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Introduction Approaches to the treatment of sexual difficulties, especially female sexual difficulties, have garnered greater attention in recent years. Some feminist sexuality scholars have cautioned that trends in biomedicine to bolster pharmaceutical interventions for sexual problems may have resulted in unnecessary medicalization of sexual difficulties. Furthermore, medicalization of other health problems can lead to iatrogenic sexual difficulties. Objective In the current study, we explore issues of antidepressant medication use and associated sexual side effects, focusing on the ways that women are impacted differently than men. We also address the lack of consensus in biomedicine around selective serotonin reuptake inhibitor (SSRI) mechanisms of action and implications for sexual and romantic side effects. Based on the role of serotonin in sexual desire and romantic interest, and existing findings indicating impacts of antidepressant use on sexual and relationship function, we investigate the impacts of SSRI treatment on various sexual and romantic ‘side effects’ for women as compared to men. Methods We conducted a secondary analysis using three waves of data from an annual online survey. All three waves included data from over 5,000 single (unmarried and unpartnered) U.S. adults ages 18 and older, and one of the three waves included additional data from over 1,000 married U.S adults. Participants answered questions about their romantic and sexual behavior, SSRI use, and background information. Results Compared to men, women were more than twice as likely to be taking SSRI medication. Across the sample, 43% reported experiencing a sexual/romantic side effect from their SSRI, including 38% of women and 51% of men. However, our data showed a significant difference between single and married participants, with 53% of married women reporting sexual/romantic side effects compared to 36% of single women. Married women were also more likely to report these side effects compared to single men. Additionally, among single women, there were different patterns of side effects and impacts than among single men. For example, we found SSRI use to be significantly associated with more interest in sexual exploration for men but not women. Conclusions Although sexual difficulties can sometimes be influenced by depression itself, existing research shows that SSRIs affect sexual functioning in ways that are unrelated to depressive symptomology. Women, who have greater levels of antidepressant use than men, experience SSRI-associated sexual side effects differently than men. Our results reflect this pattern in a large national sample of U.S. adults. Our findings raise questions about how women taking SSRIs may experience their relationships, especially considering that married women were more likely to report sexual/romantic side effects than single women. There are additional questions raised about potential challenges women may face in relationships with partners who are experiencing SSRI-associated side effects. For example, women may experience greater sexual pressure if they have a male partner with an increased desire for sexual exploration resulting from SSRI treatment. Overall, our findings highlight the need for further attention to sexual and romantic side effects associated with SSRI use and a more nuanced approach to these issues in research and in clinical settings. Disclosure Yes, this is sponsored by industry/sponsor: Match Group Clarification: Industry funding only - investigator initiated and executed study Any of the authors act as a consultant, employee or shareholder of an industry for: Match Group

Booster doses of meningococcal conjugate vaccines induce long-term protection against invasive meningococcal disease. We evaluated the immunogenicity and safety of a booster dose of MenACYW-TT in pre-school children who were primed 3 years earlier with MenACYW-TT or MCV4-TT (Nimenrix®). In this Phase III, open-label, multi-center study (NCT03476135), children (4–5 years old), who received a primary dose of MenACYW-TT or MCV4-TT as toddlers in a previous study, received a booster dose of MenACYW-TT. Titers of antibody against meningococcal serogroups A, C, W and Y were measured by serum bactericidal assay using human (hSBA) and baby rabbit (rSBA) complement in samples collected before (D0) and 30 days after (D30) booster vaccination. Safety was assessed over the 30-day study period. Ninety-one participants received the booster dose. In both study groups, hSBA titers increased from D0 to D30; serogroup C titers [95% confidence interval] were higher in the MenACYW-TT-primed vs MCV4-TT-primed group at D0 (106 [73.2, 153] vs 11.7 [7.03, 19.4], respectively) and D30 (5894 [4325, 8031] vs 1592 [1165, 2174], respectively); rSBA results were similar. Nearly all participants achieved ≥1:8 hSBA and rSBA titers at D30, which were higher or comparable to those observed post-primary dose, suggesting rapid booster responses. At D0, all hSBA and rSBA titers were higher than those observed pre-primary dose, suggesting persistence of immunogenicity. The MenACYW-TT booster dose was well-tolerated and had similar safety outcomes across study groups. These findings suggest that MenACYW-TT elicits robust booster responses in children primed 3 years earlier with MenACYW-TT or MCV4-TT. publishedVersion

