Incidence and estimated need of caesarean section,inguinal hernia repair,and operation for strangulated hernia in rural Africa.

Numbers of caesarean sections, inguinal hernia repairs, and operations for strangulated hernia performed in 1979-81 at 10 rural hospitals in eastern Africa were matched against estimated populations in the respective catchment areas. Annual rates of each operation varied considerably between hospitals, the averages being: for caesarean sections 25 per 100 000 per year; for inguinal hernia repairs 25 per 100 000 per year; and for operations for strangulated hernia four per 100 000 per year. The estimated minimum needs for these operations, based on available data for morbidity were 225, 175, and 30 per 100 000 per year, respectively. Numerous deaths and cases of permanent disability occur in remote rural villages because common conditions requiring urgent surgery are neither prevented nor properly cared for. A balanced improvement of both primary and secondary care in rural Africa is needed.     

Maternal and paternal contribution to intergenerational recurrence of breech delivery: population based cohort study

Objective To investigate intergenerational recurrence of breech delivery, with a hypothesis that both women and men delivered in breech presentation contribute to increased risk of breech delivery in their offspring.Design Population based cohort study for two generations.Setting Data from the medical birth registry of Norway, based on all births in Norway 1967-2004 (2.2 million births).Participants Generational data were provided through linkage by national identification numbers, forming 451 393 mother-offspring units and 295 253 father-offspring units. We included units where both parents and offspring were singletons and offspring were first born, forming 232 704 mother-offspring units and 154 851 father-offspring units for our analyses.Main outcome measure Breech delivery in the second generation.Results Men and women who themselves were delivered in breech presentation had more than twice the risk of breech delivery in their own first pregnancies compared with men and women who had been cephalic presentations (odds ratios 2.2, 95% confidence interval 1.8 to 2.7, and 2.2, 1.9 to 2.5, for men and women, respectively). The strongest risks of recurrence were found for vaginally delivered offspring and were equally strong for men and women. Increased risk of recurrence of breech delivery in offspring was present only for parents delivered at term.Conclusion Intergenerational recurrence risk of breech delivery in offspring was equally high when transmitted through fathers and mothers. It seems reasonable to attribute the observed pattern of familial predisposition to term breech delivery to genetic inheritance, predominantly through the fetus.     

Long-acting beta-agonists reduce mortality of patients with severe and very severe chronic obstructive pulmonary disease: a propensity score matching study

Background

Long-acting beta-agonists were one of the first-choice bronchodilator agents for stable chronic obstructive pulmonary disease. But the impact of long-acting beta-agonists on mortality was not well investigated.

Methods

National Emphysema Treatment Trial provided the data. Severe and very severe stable chronic obstructive pulmonary disease patients who were eligible for volume reduction surgery were recruited at 17 clinical centers in United States during 1988–2002. We used the 6–10 year follow-up data of patients randomized to non-surgery treatment. Hazard ratios for death by long-acting beta-agonists were estimated by three models using Cox proportional hazard analysis and propensity score matching were measured.

Results

The pre-matching cohort was comprised of 591 patients (50.6% were administered long-acting beta-agonists. Age: 66.6 ± 5.3 year old. Female: 35.4%. Forced expiratory volume in one second (%predicted): 26.7 ± 7.1%. Mortality during follow-up: 70.2%). Hazard ratio using a multivariate Cox model in the pre-matching cohort was 0.77 (P = 0.010). Propensity score matching was conducted (C-statics: 0.62. No parameter differed between cohorts). The propensity-matched cohort was comprised of 492 patients (50.0% were administered long-acting beta-agonists. Age: 66.8 ± 5.1 year old. Female: 34.8%. Forced expiratory volume in one second (%predicted) 26.5 ± 6.8%. Mortality during follow-up: 69.1%). Hazard ratio using a univariate Cox model in the propensity-matched cohort was 0.77 (P = 0.017). Hazard ratio using a multivariate Cox model in the propensity-matched cohort was 0.76 (P = 0.011).

Conclusions

Long-acting beta-agonists reduce mortality of severe and very severe chronic obstructive pulmonary disease patients.     

