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BackgroundCOPD is a major cause of morbidity and mortality in populations eligible for lung cancer screening. We investigated the role of spirometry in a community-based lung cancer screening programme.MethodsEver smokers, age 55–74, resident in three deprived areas of Manchester were invited to a ‘Lung Health Check’ (LHC) based in convenient community locations. Spirometry was incorporated into the LHCs alongside lung cancer risk estimation (Prostate, Lung, Colorectal and Ovarian Study Risk Prediction Model, 2012 version (PLCOM2012)), symptom assessment and smoking cessation advice. Those at high risk of lung cancer (PLCOM2012 ≥1.51%) were eligible for annual low-dose CT screening over two screening rounds. Airflow obstruction was defined as FEV1/FVCResults99.4% (n=2525) of LHC attendees successfully performed spirometry; mean age was 64.1±5.5, 51% were women, 35% were current smokers. 37.4% (n=944) had airflow obstruction of which 49.7% (n=469) had no previous diagnosis of COPD. 53.3% of those without a prior diagnosis were symptomatic (n=250/469). After multivariate analysis, the detection of airflow obstruction without a prior COPD diagnosis was associated with male sex (adjOR 1.84, 95% CI 1.37 to 2.47; p1/FVC ratio (adjOR 4.19, 95% CI 2.95 to 5.95; padjOR 2.80, 95% CI 1.60 to 8.42; p=0.002).ConclusionsIncorporating spirometry into a community-based targeted lung cancer screening programme is feasible and identifies a significant number of individuals with airflow obstruction who do not have a prior diagnosis of COPD.

Low-dose CT (LDCT) screening of high-risk smokers reduces lung cancer (LC) specific mortality. Determining screening eligibility using individualised risk may improve screening effectiveness and reduce harm. Here, we compare the performance of two risk prediction models (PLCOEver-smokers aged 55-74, from deprived areas of Manchester, were invited to a Lung Health Check (LHC). Individuals at higher risk (PLCOPLCOProspective comparisons of risk prediction tools are required to optimise screening selection in different settings. The PLCO

We report results from the second annual screening round (T1) of Manchester’s ‘Lung Health Check’ pilot of community-based lung cancer screening in deprived areas (undertaken June to August 2017). Screening adherence was 90% (n=1194/1323): 92% of CT scans were classified negative, 6% indeterminate and 2.5% positive; there were no interval cancers. Lung cancer incidence was 1.6% (n=19), 79% stage I, treatments included surgery (42%, n=9), stereotactic ablative radiotherapy (26%, n=5) and radical radiotherapy (5%, n=1). False-positive rate was 34.5% (n=10/29), representing 0.8% of T1 participants (n=10/1194). Targeted community-based lung cancer screening promotes high screening adherence and detects high rates of early stage lung cancer.

Background: Cardiovascular disease (CVD) is a major cause of morbidity and mortality in populations eligible for lung cancer screening. The aim of this study was to determine whether a brief CV risk assessment, delivered as part of a targeted community-based lung cancer screening programme, was effective in identifying individuals at high risk who might benefit from primary prevention. Methods: The Manchester Lung Screening Pilot consisted of annual low dose CT (LDCT) over 2 screening rounds, targeted at individuals in deprived areas at high risk of lung cancer (age 55–74 and 6-year risk ≥1.51%, using PLCOM2012 risk model). All participants of the second screening round were eligible to take part in the study. Ten-year CV risk was estimated using QRISK2 in participants without CVD and compared to age (±5 years) and sex matched Health Survey for England (HSE) controls; high risk was defined as QRISK2 score ≥10%. Coronary artery calcification (CAC) was assessed on LDCT scans and compared to QRISK2 score. Results: Seventy-seven percent (n=920/1,194) of screening attendees were included in the analysis; mean age 65.6 ± 5.4 and 50.4% female. QRISK2 and lung cancer risk (PLCOM2012) scores were correlated (r = 0.26, p < 0.001). Median QRISK2 score was 21.1% (IQR 14.9–29.6) in those without established CVD (77.6%, n = 714/920), double that of HSE controls (10.3%, IQR 6.6–16.2; n = 714) (p < 0.001). QRISK2 score was significantly higher in those with CAC (p < 0.001). Screening attendees were 10-fold more likely to be classified high risk (OR 10.2 [95% CI 7.3–14.0]). One third (33.7%, n = 310/920) of all study participants were high risk but not receiving statin therapy for primary CVD prevention. Discussion: Opportunistic CVD risk assessment within a targeted lung cancer screening programme is feasible and is likely to identify a very large number of individuals suitable for primary prevention.