Magnitude dimensions such as time and numerosity are fundamental components of our visual experience, allowing us to understand the environment and interact with it. Different magnitudes are however not processed independently from each other, but show a relationship whereby the perception of one dimension depends on the others (“magnitude integration”). In this study, we use electroencephalography (EEG) to address whether such integration may arise from a shared brain processing stage where different dimensions are integrated together, or from independent parallel processes interfering with each other. In the experiment, participants judged either the average numerosity or duration of dynamic dot-array stimuli concurrently modulated in both dimensions. First, the behavioural results show a magnitude integration effect in both tasks, with duration affecting the judgement of numerosity and vice versa. The EEG results further show that both numerosity and duration significantly modulate event-related potentials at several distinct latencies. Crucially, however, we identified a significant interaction between numerosity and duration emerging in a specific latency window (360-460 ms) irrespective of the task performed by participants. In this latency window, the modulation of ERPs provided by the interfering magnitude dimension can be predicted by the strength of the behavioural bias. Our results thus support the idea of different magnitude dimensions converging onto a shared perceptual processing stage mediating their integration. Overall, our results demonstrate a clear electrophysiological signature of magnitude integration between numerosity and time, and provide new evidence for a shared representational system encompassing different magnitude dimensions.

Patients with an aldosterone-producing adenoma (APA) carry a higher risk of cardiovascular disease and commonly have high levels of autoantibodies (AT1AA) that may activate the angiotensin II type 1 receptor (AT1R). AT1R activation is linked to an increase of the glucose metabolite methylglyoxal (MGO), a potential precursor of advanced glycation endproducts (AGEs) and driver of vascular inflammation. We investigated whether serum AT1AA levels are associated with serum MGO and AGE levels in APA patients. In a case series of 26 patients with APA we measured levels of dicarbonyls MGO, glyoxal (GO) and 3-deoxyglucosone (3-DG), and dicarbonyl-derived AGEs 5-hydro-5-methylimidazolone (MG-H1), Nε-(carboxyethyl)lysine (CEL) and Nε-(carboxymethyl)lysine (CML) with UPLC-MS/MS. We also measured AT1AA by ELISA. These measurements were repeated 1-month after adrenalectomy in a subset of 14 patients. Panels of inflammation and endothelial function were also measured by immunoassays. Although baseline higher AT1AA levels tended to be correlated with higher baseline serum MGO, GO and 3-DG levels (r = 0.18, p = 0.38; r = 0.20, p = 0.33; r = 0.23, p = 0.26; respectively), these correlations were not statistically significant. We observed no obvious correlations between higher AT1AA levels and protein-bound and free MG-H1, CEL and CML levels, and markers of inflammation and endothelial function. No decrease was observed in any of the dicarbonyls, protein-bound AGE levels and markers of inflammation and endothelial function after adrenalectomy. In patients with APA the serum levels of AT1AA were not significantly correlated with serum dicarbonyls, protein-bound and free AGE levels. Increased signalling of the AT1AA receptor may therefore be unlikely to overtly increase systemic dicarbonyl levels.