Early medication use in new-onset rheumatoid arthritis may delay joint replacement: results of a large population-based study

IntroductionUse of disease-modifying anti-rheumatic drugs (DMARDs) in rheumatoid arthritis (RA) may prevent joint damage and potentially reduce joint replacement surgeries. We assessed the association between RA drug use and joint replacement in Quebec, Canada.MethodsA cohort of new-onset RA patients was identified from Quebec’s physician billing and hospitalization databases from 2002–2011. The outcome was defined using procedure codes submitted by orthopedic surgeons. Medication use was obtained from pharmacy databases. We used alternative Cox regression models with time-dependent variables measuring the cumulative effects of past use during different time windows (one model focussing on the first year after cohort entry) for methotrexate (MTX), and other DMARDs. Models were adjusted for baseline sociodemographics, co-morbidity and prior health service use, time-dependent cumulative use of other drugs (anti-tumor necrosis factor [anti-TNF] agents, other biologics, cyclooxygenase-2 inhibitors [COXIBs], nonselective nonsteroidal antiinflammatory drugs [NSAIDs], and systemic steroids), and markers of disease severity.ResultsDuring follow-up, 608 joint replacements occurred among 11,333 patients (median follow-up: 4.6 years). The best-fitting model relied on the cumulative early use (within the first year after cohort entry) of MTX and of other DMARDs, with an interaction between MTX and other DMARDs. In this model, greater exposure within the first year, to either MTX (adjusted hazard ratio, HR = 0.95 per 1 month, 95 % confidence interval, 95 % CI 0.93-0.97) or other DMARDs (HR = 0.97, 95 % CI 0.95-0.99) was associated with longer time to joint replacement.ConclusionsOur results suggest that longer exposure to either methotrexate (MTX) or other DMARDs within the first year after RA diagnosis is associated with longer time to joint replacement surgery.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0713-3) contains supplementary material, which is available to authorized users.     

Predictive Outcome Modeling of Preoperative Clinical Symptoms and Electrodiagnostic Data in Tarsal Tunnel Surgery

Background  The relationship between tarsal tunnel syndrome (TTS), electrodiagnostic (Edx) findings, and surgical outcome is unknown. Analysis of TTS surgical release outcome patient satisfaction and comparison to Edx nerve conduction studies (NCSs) is important to improve outcome prediction when deciding who would benefit from TTS release. Methods  Retrospective study of 90 patients over 7 years that had tarsal tunnel (TT) release surgery with outcome rating and preoperative tibial NCS. Overall, 64 patients met study inclusion criteria with enough NCS data to be classified into one of the following three groups: (1) probable TTS, (2) peripheral polyneuropathy, or (3) normal. Most patients had preoperative clinical provocative testing including diagnostic tibial nerve injection, tibial Phalen''s sign, and/or Tinel''s sign and complaints of plantar tibial neuropathic symptoms. Outcome measure was percentage of patient improvement report at surgical follow-up visit. Results  Patient-reported improvement was 92% in the probable TTS group ( n  = 41) and 77% of the non-TTS group ( n  = 23). Multivariate modeling revealed that three out of eight variables predicted improvement from surgical release, NCS consistent with TTS ( p  = 0.04), neuropathic symptoms ( p  = 0.045), and absent Phalen''s test ( p  = 0.001). The R ² was 0.21 which is a robust result for this outcome measurement process. Conclusion  The best predictors of improvement in patients with TTS release were found in patients that had preoperative Edx evidence of tibial neuropathy in the TT and tibial nerve plantar symptoms. Determining what factors predict surgical outcome will require prospective evaluation and evaluation of patients with other nonsurgical modalities.     

Reducing the immediate availability of red blood cells in cardiac surgery,a single-centre experience

Background

In our institution, we have redefined our criteria for direct availability of red blood cell (RBC) units in the operation room. In this study, we sought to evaluate the safety of applying this new logistical policy of blood transfusion in the first preliminary group of patients.

Methods

In March 2010, we started a new policy concerning the elective availability of RBC units in the operation room. This policy was called: No Elective Red Cells (NERC) program. The program was applied for patients undergoing primary isolated coronary artery bypass grafting (CABG) or single valve surgery. No elective RBC units were preoperatively ordered for these patients. In case of urgent need, blood was delivered to the operating room within 20 min. The present study includes the first 500 patients who were managed according to this policy. Logistic regression analyses were performed to investigate the impact of biomedical variables on fulfilling this NERC program.