We report baseline results of a community-based, targeted, low-dose CT (LDCT) lung cancer screening pilot in deprived areas of Manchester. Ever smokers, aged 55–74 years, were invited to ‘lung health checks’ (LHCs) next to local shopping centres, with immediate access to LDCT for those at high risk (6-year risk ≥1.51%, PLCOM2012 calculator). 75% of attendees (n=1893/2541) were ranked in the lowest deprivation quintile; 56% were high risk and of 1384 individuals screened, 3% (95% CI 2.3% to 4.1%) had lung cancer (80% early stage) of whom 65% had surgical resection. Taking lung cancer screening into communities, with an LHC approach, is effective and engages populations in deprived areas.

Immune evasion is a hallmark of cancer. Losing the ability to present neoantigens through human leukocyte antigen (HLA) loss may facilitate immune evasion. However, the polymorphic nature of the locus has precluded accurate HLA copy-number analysis. Here, we present loss of heterozygosity in human leukocyte antigen (LOHHLA), a computational tool to determine HLA allele-specific copy number from sequencing data. Using LOHHLA, we find that HLA LOH occurs in 40% of non-small-cell lung cancers (NSCLCs) and is associated with a high subclonal neoantigen burden, APOBEC-mediated mutagenesis, upregulation of cytolytic activity, and PD-L1 positivity. The focal nature of HLA LOH alterations, their subclonal frequencies, enrichment in metastatic sites, and occurrence as parallel events suggests that HLA LOH is an immune escape mechanism that is subject to strong microenvironmental selection pressures later in tumor evolution. Characterizing HLA LOH with LOHHLA refines neoantigen prediction and may have implications for our understanding of resistance mechanisms and immunotherapeutic approaches targeting neoantigens. VIDEO ABSTRACT.

Selectivity against mutant nontargets with a few mismatches remains challenging in nucleic acid sensing. Sensitivity enhancement by analyte concentration does not improve selectivity because it affects targets and nontargets equally. Hydrodynamic or electrical shear enhanced selectivity is often accompanied by substantial losses in target signals, thereby leading to poor limits of detection. We introduce a platform based on depletion isotachophoresis in agarose gel generated by an ion-selective membrane that allows both selectivity and sensitivity enhancement with a two-step assay involving concentration polarization at an ion-selective membrane. By concentrating both the targets and probe-functionalized nanoparticles by ion enrichment at the membrane, the effective thermodynamic dissociation constant is lowered from 40 nM to below 500 pM, and the detection limit is 10 pM as reported previously. A dynamically optimized ion depletion front is then generated from the membrane with a high electrical shear force to selectively and irreversibly dehybridize nontargets. The optimized selectivity against a two-mismatch nontarget (in a 35-base pairing sequence) is shown to be better than the thermodynamic equilibrium selectivity by more than a hundred-fold, such that there is no detectable signal from the two-mismatch nontarget. We offer empirical evidence that irreversible cooperative dehybridization plays an important role in this kinetic selectivity enhancement and that mismatch location controls the optimum selectivity even when there is little change in the corresponding thermodynamic dissociation constant.