Summary Background In the absence of a licensed vaccine, Clostridioides (formerly Clostridium) difficile infection represents a substantial health burden. The aim of this study was to evaluate the efficacy, immunogenicity, and safety of a toxoid vaccine candidate. Methods We did a phase 3 multicentre, observer-blind, randomised, controlled trial at 326 hospitals, clinics, and clinical research centres in 27 countries in the USA, Canada, Latin America, Europe, and the Asia-Pacific region. We included adults aged 50 years or older who were considered to be at an increased risk of C difficile infection because they had previously had two hospital stays (each ≥24 h in duration) and had received systemic antibiotics in the previous 12 months (risk stratum 1), or because they were anticipating being admitted to hospital for 72 h or more for elective surgery within 60 days of enrolment (risk stratum 2). Eligible participants were stratified by geographical region and the two risk strata, and randomly assigned (2:1), with a fixed block size of three, to receive either a C difficile toxoid vaccine candidate, containing toxoids A and B (C difficile vaccine candidate group), or a placebo vaccine (placebo group). Participants, investigators, and personnel responsible for collecting safety data and analysing blood and stool samples were masked to group assignment. Personnel responsible for study product preparation and administration were not masked to group assignment. One dose (0·5 mL) of C difficile vaccine candidate or placebo vaccine was administered intramuscularly on days 0, 7, and 30. The primary outcome was the efficacy of the vaccine in preventing symptomatic C difficile infection, defined as having three or more loose stools in a period of 24 h or less, loose stools for 24 h or more, and a PCR-positive test for C difficile toxin B in a loose stool sample, within 3 years after the final vaccine dose. The primary outcome was measured in the modified intention-to-treat population (ie, all participants who received at least one injection of the assigned vaccine). The safety of the vaccine was assessed in the safety analysis set (ie, all participants who had received at least one injection, analysed according to the product received). This study is registered with WHO/ICTRP, number U111-1127-7162, and ClinicalTrials.gov , number NCT01887912 , and has been terminated. Findings Between July 30, 2013, and Nov 17, 2017, we enrolled and randomly assigned 9302 participants to the C difficile vaccine candidate group (n=6201) or to the placebo group (n=3101). 6173 (99·5%) participants in the C difficile vaccine candidate group and 3085 (99·5%) participants in the placebo group received at least one dose of the vaccine. The study was terminated after the first planned interim analysis because of futility. In the C difficile vaccine candidate group, 34 C difficile infections were reported over 11 697·2 person-years at risk (0·29 infections per 100 person-years [95% CI 0·20–0·41]) compared with 16 C difficile infections over 5789·4 person-years at risk in the placebo group (0·28 infections per 100 person-years [0·16–0·45]), indicating a vaccine efficacy of −5·2% (95% CI −104·1 to 43·5). In the C difficile vaccine candidate group, 2847 (46·6%) of 6113 participants reported an adverse event within 30 days of injection compared with 1282 (41·9%) of 3057 participants in the placebo group. The proportion of participants who had an adverse event leading to study discontinuation was 4·8% in both groups (296 participants in the C difficile vaccine candidate group and 146 participants in the placebo group). 1662 (27·2%) participants in the C difficile vaccine candidate group reported at least one serious adverse event compared with 851 (27·8%) participants in the placebo group. Interpretation In adults at risk for C difficile infection, a bivalent C difficile toxoid vaccine did not prevent C difficile infection. Since the C difficile vaccine candidate met the criteria for futility, the study was terminated and clinical development of this vaccine candidate was stopped. Funding Sanofi Pasteur.

This concise total synthesis of the Thomsen-Nouveau (Tn) glycoconjugate was accomplished using a palladium-catalyzed coupling between the glycosyl donor and Fmoc-protected serine acceptor. This is, to the best of our knowledge, the shortest synthesis reported from galactose for preparing this essential building block for large-scale solid phase peptide synthesis.

Culled dairy cows represent a considerable source of meat production, but their carcasses may vary greatly in quality because of the wide variation in the age, stage of lactation, breed, body condition, and other characteristics of the cows at slaughter. However, the effect of crossbreeding on the value of culled cows has so far received little investigation. The aim of this observational study was to compare a range of carcass attributes of cull cows from 3-breed rotational crossbreeding using Viking Red, Montbéliarde (MO), and Holstein (HO) bulls with those of HO purebred cows. Data on 1,814 dairy cows were collected. Cows were reared together in one herd and slaughtered in 4 slaughterhouses. The carcass weight, fleshiness, and fatness scores, the total value, and the price (€/kg) of each cow carcass were recorded. The culling of a few cows in the sample (n = 86) was classified by the farm manager as "urgent" following a diagnosis of injury or sickness, and this information was recorded. Carcass traits were analyzed with a mixed model which included the fixed effects of parity, days in milk, genetic group (purebred HO, 787 cows, and crossbred cows, classified according to the breed of sire within crossbreds, with 309, 428, and 290 cows sired by Viking Red, MO, and HO bulls, respectively), and interactions, and the random effects of month × year of the date of slaughter, and slaughterhouse. Logistic regression was used to investigate the association of parity, days in milk and purebred or crossbred origin with unplanned, "urgent" culling compared with regular culling. Average carcass weight across genetic groups was 297 ± 65 kg, average price €2.03 ± 0.53/kg, and average value €631 ± 269. Compared with HO, crossbred carcasses were 7 to 12% heavier depending on the breed of sire, were graded + 0.12 to + 0.28 units higher for fleshiness and + 0.26 to + 0.30 units higher for fatness, and fetched an 8 to 11% higher price. As a consequence, compared with purebred HO, carcasses from crossbreds had 15 to 24% higher value (€84 to €133 more per cow), with crossbred cows sired by MO showing the greatest values. Moreover, compared with the HO cows, the crossbred cows had a 37% lower risk of being urgently removed from the herd, which raises welfare concerns and may reduce the salvage value of cull cows. Because cull cows represent a supplemental source of income for dairy farmers, the greater overall value of crossbred cull cows should be taken into account in evaluating the economic effectiveness of crossbreeding schemes.