Results

The majority of patients (n = 409, 81 %) did not receive any RBCs during the hospital stay. In patients who did receive RBCs (n = 91, 19 %), 11 patients (2.2 %) received RBCs after 24 h postoperatively. Female gender, left ventricular ejection fraction (LVEF) and EuroSCORE were significant predictors for the need of blood transfusion (OR = 3.12; 2.79; 1.17 respectively).

Conclusion

In a selected group of patients, it is safe to perform cardiac surgery without the immediate availability of RBCs in the operating room. Transfusion was avoided in 81 % of these patients. Female gender, LVEF and EuroSCORE were associated with blood transfusion.     

Risk of incarceration of inguinal hernia among infants and young children awaiting elective surgery

Background

We determined the rate of incarceration of inguinal hernia among infants and young children waiting for elective surgery and examined the relation to wait times. We also explored the relation between wait times and the use of emergency department services before surgery.

Methods

We used linked data from administrative databases to identify infants and children less than 2 years of age who underwent surgical repair of an inguinal hernia between Apr. 1, 2002, and Mr. 31, 2004. We determined the rate of hernia incarceration during the wait for surgery and stratified the risk by patient age and sex. We used logistic regression analysis to examine factors associated with hernia incarceration and wait times.

Results

A total of 1065 infants and children less than 2 years old underwent surgical repair of an inguinal hernia during the study period. The median wait time was 35 days (interquartile range 17–77 days). Within 30 days after diagnosis, 126 (11.8%) of the patients had at least 1 emergency department visit; 23.8% of them presented with hernia incarceration. The overall rate of hernia incarceration was 11.9%. The rate was 5.2% with a wait time of up to 14 days (median time from diagnosis to first emergency department visit), as compared with 10.1% with a wait time of up to 35 days (median wait time to surgery) (p < 0.001). Factors associated with an increased risk of incarcerated hernia were age less than 1 year (odds ratio [OR] 2.07, 95% confidence interval [CI] 1.32–3.23), female sex (OR 1.75, 95% CI 1.04–2.93) and emergency department visits (1 visit, OR 2.73, 95% 1.65–4.50; ≥ 2 visits, OR 3.77, 95% CI 1.89–7.43). Children less than 1 year old who waited longer than 14 days had a significant 2-fold risk of incarcerated hernia (OR 1.92, 95% CI 1.11–3.32).

Interpretation

A wait time for surgery of more than 14 days was associated with a doubling of the risk of hernia incarceration among infants and young children with inguinal hernia. Our data support a recommendation that inguinal hernias in this patient population be repaired within 14 days after diagnosis.Inguinal hernias in infants and young children are a result of a failure of the processus vaginalis to close.¹ Once diagnosed, an inguinal hernia should be promptly repaired on an elective basis to prevent the risk of hernia incarceration. Incarceration occurs in about 12% of infants and young children with an inguinal hernia. The incidence is highest (approaching 30%) among infants (< 1 year old).² Boys who experience incarceration of an inguinal hernia have a 30% risk of testicular atrophy that may affect future fertility.³Many countries are struggling with long wait times for elective surgical procedures.^4–6 To date, research has been skewed toward examining wait times for surgery and other medical or diagnostic care in adults.^7–10 Prolonged wait times for surgery to repair hernias have not been associated with adverse outcomes in adults,¹¹ but the effect of prolonged wait times in children has not been well studied.^1,12We conducted this study to examine the relation between wait times for elective surgery and the risk of incarceration of inguinal hernia in infants and young children. We also explored the relation between wait times and the use of emergency department services before surgery.     

Smoking cessation after an acute coronary syndrome: immediate quitters are successful quitters

Background

Cardiovascular disease (CVD) prevention guidelines stress the importance of smoking cessation and recommend intensive follow-up. To guide the development of such cessation support strategies, we analysed the characteristics that are associated with successful smoking cessation after an acute coronary syndrome (ACS).

Methods

We used data from the Randomised Evaluation of Secondary Prevention for ACS patients coordinated by Outpatient Nurse SpEcialists (RESPONSE) trial (n = 754). This was designed to quantify the impact of a nurse-coordinated prevention program, focusing on healthy lifestyles, traditional CVD risk factors and medication adherence. For the current analysis we included all smokers (324/754, 43 %). Successful quitters were defined as those who reported abstinence at 1 year of follow-up.

