Lynch Syndrome and Somatic Mismatch Repair Variants in Pancreas Cancer.

Importance: Microsatellite (MS) instability (MSI-H) occurs frequently in Lynch syndrome (LS)-associated tumors and is associated with response to immune checkpoint blockade (ICB) therapy. MSI-H is conferred by germline or somatic variants in mismatch repair genes. The contribution of somatic oncogenesis to MSI-H in pancreatic cancer (PC) is unknown. Objective: To evaluate an LS-related PC cohort to define clinicogenomic features, describe somatic MSI-H cases (germline negative), characterize response to ICB, and guide preferred MS testing methods. Design, Setting, and Participants: This single-institution, retrospective analysis was conducted from March 2012 to July 2023 at Memorial Sloan Kettering Cancer Center and included 55 patients with PC and either an LS germline pathogenic variant (gPV) or somatic mismatch repair (MMR) variant. Main Outcomes and Measures: Composite MMR and MS status determined using orthogonal methods. An artificial intelligence classifier was used to account for low-cellularity specimens. Demographic and clinical data were abstracted from medical record. Zygosity status and somatic comutation landscape analyzed. Results: Fifty-five patients (23 women [42%]) had PC and an MMR variant: 32 (58%) had LS (LS cohort) and 23 (42%) had a somatic MMR variant (no germline pathogenic variant, somatic MMR cohort). In the LS cohort, 10 (31%) had gMSH2, 9 (28%) gMSH6, 8 (25%) gPMS2, 4 (13%) gMLH1, 1 (3%) gEPCAM. The median age at diagnosis was 68 years (range, 45-88 years). For composite MS status, 17 (59%) were MSI-H, 12 (41%) MS stable, and 3 MS unknown. Five cases were reclassified as MSI-H by the artificial intelligence classifier. In the somatic MMR cohort, 11 (48%) had MSH6, 7 (30%) MLH1, 3 (13%) MSH2, and 2 (9%) PMS2. The median age at diagnosis was 72 years (range, 66-85 years). For composite MS status, 10 (43%) were MSI-H, 11 (48%) MS stable, and 2 (9%) MS indeterminate. Six cases were reclassified as MSI-H by the artificial intelligence classifier. For the LS and somatic MMR cohorts, 20 received ICB (n = 17 MSI-H). The median ICB duration was 27.7 months (95% CI, 11.5 to not reached); the disease control rate was 80%. Conclusion: The results of this cross-sectional study suggest that MSI-H occurs due to LS or somatic oncogenesis in PC. Orthogonal MS testing is key in PC; the artificial intelligence classifier reclassified approximately 20% of cases, most of which were low cellularity. ICB for patients with LS or somatic MSI-H PC provided significant benefit.

Precision medicine for pancreatic cancer: characterizing the clinicogenomic landscape and outcomes of KRAS G12C-mutated disease.

BACKGROUND: Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. METHODS: Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. RESULTS: Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. CONCLUSION: Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.

Chlamydia retesting remains low among young women in Australia: an observational study using sentinel surveillance data, 2018-2022.

BACKGROUND: Chlamydia remains the most notified bacterial sexually transmissible infection in Australia with guidelines recommending testing for re-infection at 3months post treatment. This paper aimed to determine chlamydia retesting and repeat positivity rates within 2-4months among young women in Australia, and to evaluate what factors increase or decrease the likelihood of retesting. METHODS: Chlamydia retesting rates among 16-29-year-old women were analysed from Australian Collaboration for Coordinated Enhanced Sentinel Surveillance of sexually transmissible infection and bloodborne virus (ACCESS) sentinel surveillance data (n =62 sites). Among women with at least one positive test between 1 January 2018 and 31 August 2022, retesting counts and proportions within 2-4months were calculated. Logistic regression was performed to assess factors associated with retesting within 2-4months. RESULTS: Among 8758 women who were positive before 31 August 2022 to allow time for follow up, 1423 (16.2%) were retested within 2-4months, of whom 179 (12.6%) tested positive. The odds of retesting within 2-4months were 25% lower if tested in a coronavirus disease 2019 (COVID-9) pandemic year (2020-2022) (aOR=0.75; 95% CI 0.59-0.95). Among 9140 women with a positive test before 30 November 2022, 397 (4.3%) were retested too early (within 7days to 1month) and 81 (20.4%) of those were positive. CONCLUSIONS: Chlamydia retesting rates remain low with around a sixth of women retested within 2-4months in line with guidelines. Re-infection is common with around one in eight retesting positive. An increase in retesting is required to reduce the risk of reproductive complications and onward transmission.