OBJECTIVES To evaluate the Misonix bone scalpel (MBS) for craniotomies in dogs and describe clinical findings and surgical experience in three dogs with large multilobular osteochondrosarcoma (MLO) of the skull. STUDY DESIGN Cadaver evaluation and retrospective case series. ANIMALS One canine cadaver; three client-owned dogs. METHODS Craniotomies of different sizes and at different locations were performed with MBS. Dural tear and bone discoloration were recorded. Clinical, imaging, and surgical findings of dogs diagnosed with MLO and where MBS was used for craniectomies were retrospectively included. RESULTS Cadaveric evaluation identified MBS as an efficient tool for rapid craniectomies (> 5minutes) albeit dural tears and some small foci of bone discoloration were observed. Craniectomies could be performed without complications in three dogs with MLO without dural tear or bone discoloration. .Excision was in complete in all cases. The short-term outcome was good, and the long-term outcome was fair to good. CONCLUSION Piezoelectric bone surgery with the Misonix bone scalpel is an alternative technology to perform craniectomies in dogs. It was not associated with complications in 3 dogs diagnosed and surgically treated for MLO. Dural tears and suspected bone necrosis can occur. Great care should be taken when using CT to establish disease free surgical osteotomy.

Introduction: Severe COVID-19 has been associated with aberrant coagulation factor activities, particularly in patients with a thrombotic event (TE). Management of anticoagulant is critical in the care of hospitalized patients with COVID-19. Hypothesis: Evaluation of a point-of-care (POC), functional, clot-time-based coagulation test to detect the anticoagulant effect of therapeutic unfractionated heparin (UFH) in hospitalized SARS-CoV-2-positive patients who developed a TE. Methods: An IRB-approved analysis of 36 citrated plasma specimens from 26 SARS-CoV-2-positive patients and 10 matched negative controls was performed. A Clotting Time Score (CTS), a measure of factor-specific inhibition (i.e. anticoagulant activity), was derived for each patient. CTS results were compared with traditional coagulation tests. Five UFH COVID-19 samples with low CTS scores ( Results: The CTS detected sub-therapeutic UFH anticoagulation levels more frequently in COVID-19 cases compared with controls (76% vs. 17%). Prothrombin Times, activated Partial Thromboplastin Times, anti-Xa levels, and antithrombin activity did not correlate with each other or with the CTS in the COVID-19 samples. CTS correlated with both FV and Factor X activity (R 2 =0.49, Spearman R=-0.68), which form the prothrombinase complex. The CTS was 94% sensitive and 67% specific for the occurrence of TEs in patients on UFH. CTS demonstrated a consistent anticoagulant response only to argatroban (100%) compared with other anticoagulants (60%). Conclusions: The CTS, generated using a novel, low-volume, rapid POC coagulation test is a strong indicator of the therapeutic effect of UFH anticoagulation in COVID-19 patients and may provide a predictive measure of TEs potentially occurring from anticoagulation resistance.

Aim: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux. Methods: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA. Results: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907–1509) nmol/l vs. irbesartan 300 mg 1053 (820–1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years. Conclusion: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915).