Results

The majority of successful quitters quit immediately after the ACS event and remained abstinent through 1 year of follow-up, without extra support (128/156, 82 %). Higher education level (33 vs. 15 %, p < 0.01), no history of CVD (87 vs. 74 %, p < 0.01) and being on target for LDL-cholesterol level at 1 year (78 vs. 63 %, p < 0.01) were associated with successful quitting.

Conclusion

The majority of successful quitters at 1 year stopped immediately after their ACS. Patients in this group showed that it was within their own ability to quit, and they did not relapse through 1 year of follow-up. Our study indicates that in a large group of patients who quit immediately after a life-threatening event, no relapse prevention program is needed.     

Longitudinal inspiratory capacity changes in chronic obstructive pulmonary disease

Background

The changes in inspiratory capacity (IC) over time in chronic obstructive pulmonary disease (COPD) patients are unknown. The Understanding Potential Long-term Impacts on Function with Tiotropium (UPLIFT®) trial included IC measurements.

Methods

IC analysis from UPLIFT® (N = 5992) was performed at 1 and 6 months, and every 6 months through 4 years. Annualized rate of decline in pre- and post-bronchodilator IC and mean differences at each time point were analyzed by mixed-effects models. The relationships between baseline IC and exacerbation rate and mortality were explored using Cox regression analysis.

Results

Baseline characteristics: age, 65 years; 75% men; post-bronchodilator forced expiratory volume in 1 second, 1.32 L (48% predicted); pre- and post-bronchodilator IC, 2.03 and 2.33 L. Mean IC rate of decline (mL/year) was 34 ± 2 (1.7% of baseline) and 50 ± 3 (2.1% of baseline) pre- and post-bronchodilator, respectively, without significant between-group differences. Morning pre-bronchodilator (trough) IC improved with tiotropium versus placebo: 124 mL (1 month), 103 mL (1 year), 107 mL (2 years), 98 mL (3 years), and 97 mL (4 years) (all p < 0.001). Post-bronchodilator improvements were similar between treatment groups. Lower baseline IC values were associated with reduced time to first exacerbation. For the lowest quartile (n = 1413) the values in months were 14.3 (11.7–17.0) for tiotropium and 10.3 (8.8–11.7) for controls (p < 0.01).

Conclusion

IC declines from approximately 34 to 50 mL/year in patients with stage II to IV COPD. Tiotropium treatment does not change the IC decline rate but provides 24-hour improvements in IC sustained over the long term. Trough IC differences suggest that tiotropium provides sustained decrease in end-expiratory lung volume.     

Delayed inflammation decrease is associated with mortality in Tocilizumab-treated critically ill SARS-CoV-2 patients: A retrospective matched-cohort analysis

Little is known about the immuno-inflammatory response to Tocilizumab and its association with outcome in critically-ill SARS-CoV2 pneumonia. In this multicenter retrospective cohort of SARS-CoV-2 patients admitted to three intensive care units between March and April 2020, we matched on gender and SAPS II 21 Tocilizumab-treated patients to 42 non-treated patients. Need for mechanical ventilation was 76% versus 79%. IL-6, C-reactive protein, and fibrinogen had been collected within the first days of admission (T1), 3 d (T2) and 7 d (T3) later. Tocilizumab-treated patients had persistently higher IL-6 plasma levels and persistently lower C-Reactive protein and fibrinogen levels. Among Tocilizumab-treated patients, baseline levels of inflammatory biomarkers were not different according to outcome. Conversely, C-reactive protein and fibrinogen decrease was delayed in non-survivors. C-Reactive protein decreased at T1 in survivors (45 [30–98] vs 170 [69–204] mg/l, P < 0.001) but only at T2 in non-survivors (37 [13–74] vs 277 [235–288], P = 0.03). Fibrinogen decreased at T2 in survivors (4.11 [3.58–4.69] vs 614 [5.61–7.85] g/l, P = 0.005) but not in non-survivors (4.79 [4.12–7.58] vs 7.24 [6.22–9.24] g/l, P = 0.125). Tocilizumab treatment was thus associated with a persistent both increase in plasma IL-6, and decrease in C-reactive protein and fibrinogen. Among Tocilizumab-treated patients, the decrease in inflammatory biomarkers was delayed in non-survivors.     