Herein is reported the separation and identification of a previously unknown imidazoline by-product originating from the fluorescent labeling procedure when applied to enzymatically released N-linked glycans of a human IgG1. The imidazoline by-product was generated via the reductive amination procedure with either sodium cyanoborohydride or 2-picoline borane. Using ultra performance liquid chromatography (UPLC) in conjunction with hydrophilic interaction-based chromatography (HILIC), the 2-aminobenzoic acid (2-AA)-labeled glycans were well-resolved from imidazoline by-products to facilitate direct identification utilizing electrospray ionization mass spectrometry (ESI–MS) with fragmentation. It was found that this minor species (∼2%) was 18.0105 u less than the neighboring peak GlcNAc 2 Man 3 GlcNAc 2 Fuc peak, abbreviated as A2G0F at 1582.5899 u. While this mass loss corresponds to the mass of a water molecule, the molecular location of loss of water was not straightforward in consideration of the biantennary A2G0F structure. Model studies were carried out using A2G0F standard and N- acetyllactosamine to identify the impurity as an imidazoline ring structure located at the reducing end of the glycan as confirmed by high resolution mass fragment ions. Imidazoline content decreased when the reductant concentration was increased. To conclude, evidence for the imidazoline structure was accomplished through high resolution, high accuracy mass spectrometry (HRAM), and experiments showing chemical susceptibility and isotopically labeled tracers. This study is the first to identify these minor species which likely impact all N -acetylglucosamine-type N-linked glycans from biologics.

Previous studies on smokeless tobacco use and head and neck cancer (HNC) have found inconsistent and often imprecise estimates, with limited control for cigarette smoking. Using pooled data from 11 US case-control studies (1981-2006) of oral, pharyngeal, and laryngeal cancers (6,772 cases and 8,375 controls) in the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, we applied hierarchical logistic regression to estimate odds ratios and 95% confidence intervals for ever use, frequency of use, and duration of use of snuff and chewing tobacco separately for never and ever cigarette smokers. Ever use (versus never use) of snuff was strongly associated with HNC among never cigarette smokers (odds ratio (OR) = 1.71, 95% confidence interval (CI): 1.08, 2.70), particularly for oral cavity cancers (OR = 3.01, 95% CI: 1.63, 5.55). Although ever (versus never) tobacco chewing was weakly associated with HNC among never cigarette smokers (OR = 1.20, 95% CI: 0.81, 1.77), analyses restricted to cancers of the oral cavity showed a stronger association (OR = 1.81, 95% CI: 1.04, 3.17). Few or no associations between each type of smokeless tobacco and HNC were observed among ever cigarette smokers, possibly reflecting residual confounding by smoking. Smokeless tobacco use appears to be associated with HNC, especially oral cancers, with snuff being more strongly associated than chewing tobacco.

TRACERx, a prospective study of patients with primary non-small cell lung cancer, aims to map the genomic landscape of lung cancer by tracking clonal heterogeneity and tumour evolution from diagnosis to relapse., The importance of intratumour genetic and functional heterogeneity is increasingly recognised as a driver of cancer progression and survival outcome. Understanding how tumour clonal heterogeneity impacts upon therapeutic outcome, however, is still an area of unmet clinical and scientific need. TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy [Rx]), a prospective study of patients with primary non-small cell lung cancer (NSCLC), aims to define the evolutionary trajectories of lung cancer in both space and time through multiregion and longitudinal tumour sampling and genetic analysis. By following cancers from diagnosis to relapse, tracking the evolutionary trajectories of tumours in relation to therapeutic interventions, and determining the impact of clonal heterogeneity on clinical outcomes, TRACERx may help to identify novel therapeutic targets for NSCLC and may also serve as a model applicable to other cancer types.

Joint hypermobility is a rarely recognised aetiology for focal or diffuse musculoskeletal symptoms. To assess the occurrence and importance of joint hypermobility in adult patients referred to a rheumatologist, we prospectively evaluated 130 consecutive new patients for joint hypermobility. Twenty women (15%) had joint hypermobility at three or more locations (greater than or equal to 5 points on a 9 point scale). Most patients with joint hypermobility had common musculoskeletal problems as the reason for referral. Two patients referred with a diagnosis of rheumatoid arthritis were correctly reassigned a diagnosis of hypermobility syndrome. Three patients with systemic lupus erythematosus had diffuse joint hypermobility. There was a statistically significant association between diffuse joint hypermobility and osteoarthritis. Most patients (65%) had first degree family members with a history of joint hypermobility. These results show that joint hypermobility is common, familial, found in association with common rheumatic disorders, and statistically associated with osteoarthritis. The findings support the hypothesis that joint hypermobility predisposes to musculoskeletal disorders, especially osteoarthritis.