Tuberculosis (TB) is the leading cause of infectious death worldwide. Development of improved TB vaccines that boost or replace BCG is a major global health goal. ID93 + GLA-SE is a fusion protein TB vaccine candidate combined with the Toll-like Receptor 4 agonist adjuvant, GLA-SE. We conducted a phase 1, randomized, double-blind, dose-escalation clinical trial to evaluate two dose levels of the ID93 antigen, administered intramuscularly alone or in combination with two dose levels of the GLA-SE adjuvant, in 60 BCG-naive, QuantiFERON-negative, healthy adults in the US (ClinicalTrials.gov identifier: NCT01599897). When administered as 3 injections, 28 days apart, all dose levels of ID93 alone and ID93 + GLA-SE demonstrated an acceptable safety profile. All regimens elicited vaccine-specific humoral and cellular responses. Compared with ID93 alone, vaccination with ID93 + GLA-SE elicited higher titers of ID93-specific antibodies, a preferential increase in IgG1 and IgG3 subclasses, and a multifaceted Fc-mediated effector function response. The addition of GLA-SE also enhanced the magnitude and polyfunctional cytokine profile of CD4+ T cells. The data demonstrate an acceptable safety profile and indicate that the GLA-SE adjuvant drives a functional humoral and T-helper 1 type cellular response., Tuberculosis: novel vaccine formulation elicits strong immune responses A tuberculosis vaccine containing an immunity-potentiating agent stimulated strong immune responses in a first-in-human trial. Tuberculosis (TB) is the world’s foremost cause of infectious disease deaths, yet lacks an effective vaccine for adult humans. Rhea Coler, of the Infectious Disease Research Institute, Seattle, and a team from the United States and South Africa, tested their prophylactic on 60 healthy US adults. The vaccine consisted of ID93, a fusion of TB therapeutic target proteins, and GLA-SE—a supplement to boost immune responses. The candidate proved safe in all participants, with mild-to-moderate adverse effects, and provoked promising immune responses. The formulation was significantly more effective with GLA-SE than without. Further studies will elucidate the therapeutic benefit of this formulation and its ability to combat the pathogenicity of TB.

OBJECTIVE To determine variance effects influencing ground reaction forces (GRFs) in a heterogeneous population of lame dogs during trotting. ANIMALS 30 client-owned dogs with thoracic limb lameness and 31 dogs with pelvic limb lameness. PROCEDURES GRFs, velocity, height at the dorsal aspect of the scapulae (ie, withers), and shoulder height were obtained. Each dog was trotted across a force platform at its preferred velocity. Variance effects for 12 velocity and associated relative velocity (V*) ranges were examined. RESULTS Individual dog, velocity, V*, and limb significantly influenced GRFs. Withers height V* ranges were associated with small variance in GRFs, but all absolute and V* ranges were associated with significant effects for all 4 limbs and both types of lameness. Significant changes in lame limb GRFs and velocity in ipsilateral trials in dogs with thoracic limb and pelvic limb lameness were evident with trial repetition. Withers height V* range of 0.55 to 0.93 captured a large proportion of trials (> 90%) in dogs with thoracic limb or pelvic limb lameness, with limited effects on peak vertical force and vertical impulse. CONCLUSIONS AND CLINICAL RELEVANCE Trial repetition caused alterations to GRFs and subject velocity that may have confounded assessment of lameness, which supported the concept that a priori selection of a velocity or V* range for force platform gait analysis should use a range that captures valid trials efficiently while minimizing GRF variance. These ranges typically would span the preferred velocity of subject dogs, such as withers height V* of 0.55 to 0.93.

OBJECTIVE To determine whether walking at specific ranges of absolute and relative (V*) velocity would aid efficient capture of gait trial data with low ground reaction force (GRF) variance in a heterogeneous sample of dogs. ANIMALS 17 clinically normal dogs of various breeds, ages, and sexes. PROCEDURES Each dog was walked across a force platform at its preferred velocity, with controlled acceleration within 0.5 m/s2. Ranges in V* were created for height at the highest point of the shoulders (withers; WHV*). Variance effects from 8 walking absolute velocity ranges and associated WHV* ranges were examined by means of repeated-measures ANCOVA. RESULTS The individual dog effect provided the greatest contribution to variance. Narrow velocity ranges typically resulted in capture of a smaller percentage of valid trials and were not consistently associated with lower variance. The WHV* range of 0.33 to 0.46 allowed capture of valid trials efficiently, with no significant effects on peak vertical force and vertical impulse. CONCLUSIONS AND CLINICAL RELEVANCE Dogs with severe lameness may be unable to trot or may have a decline in mobility with gait trial repetition. Gait analysis involving evaluation of individual dogs at their preferred absolute velocity, such that dogs are evaluated at a similar V*, may facilitate efficient capture of valid trials without significant effects on GRF. Use of individual velocity ranges derived from a WHV* range of 0.33 to 0.46 can account for heterogeneity and appears suitable for use in clinical trials involving dogs at a walking gait.