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

Introduction

The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods

In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results

During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions

In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial registrations

ISRCTN11916566 and EudraCT2006-006186-16     

Meniscal extrusion promotes knee osteoarthritis structural progression: protective effect of strontium ranelate treatment in a phase III clinical trial

IntroductionTo evaluate the impact of meniscal extrusion (Ext) on knee osteoarthritis (OA) structural progression and on response to strontium ranelate (SrRan) treatment at 36 months in patients with (+) or without (-) Ext, in association (+) or not (-) with bone marrow lesions (BML) in the medial compartment using X-rays (JSW) and qMRI.MethodsPatients from the qMRI substudy of the SEKOIA trial (SrRan 1 g/day, n = 113; SrRan 2 g/day, n = 105; placebo, n = 112) were stratified based on whether meniscal extrusion and/or BML were present or not in the medial compartment.ResultsIn the placebo group, Ext+ patients (n = 26) had more JSW loss (p = 0.002) and cartilage volume loss in the global knee (p = 0.034) and plateau (p = 0.005), and medial compartment (p = 0.0005) than Ext- patients (n = 86). Ext-BML+ patients (n = 18) demonstrated more JSW loss (p = 0.003) and cartilage volume loss in the global (p = 0.020) and medial femur (p = 0.055) than Ext-BML- (n = 68). Compared to Ext+ BML- (n = 14), Ext+ BML+ patients (n = 12) had more cartilage volume loss in the global femur (p = 0.028), with no change in JSW. The JSW loss (p = 0.0004) and cartilage volume loss (global knee, p = 0.033, medial compartment, p = 0.0005) were greater when Ext and BML were simultaneously present in the medial compartment. SrRan 2 g/day treatment demonstrated a reduction in OA knee structural progression with qMRI, but not with JSW, in which less cartilage volume loss was found in the plateaus (p = 0.007) in Ext+ patients (n = 15), and in the medial plateau (p = 0.046) in patients in whom both Ext and BML were co-localized.ConclusionThe findings of this study are novel and could have an impact on future strategies regarding clinical trials. Indeed, data first argue for a combined, cumulative effect of meniscal extrusion and bone marrow lesions on cartilage loss and, secondly, they showed that SrRan may have protective effects in OA patients with meniscal extrusion as well as when both meniscal extrusion and BML are co-localized.     

Bone marrow lesion volume reduction is not associated with improvement of other periarticular bone measures: data from the Osteoarthritis Initiative

Introduction

We evaluated the associations between bone marrow lesion (BML) volume change and changes in periarticular bone mineral density (paBMD) as well as subchondral sclerosis to determine whether BML change is associated with other local bone changes.

Methods

The convenience sample comprised participants in the Osteoarthritis Initiative (OAI) with weight-bearing posterior-anterior knee radiographs and magnetic resonance images (MRIs) at the 24- and 48-month visits and dual-energy x-ray absorptiometry (DXA) at the 30-/36-month and 48-month visits. The right knee was assessed unless contraindicated for MRI. We used knee DXA scans to measure medial tibia paBMD and medial/lateral paBMD ratio (M:L paBMD). Knee radiographs were scored for sclerosis (grades 0 to 3) in the medial tibia. Two raters determined BML volume on sagittal fat-suppressed MRI by using a semiautomated segmentation method. To focus on knees with only medial tibia BML changes, knees with lateral tibial BMLs were excluded. Medial tibial BML volume change was classified into three groups: BML regression (lowest quartile of medial tibial BML volume change), no-to-minimal change (middle two quartiles), and BML progression (highest quartile). We used proportional odds logistic regression models to evaluate the association between quartiles of changes in medial paBMD or M:L paBMD ratio, as outcomes, and BML volume change.