Pancreatic Cancer: BRCA Targeted Therapy and Beyond.

Pancreatic ductal adenocarcinoma (PDAC) is projected to become the second leading cause of cancer-related death in the US by 2030, despite accounting for only 5% of all cancer diagnoses. Germline gBRCA1/2-mutated PDAC represents a key subgroup with a favorable prognosis, due at least in part to additional approved and guideline-endorsed therapeutic options compared with an unselected PDAC cohort. The relatively recent incorporation of PARP inhibition into the treatment paradigm for such patients has resulted in renewed optimism for a biomarker-based approach to the management of this disease. However, gBRCA1/2 represents a small subgroup of patients with PDAC, and efforts to extend the indication for PARPi beyond BRCA1/2 mutations to patients with PDAC and other genomic alterations associated with deficient DNA damage repair (DDR) are ongoing, with several clinical trials underway. In addition, despite an array of approved therapeutic options for patients with BRCA1/2-associated PDAC, both primary and acquired resistance to platinum-based chemotherapies and PARPi presents a significant challenge in improving long-term outcomes. Herein, we review the current treatment landscape of PDAC for patients with BRCA1/2 and other DDR gene mutations, experimental approaches under investigation or in development, and future directions.

Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice.

PURPOSE: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). EXPERIMENTAL DESIGN: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. RESULTS: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3-not reached (NR)], 27.1 months (95% CI: 22.7-NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9-NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2-29) relative to breast (18, 3-55) or ovarian (25, 3-56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. CONCLUSIONS: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes.

BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity.

BACKGROUND: /Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. METHODS: Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. RESULTS: Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months). CONCLUSIONS: LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.

Renal function change after switching tenofovir disoproxil fumarate for tenofovir alafenamide in the HIV-positive patients of a metropolitan sexual health service.

BACKGROUND: Tenofovir disoproxil fumarate (TDF) is widely used in the management of HIV-infection, but has been associated with renal impairment in a small proportion of patients. Tenofovir alafenamide (TAF), a novel prodrug of tenofovir, causes less renal impairment and can improve renal function in patients switched from TDF. The factors which predict improved renal function in patients switching from TDF to TAF have yet to be described. AIM: To determine which patient factors are associated with an improvement in renal function following the switch from a TDF- to a TAF-based HIV antiretroviral regimen. METHODS: A retrospective analysis was performed of a cohort from a publicly funded sexual health clinic in Sydney, Australia. All HIV-positive clinic patients switched from a TDF- to TAF-containing regimen between January 2016 and August 2018 were eligible for inclusion. Laboratory results were obtained from patients' electronic medical records. The statistical significance of differences between pre- and post-switch means was determined by paired t-tests, adjusted for baseline values, and associations between continuous variables by univariate linear regression. RESULTS: 79 patients met inclusion criteria. The majority were male (89%), with a median age of 44 years (IQR: 34.5 to 53). Patients had a mean pre-switch estimated glomerular filtration rate (eGFR) of 95 ± 2 mL/min/1.73 m2, and there was no significant change post-switch (p = 0.062). Pre-switch eGFR was a significant predictor of the magnitude of eGFR change after the switch (p < 0.001), but there was no significant association with age (p = 0.189), cumulative TDF exposure (p = 0.454) or baseline urinary protein to creatinine ratio (p = 0.814). CONCLUSION: While there was no significant difference in mean eGFR, in patients switched from TDF to TAF, baseline eGFR was a significant predictor of the change in eGFR. This suggests that patients on TDF with poorer baseline renal function would benefit more from switching to TAF. Further study to explore this association is warranted.

The prevalence and risk of non-infectious comorbidities in HIV-infected and non-HIV infected men attending general practice in Australia.