This paper is a contribution to the special issue on Advances in Convection-Permitting Climate Modeling, consisting of papers that focus on the evaluation, climate change assessment, and feedback processes in kilometer-scale simulations and observations., A recently launched project under the auspices of the World Climate Research Program’s (WCRP) Coordinated Regional Downscaling Experiments Flagship Pilot Studies program (CORDEX-FPS) is presented. This initiative aims to build first-of-its-kind ensemble climate experiments of convection permitting models to investigate present and future convective processes and related extremes over Europe and the Mediterranean. In this manuscript the rationale, scientific aims and approaches are presented along with some preliminary results from the testing phase of the project. Three test cases were selected in order to obtain a first look at the ensemble performance. The test cases covered a summertime extreme precipitation event over Austria, a fall Foehn event over the Swiss Alps and an intensively documented fall event along the Mediterranean coast. The test cases were run in both “weather-like” (WL, initialized just before the event in question) and “climate” (CM, initialized 1 month before the event) modes. Ensembles of 18–21 members, representing six different modeling systems with different physics and modelling chain options, was generated for the test cases (27 modeling teams have committed to perform the longer climate simulations). Results indicate that, when run in WL mode, the ensemble captures all three events quite well with ensemble correlation skill scores of 0.67, 0.82 and 0.91. They suggest that the more the event is driven by large-scale conditions, the closer the agreement between the ensemble members. Even in climate mode the large-scale driven events over the Swiss Alps and the Mediterranean coasts are still captured (ensemble correlation skill scores of 0.90 and 0.62, respectively), but the inter-model spread increases as expected. In the case over Mediterranean the effects of local-scale interactions between flow and orography and land–ocean contrasts are readily apparent. However, there is a much larger, though not surprising, increase in the spread for the Austrian event, which was weakly forced by the large-scale flow. Though the ensemble correlation skill score is still quite high (0.80). The preliminary results illustrate both the promise and the challenges that convection permitting modeling faces and make a strong argument for an ensemble-based approach to investigating high impact convective processes., IG and LS have been supported by the Croatian Science Foundation (HrZZ) project CARE (no. 2831). JF acknowledges support by the Spanish R + D programme through MINECO/FEDER co-funded project INSIGNIA (CGL2016-79210-R). AL-G is supported by the Spanish government though grant BES-2016-078158 and MINECO/FEDER co-funded project MULTI-SDM (CGL2015-66583-R). JM and KW-S gratefully acknowledge the support by the German Science Foundation (DFG) through project FOR 1695. DM, MP, and HT gratefully acknowledge the support received via the Austrian Science Fund (FWF) project NHCM-2 (no. P24758-N29) and the projects HighEnd:Extremes and EASICLIM, funded by the Austrian Climate Research Programme (ACRP) of the Klima- und Energiefonds (nos. KR13AC6K10981 and KR16AC0K13160, respectively). SS and TL acknowledge the support of NOTUR project no. NN9280K and the Research Council of Norway and its basic institute support of their strategic project on Climate Services. RMC and PMMS gratefully acknowledge the support of the SOLAR project (PTDC/GEOMET/7078/2014) financed by the Portuguese Foundation for Science and Technology. EJ Kendon gratefully acknowledges funding from the Joint Department of Energy and Climate Change (DECC) and Department for Environment Food and Rural Affairs (Defra) Met Office Hadley Centre Climate Programme (GA01101). S. Khodayar research is supported by the Bundesministerium für Bildung und Forschung (BMBF; German Federal Ministry of Education and Research). Support of Ministry of Education, Youth and Sports of the Czech Republic for funding the participation in Euro-CORDEX activities via the scheme INTER-TRANSFER under the Grant no. LTT17007. Funding from the Research Council of Norway through the SUPER (Grant no. 250573) and HYPRE (Grant no. 243942) projects.

Objective The perioperative risk of an acute venous thromboembolism (VTE) event after inferior vena cava (IVC) reconstruction is unknown. We sought to describe VTE outcomes of our 15-year IVC reconstruction experience. Methods We performed a retrospective institutional review of all patients who underwent IVC reconstruction (September 1999-October 2014) and describe perioperative VTE outcomes. Results Sixty-five patients (mean age 58 ± 2 years) underwent IVC reconstruction (primary repair, 25%; patch, 43%; graft, 32%), most commonly for renal cell carcinoma (51%) and retroperitoneal sarcoma (22%). The overall incidence of perioperative VTE was 22% (n = 14), including isolated deep vein thrombosis (DVT) in 9% (n = 6) and pulmonary embolism in 12% (n = 8; 4 with concomitant DVT). Median time to diagnosis was 6 days (range, 1-37 days). Most VTE patients were symptomatic (57%; 8 of 14), including lower extremity edema in 50%, acute desaturation in 43%, and hemodynamic compromise in 36%. No patient died as a result of his or her VTE. There was a trend for more overall VTE events in patients who underwent graft reconstruction (primary, 13%; patch, 18%; graft, 33%; P = .06). VTE was also significantly associated with larger tumor size, renal vein reimplantation, and blood transfusions ( P ≤ .05). Late complications of VTE included lower extremity edema in two patients and graft thrombosis in one patient. Conclusions IVC reconstruction can be performed safely with low VTE-associated morbidity. Routine anticoagulation might not be warranted in these patients, but early postoperative screening for DVT should be considered, especially in cases with large tumor burden or when graft reconstruction is performed.