Results

The sample (n = 308) included 163 (53%) female subjects, 212 (69%) knees with radiographic osteoarthritis, and participants with a mean age of 63.8 ± 9.3 years and mean body mass index of 29.8 ± 4.7 kg/m². We found an association between greater increases in medial tibia paBMD and BML regression (OR = 1.7 (95% confidence interval (CI) = 1.1 to 2.8)) and a similar trend for BML progression (OR = 1.6 (95% CI = 1.0 to 2.6]). We also detected associations between greater increase in M:L paBMD and BML regression (OR = 1.6 (95% CI = 1.0 to 2.7]) and BML progression (OR = 1.8 (95% CI = 1.1 to 3.0)), although BML regression had borderline statistical significance. The frequency of sclerosis progression in the medial tibia (n = 14) was greater among knees with BML progression or regression compared with knees without BML change (P = 0.01 and P = 0.04, respectively).

Conclusion

BML regression and BML progression are characterized by concurrent increases in paBMD and sclerosis, which are characteristic of increased radiographic osteoarthritis severity. At least during 24 months, BML regression is not representative of improvement in other periarticular bone measures.     

Association between individual quadriceps muscle volume/enthesis and patello femoral joint cartilage morphology

Introduction

The aim of this study was to determine the association between individual quadriceps muscle volumes and the quadriceps enthesis structures and cartilage morphology at the patellofemoral joint (PFJ).

Methods

We studied 12 cadavers (age 75 ± 5 years). For both legs, individual quadriceps muscles (vastus lateralis (VL), rectus femoris (RF), vastus intermedialis (VI) and vastus medialis (VM)) were dissected and their volumes measured. Cartilage areas at the PFJ were classified using the International Cartilage Repair Society (ICRS) score. Histological sections were evaluated at the quadriceps tendon enthesis (laterally, centrally and medially). Several variables were calculated on the binary images based on two-dimensional analysis. These were apparent bone area (BA) and apparent trabecular thickness (TH). A Spearman rank test was used to determine the strength of correlation between individual quadriceps muscles volume, the structure of the quadriceps tendon enthesis and the ICRS score.

Results

The thickness of calcified fibrocartilage tissue was significantly greater in the central part of the enthesis than both medially (P = 0.03) and laterally (P = 0.04). Uncalcified fibrocartilage was significantly thicker laterally (P = 0.04) and centrally (P = 0.02) than medially. Muscle volume was highest (P <0.05) for the VL, followed by the VI, VM and RF. There was no association between total and individual muscle volumes and ICRS or BA. However, there was a strong positive correlation (r = 0.81) between the VL/VM volume ratio and BA ratio (bone volume at the lateral part divided by bone volume at the medial part). There was a moderate positive correlation between VL/VM and ICRS (r = 0.65) and between ICRS and BA ratio (lateral/medial; r = 0.74).

Conclusions

Individual and total quadriceps volumes were not correlated with cartilage loss at the PFJ or fibrocartilage thickness. However, both VL/VM and BA ratio (lateral/medial) were positively correlated with ICRS scoring and therefore could be a tool for predicting degree of PFJ osteoarthritis severity.     

Genetically Predicted Body Mass Index and Breast Cancer Risk: Mendelian Randomization Analyses of Data from 145,000 Women of European Descent

BackgroundObservational epidemiological studies have shown that high body mass index (BMI) is associated with a reduced risk of breast cancer in premenopausal women but an increased risk in postmenopausal women. It is unclear whether this association is mediated through shared genetic or environmental factors.MethodsWe applied Mendelian randomization to evaluate the association between BMI and risk of breast cancer occurrence using data from two large breast cancer consortia. We created a weighted BMI genetic score comprising 84 BMI-associated genetic variants to predicted BMI. We evaluated genetically predicted BMI in association with breast cancer risk using individual-level data from the Breast Cancer Association Consortium (BCAC) (cases  =  46,325, controls  =  42,482). We further evaluated the association between genetically predicted BMI and breast cancer risk using summary statistics from 16,003 cases and 41,335 controls from the Discovery, Biology, and Risk of Inherited Variants in Breast Cancer (DRIVE) Project. Because most studies measured BMI after cancer diagnosis, we could not conduct a parallel analysis to adequately evaluate the association of measured BMI with breast cancer risk prospectively.ResultsIn the BCAC data, genetically predicted BMI was found to be inversely associated with breast cancer risk (odds ratio [OR]  =  0.65 per 5 kg/m² increase, 95% confidence interval [CI]: 0.56–0.75, p = 3.32 × 10⁻¹⁰). The associations were similar for both premenopausal (OR   =   0.44, 95% CI:0.31–0.62, p  =  9.91 × 10⁻⁸) and postmenopausal breast cancer (OR  =  0.57, 95% CI: 0.46–0.71, p  =  1.88 × 10⁻⁸). This association was replicated in the data from the DRIVE consortium (OR  =  0.72, 95% CI: 0.60–0.84, p   =   1.64 × 10⁻⁷). Single marker analyses identified 17 of the 84 BMI-associated single nucleotide polymorphisms (SNPs) in association with breast cancer risk at p < 0.05; for 16 of them, the allele associated with elevated BMI was associated with reduced breast cancer risk.ConclusionsBMI predicted by genome-wide association studies (GWAS)-identified variants is inversely associated with the risk of both pre- and postmenopausal breast cancer. The reduced risk of postmenopausal breast cancer associated with genetically predicted BMI observed in this study differs from the positive association reported from studies using measured adult BMI. Understanding the reasons for this discrepancy may reveal insights into the complex relationship of genetic determinants of body weight in the etiology of breast cancer.     