BACKGROUND: Non-AIDS-related mortality rates among HIV-infected patients still exceed those of their uninfected peers. A major driver of this excess mortality is a higher risk of non-infectious comorbidities, including cardiovascular disease, chronic kidney disease, type 2 diabetes mellitus, osteoporosis and cancer. The prevalence of mental illness and other chronic non-infectious comorbidities is identified as a primary concern of antiretroviral prescribers in Australia. METHODS: We conducted a cross-sectional, observational study using data from MedicineInsight, a large-scale Australian primary care database comprising longitudinal data from electronic clinical information systems. The HIV-infected cohort included all men with a recorded diagnosis of HIV. The non-HIV-infected cohort comprised all other men from the same practices. The prevalence and risk of cardiovascular disease, chronic kidney disease, type 2 diabetes mellitus, osteoporosis, cancer, anxiety and depression were compared between the groups. RESULTS: We included 2,406 HIV-infected males and 648,205 males with no record of HIV diagnosis attending primary care in this study. HIV-infected men were less socioeconomically disadvantaged and more urban-dwelling than men in the primary care cohort. We found that HIV-infected men attending primary care in Australia are at increased risk of chronic kidney disease, cancer, osteoporosis, anxiety and depression. There appears to be a risk of premature onset of cardiovascular disease, osteoporosis and cancer among younger HIV-infected patients. There is a high prevalence of anxiety and depression among HIV-infected men. CONCLUSIONS: Increased prevalence of non-infectious comorbidities among HIV-infected men has broad implications for the effective management of those with these chronic conditions. Education to raise awareness among both HIV-infected men and their care providers, together with a greater focus on risk reduction, monitoring and preventive care, may be effective strategies in primary healthcare settings to further narrow the gap in health outcomes between people living with HIV and their uninfected counterparts.

Human immunodeficiency virus-infected young people in Australia: data from the Australian HIV Observational Database.

BACKGROUND: Individuals aged 13-24 years undergo vast physical, cognitive, social and psychological changes. Australian data regarding clinical outcomes of those diagnosed with HIV in this age are sparse. AIM: We aimed to describe demographic factors, virologic and clinical outcomes of individuals aged 13-24 years diagnosed with human immunodeficiency virus (HIV). METHODS: Patients diagnosed with HIV after 1997 in the Australian HIV Observational Database were divided into young adults, diagnosed at age <25 years (n = 223), and older adults (n = 1957). Demographic and clinical factors were compared between groups. RESULTS: Young adults had a median age at diagnosis of 22 years (inter quartile range (IQR) 20-24) and median age at treatment initiation of 24 years (IQR 22-26). They were more likely to be female than the older cohort (21.1 vs 10.8%; P < 0.001). Men who have sex with men was the most common exposure category in both groups. CD4 count at diagnosis was significantly higher in younger than older adults (median 460 vs 400 cells/mm3 , P = 0.006), whereas HIV viral load at diagnosis was lower (35 400 vs 61 659 copies/mL, P = 0.011). The rate of loss to follow up (LTFU) was higher in young adults (8.0 vs 4.3 per 100PY, P < 0.001). Young adults were more likely to have a treatment interruption compared to older adults (5.3 vs 4.0 per 100PY, P = 0.039). Rates of treatment switch, time to treatment change, and CD4 and viral load responses to treatment were similar between groups. CONCLUSIONS: Young adults were diagnosed with HIV at higher CD4 counts and lower viral loads than their older counterparts. LTFU and treatment interruption were more common highlighting the need for extra efforts directed towards retention in care and education regarding the risks of treatment interruptions.

Understanding the Targeting and Uptake of HIV Testing Among Gay and Bisexual Men Attending Sexual Health Clinics.

We assessed trends in HIV testing outcomes during a period of clinic-based initiatives introduced to increase HIV testing among gay and bisexual men (GBM) attending sexual health clinics (SHCs) in New South Wales (NSW). A cohort of 25,487 HIV-negative GBM attending 32 SHCs in NSW (2009-2015) was classified into six sub-groups each year based on client-type (new/existing), risk-status (low/high-risk), and any recent HIV testing. Poisson regression methods were used to assess HIV testing outcomes in sub-groups of GBM. HIV testing outcomes and the sub-groups with greatest statistically significant annual increases were: individuals attending (26% in high-risk existing clients with recent testing); testing uptake (4% in low-risk existing clients with no recent testing); testing frequency (6% in low-risk existing clients with no recent testing and 5% in high-risk existing clients with recent testing); and total tests (31% in high-risk existing clients with recent testing). High-risk existing clients with recent testing had a 13% annual increase in the proportional contribution to total tests. Our findings show improved targeting of testing to high-risk GBM at NSW SHCs. The clinic-based initiatives should be considered for translation to other similar settings.