Anterior cruciate ligament (ACL) rupture is an important condition of the human knee. Second ruptures are common and societal costs are substantial. Canine cranial cruciate ligament (CCL) rupture closely models the human disease. CCL rupture is common in the Labrador Retriever (5.79% prevalence), ~100-fold more prevalent than in humans. Labrador Retriever CCL rupture is a polygenic complex disease, based on genome-wide association study (GWAS) of single nucleotide polymorphism (SNP) markers. Dissection of genetic variation in complex traits can be enhanced by studying structural variation, including copy number variants (CNVs). Dogs are an ideal model for CNV research because of reduced genetic variability within breeds and extensive phenotypic diversity across breeds. We studied the genetic etiology of CCL rupture by association analysis of CNV regions (CNVRs) using 110 case and 164 control Labrador Retrievers. CNVs were called from SNPs using three different programs (PennCNV, CNVPartition, and QuantiSNP). After quality control, CNV calls were combined to create CNVRs using ParseCNV and an association analysis was performed. We found no strong effect CNVRs but found 46 small effect (max(T) permutation PP = 6.6E-13). This gene cluster influences cranial-caudal body pattern formation during embryonic limb development. Clustered genes were found in 3 CNVRs on chromosome 14 (HoxA), 28 (NKX6-2), and 36 (HoxD). When analysis was limited to deletion CNVRs, the association was strengthened (P = 8.7E-16). This study suggests a component of the polygenic risk of CCL rupture in Labrador Retrievers is associated with small effect CNVs and may include aspects of stifle morphology regulated by homeobox domain transcript regulator genes.

Background Anterior cruciate ligament rupture (ACLR) is a debilitating and potentially life-changing condition in humans, as there is a high prevalence of early-onset osteoarthritis after injury. Identification of high-risk individuals before they become patients is important, as post-treatment lifetime burden of ACLR in the USA ranges from $7.6 to $17.7 billion annually. ACLR is a complex disease with multiple risk factors including genetic predisposition. Naturally occurring ACLR in the dog is an excellent model for human ACLR, as risk factors and disease characteristics in humans and dogs are similar. In a univariate genome-wide association study (GWAS) of 237 Labrador Retrievers, we identified 99 ACLR candidate loci. It is likely that additional variants remain to be identified. Joint analysis of multiple correlated phenotypes is an underutilized technique that increases statistical power, even when only one phenotype is associated with the trait. Proximal tibial morphology has been shown to affect ACLR risk in both humans and dogs. In the present study, tibial plateau angle (TPA) and relative tibial tuberosity width (rTTW) were measured on bilateral radiographs from purebred Labrador Retrievers that were recruited to our initial GWAS. We performed a multivariate genome wide association analysis of ACLR status, TPA, and rTTW. Results Our analysis identified 3 loci with moderate evidence of association that were not previously associated with ACLR. A locus on Chr1 associated with both ACLR and rTTW is located within ROR2, a gene important for cartilage and bone development. A locus on Chr4 associated with both ACLR and TPA resides within DOCK2, a gene that has been shown to promote immune cell migration and invasion in synovitis, an important predictor of ACLR. A third locus on Chr23 associated with only ACLR is located near a long non-coding RNA (lncRNA). LncRNA’s are important for regulation of gene transcription and translation. Conclusions These results did not overlap with our previous GWAS, which is reflective of the different methods used, and supports the need for further work. The results of the present study are highly relevant to ACLR pathogenesis, and identify potential drug targets for medical treatment. Electronic supplementary material The online version of this article (10.1186/s12863-018-0626-7) contains supplementary material, which is available to authorized users.