Rheumatoid arthritis response to treatment across IgG1 allotype – anti-TNF incompatibility: a case-only study

IntroductionWe have hypothesized that incompatibility between the G1m genotype of the patient and the G1m1 and G1m17 allotypes carried by infliximab (INX) and adalimumab (ADM) could decrease the efficacy of these anti-tumor necrosis factor (anti-TNF) antibodies in the treatment of rheumatoid arthritis (RA).MethodsThe G1m genotypes were analyzed in three collections of patients with RA totaling 1037 subjects. The first, used for discovery, comprised 215 Spanish patients. The second and third were successively used for replication. They included 429 British and Greek patients and 393 Spanish and British patients, respectively. Two outcomes were considered: change in the Disease Activity Score in 28 joint (ΔDAS28) and the European League Against Rheumatism (EULAR) response criteria.ResultsAn association between less response to INX and incompatibility of the G1m1,17 allotype was found in the discovery collection at 6 months of treatment (P = 0.03). This association was confirmed in the replications (P = 0.02 and 0.08, respectively) leading to a global association (P = 0.001) that involved a mean difference in ΔDAS28 of 0.4 units between compatible and incompatible patients (2.3 ± 1.5 in compatible patients vs. 1.9 ± 1.5 in incompatible patients) and an increase in responders and decrease in non-responders according to the EULAR criteria (P = 0.03). A similar association was suggested for patients treated with ADM in the discovery collection, but it was not supported by replication.ConclusionsOur results suggest that G1m1,17 allotypes are associated with response to INX and could aid improved therapeutic targeting in RA.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0571-z) contains supplementary material, which is available to authorized users.     

Impact of self-reported Gastroesophageal reflux disease in subjects from COPDGene cohort

Background

The coexistence of gastroesophageal reflux disease (GERD) and COPD has been recognized, but there has been no comprehensive evaluation of the impact of GERD on COPD-related health status and patient-centered outcomes.

Methods

Cross-sectional and longitudinal study of 4,483 participants in the COPDGene cohort who met GOLD criteria for COPD. Physician-diagnosed GERD was ascertained by questionnaire. Clinical features, spirometry and imaging were compared between COPD subjects without versus with GERD. We evaluated the relationship between GERD and symptoms, exacerbations and markers of microaspiration in univariate and multivariate models. Associations were additionally tested for the confounding effect of covariates associated with a diagnosis of GERD and the use of proton-pump inhibitor medications (PPIs). To determine whether GERD is simply a marker for the presence of other conditions independently associated with worse COPD outcomes, we also tested models incorporating a GERD propensity score.

Results

GERD was reported by 29% of subjects with female predominance. Subjects with GERD were more likely to have chronic bronchitis symptoms, higher prevalence of prior cardiovascular events (combined myocardial infarction, coronary artery disease and stroke 21.3% vs. 13.4.0%, p < 0.0001). Subjects with GERD also had more severe dyspnea (MMRC score 2.2 vs. 1.8, p < 0.0001), and poorer quality of life (QOL) scores (St. George’s Respiratory Questionnaire (SGRQ) total score 41.8 vs. 34.9, p < 0.0001; SF36 Physical Component Score 38.2 vs. 41.4, p < 0.0001). In multivariate models, a significant relationship was detected between GERD and SGRQ (3.4 points difference, p < 0.001) and frequent exacerbations at baseline (≥2 exacerbation per annum at inclusion OR 1.40, p = 0.006). During a mean follow-up time of two years, GERD was also associated with frequent (≥2/year exacerbations OR 1.40, p = 0.006), even in models in which PPIs, GERD-PPI interactions and a GERD propensity score were included. PPI use was associated with frequent exacerbator phenotype, but did not meaningfully influence the GERD-exacerbation association.