Human papillomavirus vaccination and genital warts in young Indigenous Australians: national sentinel surveillance data.

OBJECTIVES: To examine the impact of the national human papillomavirus (HPV) vaccination program (available to girls and women [12-26 years] since 2007 and to boys [12-15 years] since 2013) on the number of diagnoses of genital warts in Australian Aboriginal and Torres Strait Islander (Indigenous) people. DESIGN, SETTING, PARTICIPANTS: Analysis of routinely collected data from patients attending 39 sexual health clinics (SHCs) in the Genital Warts Surveillance Network for the first time.Major outcome: The average annual proportion of Indigenous and non-Indigenous SHC patients diagnosed with genital warts during the pre-vaccination (2004-2007) and vaccination periods (2008-2014), stratified by age group and sex. RESULTS: 7.3% of the 215 599 Australian-born patients with known Indigenous status and seen for the first time at participating SHCs during 2004-2014 were Indigenous Australians. The average proportion of female Indigenous patients diagnosed with warts was lower during the vaccination period than during the pre-vaccination period (in those under 21, summary rate ratio [SRR], 0.12; 95% CI, 0.07-0.21; P < 0.001); in 21-30-year olds: SRR, 0.41; 95% CI, 0.27-0.61; P < 0.001); there was no significant difference for women over 30 (SRR, 0.84; 95% CI, 0.51-1.36; P = 0.47). The proportion of male Indigenous heterosexual SHC patients under 21 diagnosed with warts was also lower during the vaccination period (SRR, 0.25; 95% CI, 0.12-0.49; P < 0.001), with no significant changes among older Indigenous men over 30. CONCLUSIONS: There were marked declines in the proportions of diagnoses of genital warts in young Indigenous women and men attending SHCs after the introduction of the HPV vaccination program. If high levels of HPV vaccine coverage are sustained, HPV-related cancer rates should also decline.

Screening and management practices for renal disease in the HIV-positive patient population of an inner metropolitan sexual health service.

Renal disease is an important and commonly encountered co-morbidity in HIV infection. Despite this, few data are available concerning renal disease in this patient group. A retrospective review was conducted of all HIV-positive patients of an inner metropolitan sexual health service who attended from 1 August 2013 to 31 July 2014 for HIV management. One hundred eighty-eight HIV-positive patients attended the clinic during the study period. The majority were male (96%), Caucasian (70%) and 30-39 years of age (37%). There was a high prevalence of renal risk factors in the population, including potentially nephrotoxic antiretroviral therapy (61%), smoking (38%), hypertension (12%), dyslipidemia (11%) and hepatitis C co-infection (7%). In the previous year, measurements of estimated glomerular filtration rate were performed in all patients, but measurements of lipid profiles, urinary protein and serum phosphate were performed within the last year in only 48%, 33% and 30% of patients, respectively. These are the first comprehensive data regarding renal disease, associated risk factors and screening and management practices in the HIV-positive patient population of a specialized sexual health service in Australia. This patient population demonstrates a particularly high prevalence of risk factors for renal disease. Despite this, screening investigations were not performed as recommended. This represents a potential area to improve patient care.

Screening and management of risk factors for cardiovascular disease in HIV-positive patients attending an Australian urban sexual health clinic.

Background Few data exist regarding cardiovascular risk among HIV-infected patients attending sexual health clinics (SHC) in Australia. METHODS: The medical records of 188 patients attending an inner-city SHC between August 2013 and July 2014 were retrospectively reviewed for cardiovascular risk factors and associated screening and management practices. RESULTS: Cardiovascular risk factors were common among attendees of the SHC, including smoking (38%), hypertension (14%) and dyslipidaemia (11%). Of the 188 patients, 23% reported using potentially cardiotoxic recreational drugs, 25% of dyslipidaemic patients were not on therapy and 10% of patients were hypertensive; none were prescribed treatment. A smoking cessation program was offered to all patients. CONCLUSION: A high prevalence of risk factors for cardiovascular disease was demonstrated. Modification of risk factors could be improved.

The impact of smoke exposure on the clinical phenotype of alpha-1 antitrypsin deficiency in Ireland: exploiting a national registry to understand a rare disease.