Although cigarette smoking and alcohol consumption increase risk for head and neck cancers, there have been few attempts to model risks quantitatively and to formally evaluate cancer site-specific risks. The authors pooled data from 15 case-control studies and modeled the excess odds ratio (EOR) to assess risk by total exposure (pack-years and drink-years) and its modification by exposure rate (cigarettes/day and drinks/day). The smoking analysis included 1,761 laryngeal, 2,453 pharyngeal, and 1,990 oral cavity cancers, and the alcohol analysis included 2,551 laryngeal, 3,693 pharyngeal, and 3,116 oval cavity cancers, with over 8,000 controls. Above 15 cigarettes/day, the EOR/pack-year decreased with increasing cigarettes/day, suggesting that greater cigarettes/day for a shorter duration was less deleterious than fewer cigarettes/day for a longer duration. Estimates of EOR/pack-year were homogeneous across sites, while the effects of cigarettes/day varied, indicating that the greater laryngeal cancer risk derived from differential cigarettes/day effects and not pack-years. EOR/drink-year estimates increased through 10 drinks/day, suggesting that greater drinks/day for a shorter duration was more deleterious than fewer drinks/day for a longer duration. Above 10 drinks/day, data were limited. EOR/drink-year estimates varied by site, while drinks/day effects were homogeneous, indicating that the greater pharyngeal/oral cavity cancer risk with alcohol consumption derived from the differential effects of drink-years and not drinks/day.

Can combining HIV testing with legal support help pregnant women disclose their HIV status safely to their partners? Suzanne Maman and her colleagues describe the South Africa HIV Antenatal Care Post-Test Support Study (SAHAPS), a unique intervention to include legal education and referral with a package of post-test support services in KwaZulu-Natal, South Africa.

Background: At least 75% of head and neck cancers are attributable to a combination of cigarette smoking and alcohol drinking. A precise understanding of the independent association of each of these factors in the absence of the other with the risk of head and neck cancer is needed to elucidate mechanisms of head and neck carcinogenesis and to assess the efficacy of interventions aimed at controlling either risk factor. Methods: We examined the extent to which head and neck cancer is associated with cigarette smoking among never drinkers and with alcohol drinking among never users of tobacco. We pooled individual-level data from 15 case - control studies that included 10 244 head and neck cancer case subjects and 15 227 control subjects, of whom 1072 case subjects and 5775 control subjects were never users of tobacco and 1598 case subjects and 4051 control subjects were never drinkers of alcohol. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. All statistical tests were two-sided. Results: Among never drinkers, cigarette smoking was associated with an increased risk of head and neck cancer (OR for ever versus never smoking = 2.13, 95% CI = 1.52 to 2.98), and there were clear dose - response relationships for the frequency, duration, and number of pack-years of cigarette smoking. Approximately 24% (95% CI = 16% to 31%) of head and neck cancer cases among nondrinkers in this study would have been prevented if these individuals had not smoked cigarettes. Among never users of tobacco, alcohol consumption was associated with an increased risk of head and neck cancer only when alcohol was consumed at high frequency (OR for three or more drinks per day versus never drinking = 2.04, 95% CI = 1.29 to 3.21). The association with high-frequency alcohol intake was limited to cancers of the oropharynx/hypopharynx and larynx. Conclusions: Our results represent the most precise estimates available of the independent association of each of the two main risk factors of head and neck cancer, and they exemplify the strengths of large-scale consortia in cancer epidemiology. © The Author 2007. Published by Oxford University Press.