Conclusions

In COPD the presence of physician-diagnosed GERD is associated with increased symptoms, poorer QOL and increased frequency of exacerbations at baseline and during follow-up. These associations are maintained after controlling for PPI use. The PPI-exacerbations association could result from confounding-by-indication.     

The clinical significance,natural history and predictors of bone marrow lesion change over eight years

Introduction

There is increasing evidence to suggest that bone marrow lesions (BMLs) play a key role in the pathogenesis of osteoarthritis (OA). However, there is a lack of long term data. The aim of this study was to describe the natural history of knee BMLs, their association with knee pain and examine predictors of BML change over eight years.

Methods

A total of 198 subjects (109 adult offspring of subjects who had a knee replacement and 89 community-based controls) were studied. Knee pain and BML size were assessed at two and ten year visits.

Results

At the two year visit, 64% of participants (n = 127) had 229 BMLs (34% patella, 26% femoral and 40% tibial). Over eight years, 24% (55/229) increased in size, 55% (125/229) remained stable and 21% (49/229) decreased in size or resolved completely. Of the participants without BMLs at baseline, 52% (37/71) developed incident BMLs.After adjusting for confounders, eight year change in total BML size was associated with change in knee pain in offspring (β = 2.50, 95% confidence interval (CI) 0.96 to 4.05) but not controls. This association was stronger in males. Incident BMLs were associated with increase in pain (β = 3.60, 95% CI 1.14 to 6.05). Body mass index (BMI) and strenuous activity (but not radiographic osteoarthritis or smoking) were associated with an increase in BML size.

Conclusion

In this midlife cohort, the proportion of BMLs increasing in size was similar to those decreasing in size with the majority remaining stable. Change in BMLs was predicted by BMI and strenuous activity. An increase in BML size or a new BML resulted in an increase in pain especially in males and those with a family history of OA.     

Cumulative risk adjusted mortality chart for detecting changes in death rate: observational study of heart surgery

Objective: To detect changes in mortality after surgery, with allowance being made for variations in case mix. Design: Observational study of postoperative mortality from January 1992 to August 1995. Setting: Regional cardiothoracic unit. Subjects: 3983 patients aged 16 and over who had open heart operations. Main outcome measures: Preoperative risk factors and postoperative mortality in hospital within 30 days were recorded for all surgical heart operations. Mortality was adjusted for case mix using a preoperative estimate of risk based on additive Parsonnet factors. The number of operations required for statistical power to detect a doubling of mortality was examined, and control limits at a nominal significance level of P=0.01 for detection of an adverse trend were determined. Results: Total mortality of 7.0% was 26% below the Parsonnet predictor (P<0.0001). There was a highly significant variation in annual case mix (Parsonnet scores 8.7-10.6, P<0.0001). There was no significant variation in mortality after adjustment for case mix (odds ratio 1-1.5, P=0.18) with monitoring by calendar year. With continuous monitoring, however, nominal 99% control limits based on 16 expected deaths were crossed on two occasions. Conclusions: Hospital league tables for mortality from heart surgery will be of limited value because year to year differences in death rate can be large (odds ratio 1.5) even when the underlying risk or case mix does not change. Statistical quality control of a single series with adjustment for case mix is the only way to take into account recent performance when informing a patient of the risk of surgery at a particular hospital. If there is an increase in the number of deaths the chances of the next patient surviving surgery can be calculated from the last 16 deaths.

Key messages

• Changes in the patient population affect a hospital’s annual death rate
• Year to year differences in death rate can be large even when there is no change in the underlying risk or case mix
• It takes surprisingly many operations before an increase in death rate can be distinguished from random fluctuation
• A formal inquiry should take place in a hospital if the death rate rises above control limits
• The chances of the next patient surviving surgery should be calculated using the surgeon’s most recent results