Individuals with Alpha-1 antitrypsin deficiency (AATD) have mutations in the SERPINA1 gene causing genetic susceptibility to early onset lung and liver disease that may result in premature death. Environmental interactions have a significant impact in determining the disease phenotype and outcome in AATD. The aim of this study was to assess the impact of smoke exposure on the clinical phenotype of AATD in Ireland. Clinical demographics and available thoracic computerised tomography (CT) imaging were detected from 139 PiZZ individuals identified from the Irish National AATD Registry. Clinical information was collected by questionnaire. Data was analysed to assess AATD disease severity and evaluate predictors of clinical phenotype. Questionnaires were collected from 107/139 (77%) and thoracic CT evaluation was available in 72/107 (67.2%). 74% of respondents had severe Chronic Obstructive Pulmonary Disease (COPD) (GOLD stage C or D). Cigarette smoking was the greatest predictor of impairment in FEV1 and DLCO (%predicted) and the extent of emphysema correlated most significantly with DLCO. Interestingly the rate of FEV1 decline was similar in ex-smokers when compared to never-smokers. Passive smoke exposure in childhood resulted in a greater total pack-year smoking history. Radiological evidence of bronchiectasis was a common finding and associated with increasing age. The Irish National AATD Registry facilitates clinical and basic science research of this condition in Ireland. This study illustrates the detrimental effect of smoke exposure on the clinical phenotype of AATD in Ireland and the benefit of immediate smoking cessation at any stage of lung disease.

Cervical screening uptake and abnormalities among women attending sexual health clinics for HIV care.

The aim of this study was to describe cervical screening uptake and assess correlates of screen-detected abnormalities in women attending sexual health services for HIV care. Of 156 women, 115 had documentation of a Pap test at least once in 3 years and 9.6% had an annual Pap test performed. Pap abnormalities were associated with younger age, being born in Sub-Saharan Africa, more recent arrival in Australia, lower CD4 count, detectable viral load, shorter time on antiretroviral therapy and more recent HIV diagnosis. Women accessing sexual health services for HIV care, especially those from culturally and linguistically diverse backgrounds, appear to be substantially under-screened and efforts to optimise screening are needed.

Clarification of the risk of chronic obstructive pulmonary disease in α1-antitrypsin deficiency PiMZ heterozygotes.

RATIONALE: Severe α1-antitrypsin deficiency (typically PiZZ homozygosity) is associated with a significantly increased risk of airflow obstruction and emphysema but the risk of chronic obstructive pulmonary disease (COPD) in PiMZ heterozygotes remains uncertain. OBJECTIVES: This was a family-based study to determine the risk of COPD in PiMZ individuals. METHODS: We compared 99 PiMM and 89 PiMZ nonindex subjects recruited from 51 index probands who were confirmed PiMZ heterozygotes and also had a diagnosis of COPD Global Initiative for Chronic Obstructive Lung Disease stage II-IV. The primary outcome measures of interest were quantitative variables of pre- and post-bronchodilator FEV1/FVC ratio, FEV1 (liters), FEV1 (% predicted), forced expiratory flow midexpiratory phase (FEF25-75; liters per second), FEF25-75 (% predicted), and a categorical outcome of COPD. MEASUREMENTS AND MAIN RESULTS: PiMZ heterozygotes compared with PiMM individuals had a reduced median (interquartile range) post-bronchodilator FEV1 (% predicted) (92.0 [75.6-105.4] vs. 98.6 [85.5-109.7]; P = 0.04), FEV1/FVC ratio (0.75 [0.66-0.79] vs. 0.78 [0.73-0.83]; P = 0.004), and FEF25-75 (% predicted) (63.84 [38.45-84.35] vs. 72.8 [55.5-97.7]; P = 0.0013) compared with PiMM individuals. This effect was abrogated in never-smoking and accentuated in ever-smoking PiMZ individuals. PiMZ heterozygosity was associated with an adjusted odds ratio for COPD of 5.18 (95% confidence interval, 1.27-21.15; P = 0.02) and this was higher (odds ratio, 10.65; 95% confidence interval, 2.17-52.29; P = 0.004) in ever-smoking individuals. CONCLUSIONS: These results indicate that PiMZ heterozygotes have significantly more airflow obstruction and COPD than PiMM individuals and cigarette smoke exposure exerts a significant modifier effect.

The prevalence of alpha-1 antitrypsin deficiency in Ireland.