Purpose Thalidomide is effective for the treatment of severe cutaneous lupus. Our aim was to study the safety and efficacy of different doses of thalidomide in this condition. Methods We studied patients with severe cutaneous lupus that was unresponsive to antimalarials, prednisolone, methotrexate, azathioprine, and cyclosporin A. Starting doses of 100 mg daily (n = 16 patients), 50 mg daily (n = 17), or 50 mg on alternate days (n = 15) were compared. The response to thalidomide was categorized as complete remission, partial remission, or no visible improvement. All patients received a baseline electromyogram (EMG) followed by repeat EMG every 3 to 6 months, or sooner if neuropathic symptoms developed. Results Forty-eight patients (46 female; mean [± SD] age, 44 ± 12 years; range, 22 to 71 years) with discoid lupus (n = 18), subacute cutaneous lupus (n = 6), or systemic lupus erythematosus with skin involvement (n = 24) were included. The response rate was 81%, including 29 patients (60%) in complete remission and 10 (21%) in partial remission. Nine patients (19%) failed to respond. Thirteen patients (27%) developed peripheral neuropathy, which was EMG-proven in 11, including 4 patients in the 50-mg alternate-day group. Other side effects included drowsiness, constipation or abdominal pain, and amenorrhea. The relapse rate after stopping thalidomide was 67% (26/39). There was no association between a positive response to the drug and either starting doses or cumulative dose. Similarly, no association was found between peripheral neuropathy and the starting or cumulative dose. Conclusion Thalidomide is effective for the treatment of severe cutaneous lupus. There were no clear dose-dependent effects. However, the high incidence of neurotoxicity, even at low doses, suggests that it may be most useful as a remission-inducing drug.

A new inter-professional subject has been offered at a Canadian university, which examines issues related to professionals' integrating into rural practice; understanding the history and geography of rural communities and important issues affecting life in rural settings.

Work in the construction industry involves about a threefold increased risk of fatal injury compared with all industries combined. The purpose of this study was to identify potential risk factors for fatal injury in the construction industry in New Jersey. Multiple data sources including death certificates, medical examiner reports, Occupational Safety and Health fatality files, and Workers' Compensation reports were used to identify 200 construction-related fatalities in New Jersey during the years 1983 to 1989. All deaths were in men. The death rate was 14.5 per 100,000 employed person-years over the study period. Death rates tended to diminish with increasing age after 34 until age 65 when the death rate was the highest (27.7). Death rates were higher for Hispanics (34.8) and African-Americans (24) than whites (10.6). Ironworkers and roofers had highest rates (109.0 and 56.2, respectively) among specific occupational groups within the construction industry. The leading cause of death was falls (46%). These data suggest that intervention efforts directed toward workers at heights is needed. Further research is warranted to elucidate the factors contributing to the elevated fatality rate of workers over age 65, and to Hispanic and African-American workers. Language: en

About 19,000 finger amputations occur at work each year in the United States. Twenty percent of these injuries are severe enough to require hospitalization. Hospital discharge data from New Jersey (1985, 1986) were used to describe the demographic characteristics of persons with such injuries and to identify potential subjects for telephone interview. A total of 637 persons hospitalized for finger amputations were sent letters asking for their participation. Of 637 persons, 355 (56%) were contacted and 228 (36%) were interviewed, of whom 134 (59%) said their injury occurred at work. The annual rate of finger amputations at work was 9.3 per 100,000 employed persons. The rate was higher for males (14.7) than females (1.9). The age-adjusted rates were higher for Hispanic (52.8) and black (28.9) males than for white males (9.5). Persons working with machines or maintaining them in the manufacturing industry were at highest risk. Unjamming or repairing machinery (e.g., presses, saws, or slicers) while in operation was particularly hazardous. These data can be used to target occupations and industries for specific worksite intervention to prevent finger amputations. One limitation of this study, however, is that hospitalized occupational finger amputations may not be representative of all finger amputations, the majority of which are less severe and do not require hospitalization. Language: en

A 5-month-old girl given an allogeneic bone marrow transplant for Hurler's syndrome succumbed to fatal pneumonia 5 weeks after the transplant. Adenovirus type 2 was isolated from her urine before she died. Immunoperoxidase and electron microscopical studies of liver and lungs post mortem confirmed a disseminated adenovirus infection. The serological findings and the patient's young age suggested that the infection was a primary one. The importance of considering exogenous sources of adenovirus infection in bone marrow transplant recipients is discussed.

