: Parents of 306 cases and 950 controls completed detailed occupational histories. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated for both maternal and paternal exposure to benzene, other aromatics, aliphatics and chlorinated solvents in key time periods relative to the birth of their child. Adjustments were made for matching variables (child's age, sex and state of residence), best parental education and occupational exposure to diesel exhaust. RESULTS: An increased risk of CBT was observed with maternal occupational exposures to chlorinated solvents (OR=8.59, 95% CI 0.94-78.9) any time before birth. Paternal exposure to solvents in the year before conception was associated with an increased CBT risk: OR=1.55 (95% CI 0.99-2.43). This increased risk appeared to be mainly attributable to exposure to aromatic solvents: OR=2.72 (95% CI 0.94-7.86) for benzene and OR=1.76 (95% CI 1.10-2.82) for other aromatics. CONCLUSIONS: Our results indicate that parental occupational exposures to solvents may be related to an increased risk of CBT.

Acute myeloid and chronic lymphoid leukaemias and exposure to low-level benzene among petroleum workers.

BACKGROUND: High benzene exposure causes acute myeloid leukaemia (AML). Three petroleum case-control studies identified 60 cases (241 matched controls) for AML and 80 cases (345 matched controls) for chronic lymphoid leukaemia (CLL). METHODS: Cases were classified and scored regarding uncertainty by two haematologists using available diagnostic information. Blinded quantitative benzene exposure assessment used work histories and exposure measurements adjusted for era-specific circumstances. Statistical analyses included conditional logistic regression and penalised smoothing splines. RESULTS: Benzene exposures were much lower than previous studies. Categorical analyses showed increased ORs for AML with several exposure metrics, although patterns were unclear; neither continuous exposure metrics nor spline analyses gave increased risks. ORs were highest in terminal workers, particularly for Tanker Drivers. No relationship was found between benzene exposure and risk of CLL, although the Australian study showed increased risks in refinery workers. CONCLUSION: Overall, this study does not persuasively demonstrate a risk between benzene and AML. A previously reported strong relationship between myelodysplastic syndrome (MDS) (potentially previously reported as AML) at our study's low benzene levels suggests that MDS may be the more relevant health risk for lower exposure. Higher CLL risks in refinery workers may be due to more diverse exposures than benzene alone.

The association between different night shiftwork factors and breast cancer: a case-control study.

BACKGROUND: Research on the possible association between shiftwork and breast cancer is complicated because there are many different shiftwork factors, which might be involved including: light at night, phase shift, sleep disruption and changes in lifestyle factors while on shiftwork (diet, physical activity, alcohol intake and low sun exposure). METHODS: We conducted a population-based case-control study in Western Australia from 2009 to 2011 with 1205 incident breast cancer cases and 1789 frequency age-matched controls. A self-administered questionnaire was used to collect demographic, reproductive, and lifestyle factors and lifetime occupational history and a telephone interview was used to obtain further details about the shiftwork factors listed above. RESULTS: A small increase in risk was suggested for those ever doing the graveyard shift (work between midnight and 0500 hours) and breast cancer (odds ratio (OR)=1.16, 95% confidence interval (CI)=0.97-1.39). For phase shift, we found a 22% increase in breast cancer risk (OR=1.22, 95% CI=1.01-1.47) with a statistically significant dose-response relationship (P=0.04). For the other shiftwork factors, risks were marginally elevated and not statistically significant. CONCLUSION: We found some evidence that some of the factors involved in shiftwork may be associated with breast cancer but the ORs were low and there were inconsistencies in duration and dose-response relationships.

Risk of childhood acute lymphoblastic leukaemia following parental occupational exposure to extremely low frequency electromagnetic fields.

BACKGROUND: Earlier studies have reported moderate increases in the risk of acute lymphoblastic leukaemia (ALL) among children whose mothers have been occupationally exposed to extremely low frequency (ELF) electromagnetic fields. Other studies examining parental occupational exposure to ELF and ALL have reported mixed results. METHODS: In an Australian case-control study of ALL in children aged < 15 years, parents were asked about tasks they undertook in each job. Exposure variables were created for any occupational exposure before the birth of the child, in jobs 2 years before birth, in jobs 1 year before birth and up to 1 year after birth. RESULTS: In all, 379 case and 854 control mothers and 328 case and 748 control fathers completed an occupational history. Exposure to ELF in all time periods was similar in case and control mothers. There was no difference in exposure between case and control fathers. There was no association between maternal (odds ratio (OR)=0.96; 95% CI=0.74-1.25) or paternal (OR=0.78; 95% CI=0.56-1.09) exposure to ELF any time before the birth and risk of childhood ALL. CONCLUSION: We did not find an increased risk of ALL in offspring of parents with occupational exposure to ELF.

Hypotheses for mechanisms linking shiftwork and cancer.

Shift work has been associated with various adverse health outcomes. In particular, there has been a recent flourish in investigating potential cancer risk associated with working night shifts and other shift schedules. Epidemiologic studies have revealed generally weak associations due to several methodological challenges such as lack of standard classifications of shift or night work. The field also has been hindered by a lack of clarity about the possible mechanisms by which shiftwork could have an effect on cancer risk. One possible mechanism is reduced production of melatonin caused by exposure to light at night. Although there is a growing body of evidence that provides some support for this mechanism, several other mechanisms also make sense from a biological point of view. Further, the relatively weak magnitude of the associations between light at night and melatonin level suggests that multiple factors may be operating along the pathway between shift work and adverse health consequences (including cancer risk). Here we propose four additional mechanisms that should be considered for a comprehensive investigation of these potential pathways. These are: phase shift; sleep disruption; lifestyle factors (such as poor quality diets, less physical activity and higher BMI); and lower vitamin D. Consideration of all these mechanisms is necessary in order to design effective preventative workplace strategies. In developed countries, approximately 20% of the population undertake shiftwork and, while we are unlikely to be able to eliminate shiftwork from current work practices, there are aspects of shiftwork that can be modified and there may be facets of individual susceptibility that we may be able to identify and target for prevention.