BACKGROUND: Alpha-1 antitrypsin deficiency (AATD) results from mutations in the SERPINA1 gene and classically presents with early-onset emphysema and liver disease. The most common mutation presenting with clinical evidence is the Z mutation, while the S mutation is associated with a milder plasma deficiency. AATD is an under-diagnosed condition and the World Health Organisation recommends targeted detection programmes for AATD in patients with chronic obstructive pulmonary disease (COPD), non-responsive asthma, cryptogenic liver disease and first degree relatives of known AATD patients. METHODS: We present data from the first 3,000 individuals screened following ATS/ERS guidelines as part of the Irish National Targeted Detection Programme (INTDP). We also investigated a DNA collection of 1,100 individuals randomly sampled from the general population. Serum and DNA was collected from both groups and mutations in the SERPINA1 gene detected by phenotyping or genotyping. RESULTS: The Irish National Targeted Detection Programme identified 42 ZZ, 44 SZ, 14 SS, 430 MZ, 263 MS, 20 IX and 2 rare mutations. Analysis of 1,100 randomly selected individuals identified 113 MS, 46 MZ, 2 SS and 2 SZ genotypes. CONCLUSION: Our findings demonstrate that AATD in Ireland is more prevalent than previously estimated with Z and S allele frequencies among the highest in the world. Furthermore, our targeted detection programme enriched the population of those carrying the Z but not the S allele, suggesting the Z allele is more important in the pathogenesis of those conditions targeted by the detection programme.

Re-testing for chlamydia at sexual health services in Australia, 2004-08.

OBJECTIVE: To describe the frequency of the 3-month test for re-infection among sexual health service patients in Australia. METHODS: We assessed the re-testing rates at 30-120 days after chlamydia infection in men who have sex with men (MSM), heterosexual males and females attending sexual health services across Australia between 2004 and 2008. A χ(2)-test was used to determine significant differences in re-testing rates according to demographic characteristics and trends over time. RESULTS: In the 5-year period, 10207 MSM, 28530 heterosexual males and 31190 heterosexual females were tested for chlamydia. Of those tested, 9057 (13.0%) were positive. The proportion of patients with chlamydia infection who were re-tested in 30-120 days was 8.6% in MSM, 11.9% in heterosexual males and 17.8% in heterosexual females. Among MSM, chlamydia re-testing rates were lower in men aged <30 years (8.4%) than ≥30 years (12.5%) (P=0.04) and lower in travellers and migrants (2.9%) than non-travellers (9.9%) (P=0.002). In heterosexual males, chlamydia re-testing rates were lower in men in regional and rural areas (10.5%) than metropolitan areas (13.5%) (P=0.017). There was no increasing trend in re-testing rates between 2004 and 2008 (P=0.787). Of the patients re-tested, 44.1% of MSM were positive, 21.0% of heterosexual males and 16.1% of females. DISCUSSION: The high chlamydia positivity at 30-120 days support recommendations that call for a 3-month test for re-infection following a positive test. The low re-testing rates highlight the need for innovative strategies to increase re-testing.

An audit of Colposcopy referrals from a GU/STD clinic.

BACKGROUND: Cervical cancer is increasing at 1.5% per year in Ireland with 50% mortality giving 2.2% of all cancer deaths. In the Mid-West region a pilot screening programme has begun to screen all women 25-60 years. 66% of Genitourinary/Sexually transmitted disease (GU/STD) clinics' abnormal smears are <25 years. Requests to abandon "opportunistic" screening prompted this GU/STD clinic audit. METHODS: 221(8.4%) patients referred to colposcopy over 4 years were audited. Retrospective analysis was carried out on GU/STD clinic files, hospital files and computer records for biopsy reports. Ethical approval was prospectively granted. RESULTS: 2637 smears were carried out from November 1999 - September 2003.221 patients referred to colposcopy were audited.1%, 3%, 5% had severe, moderate and, mild dyskaryosis, respectively, on cervical screening while 0.8%, 1.2%, 1.5% had CIN3, CIN2, CIN1 abnormalities, respectively, on biopsy with 3.5% having no abnormality (Cervical Intraepithelial Neoplasia = CIN).53% referred to colposcopy were <25 years. CONCLUSION: 2% had high grade lesions. 37% of high grade lesions are <25 years.Of the high grade lesions 13% had Chlamydia trachomatis (27% of CIN3) and 44% had HPV despite Relative Risks (RR) being 0.75 and 1.09 respectively. Older women had higher grade changes. No statistical difference was found for progression, regression and persistence in those over and under 25.