Computerized population-based hospital discharge data in New Jersey offer new opportunities for surveillance of serious work-related injuries. This database was evaluated for its potential in identifying selected injuries that occurred at work during 1985 and 1986. Hospital discharge data were compared with data collected by telephone interview of discharged patients. A total of 1,575 unique hospital discharge records for the selected injuries included finger amputation (1,041), thumb amputation (209), crush injury of the lower limb (208), toxic effects of heavy metals (69), and eye burns (48). Of 809 study subjects sent letters, 445 (55%) could be contacted and 289 (36%) were interviewed for the study. Sixty-one percent (175) said their injury was work related. A comparison was made between self-reported injury at work, and the presence of workers' compensation payer codes on the discharge database. The agreement beyond chance (Kappa) was 0.78 (95% CI = 0.67, 0.89). The sensitivity of this indicator of work relatedness was 83%; specificity was 98%. These data suggest that workers' compensation payment on the hospital discharge database may be a good to excellent proxy indicator of the work relatedness of these injuries. However, this proxy indicator will underestimate the number of work-related injuries by about 20%. Only 11% of hospital discharge records had external cause of injury codes (E-codes), which reduces the utility of the database for understanding the causal mechanisms of work-related injuries. Language: en

Cost-containment strategies initiated in the early 1980s caused a major shift in site of care delivery for persons needing nursing care. Where once the majority of clients were cared for in the acute-care setting until they were self-sufficient, now most are discharged to the home environment still requiring acute-care nursing interventions as well as community health nursing skills. This rapid shift in practice sites has placed severe strain on community health nursing agencies. Not only are more nurses required to fill the increased demand for services, but the demand comes at a time when we are experiencing a severe nursing shortage. This has forced many agencies to hire acute care nurses who have little or no community health nursing experience. These nurses come to community health nursing expecting to use the same set of skills and knowledge base used in their acute-care practice; however, the skill levels and concepts required for community health nursing are quite different from the acute care setting. Educational preparation has not kept pace with this shift in practice. Consequently, many nurses are not adequately prepared to enter community health nursing. Preparation must include theoretical and experiential components that focus on assessment skills (of the community and individual), decision making, case management, health systems management, teaching, and leadership. Collaborative efforts between community health organizations and educational institutions would seem to be one solution that would ensure adequately prepared nurses for community health nursing. The establishment and maintenance of strong staff-development programs within community health nursing agencies are also required.

Brief, behaviorally oriented treatment of sexual dysfunction is gaining increasing acceptance in medicine and psychiatry. However, relatively few clinics have published their treatment results. During a 2 1/2-year period, 36 couples with diagnoses of sexual dysfunction were treated with a modified Masters and Johnson protocol. The initial success rate was 83%, but the degree of improvement reported by the couples varied from marked to equivocal. Eighty-nine percent of the male partners and 83% of the female partners manifested psychologic signs or symptoms that either warranted a psychiatric diagnosis or were noted as significant traits or symptoms. With an average of 7.9 months of follow-up, the failure rate increased from 17% to 38%. This increase was attributed in part to the degree of combined psychosexual disorder identified in the patients. The etiologic relationships between psychiatric conditions and sexual dysfunctions are not fully understood and will require further study.

Peripheral neuropathy and hypertension caused by lead intoxication are reported in two children with sickle cell anemia. One child had generalized weakness in the initial occurrence and distal paralysis during a relapse two years later. The second child had foot and wrist drop. Both had slow peripheral nerve conduction velocities during the episodes. Chelation therapy was successful and resulted in a return of strength (over a period of several months) and a normalization of the blood pressures. Children with sickle cell anemia who are subjected to lead intoxication appear to be predisposed to peripheral nerve damage.