OBJECTIVE: Procedural characteristics, including stent design, may influence the outcome of carotid artery stenting (CAS). A thorough comparison of the effect of stent design on outcome of CAS is thus warranted to allow for optimal evidence-based clinical decision making. This study sought to evaluate the effect of stent design on clinical and radiologic outcomes of CAS. METHODS: A systematic search was conducted in MEDLINE, Embase, and Cochrane databases in May 2018. Included were articles reporting on the occurrence of clinical short- and intermediate-term major adverse events (MAEs; any stroke or death) or radiologic adverse events (new ischemic lesions on postprocedural magnetic resonance diffusion-weighted imaging [MR-DWI], restenosis, or stent fracture) in different stent designs used to treat carotid artery stenosis. Random effects models were used to calculate combined overall effect sizes. Metaregression was performed to identify the effect of specific stents on MAE rates. RESULTS: From 2654 unique identified articles, two randomized, controlled trials and 66 cohort studies were eligible for analysis (including 46,728 procedures). Short-term clinical MAE rates were similar for patients treated with open cell vs closed cell or hybrid stents. Use of an Acculink stent was associated with a higher risk of short-term MAE compared with a Wallstent (risk ratio [RR], 1.51; P = .03), as was true for use of Precise stent vs Xact stent (RR, 1.55; P < .001). Intermediate-term clinical MAE rates were similar for open vs closed cell stents. Use of open cell stents predisposed to a 25% higher chance (RR, 1.25; P = .03) of developing postprocedural new ischemic lesions on MR-DWI. No differences were observed in the incidence of restenosis, stent fracture, or intraprocedural hemodynamic depression with respect to different stent design. CONCLUSIONS: Stent design is not associated with short- or intermediate-term clinical MAE rates in patients undergoing CAS. Furthermore, the division in open and closed cell stent design might conceal true differences in single stent efficacy. Nevertheless, open cell stenting resulted in a significantly higher number of subclinical postprocedural new ischemic lesions detected on MR-DWI compared with closed cell stenting. An individualized patient data meta-analysis, including future studies with prospective homogenous study design, is required to adequately correct for known risk factors and to provide definite conclusions with respect to carotid stent design for specific subgroups.

The aim of this study was to evaluate whether a mental training protocol could improve gymnastic jumping performance. Seventy-two rhythmic gymnasts were randomly divided into an experimental and control group. At baseline, experimental group completed the Movement Imagery Questionnaire Revised (MIQ-R) to assess the gymnast ability to generate movement imagery. A repeated measures design was used to compare two different types of training aimed at improving jumping performance: (a) video observation and PETTLEP mental training associated with physical practice, for the experimental group, and (b) physical practice alone for the control group. Before and after six weeks of training, their jumping performance was measured using the Hopping Test (HT), Drop Jump (DJ), and Counter Movement Jump (CMJ). Results revealed differences between jumping parameters F(1,71)=11.957; p

We investigate the effect of political connections in Italy, for each level of government, on the credit markets and we find robust evidence that politically connected firms benefit from lower interest rates when the political link is at a local level. Our results show that this preferential treatment is stronger when connected firms borrow from banks with politicians on their boards and when the degree of autonomy granted to local loan officers is higher. The latter result provides a novel addition to the literature on the effects of the delegation of lending decisions within the bank. We also show that the effect is stronger in geographical areas where the incidence of corruption is higher. Overall, our results show that on aggregate the impact of political connections on interest rates is limited but it may rise significantly in specific (local) situations due to a combination of factors such as the delegation of lending decisions, a weaker rule of law and some governance characteristics of banks.

The aim of the present study was to analyse the daily variation of balance in two groups of female adolescents: elite athletes (n=20, aged 13.2 ± 0.5 years) and untrained students (n=20, aged 12.9 ± 0.6 years). Participants underwent two testing sessions over two days at two different times each day. Morningness-Eveningness self-assessment questionnaire was administered to assess the chronotype of the participants and oral temperature was measured too. Significant group differences were found in the overall balance tests (p

Regulation in the United States mandating the use of pressure testing as an assessment tool for the construction and commissioning of pipelines was initiated in 1970. Prior to regulation, however, pressure testing was being applied within the pipeline industry to provide confidence in the operational integrity of pipeline systems. Additional assessment technologies and processes including high resolution in-line inspection continue to be developed and further enhanced; however pressure testing remains a valuable and acceptable tool in the management of pipeline integrity. Current applications include quality verification of original construction practices, integrity assessment of existing pipelines, and verification of material yield strength when key records may be missing or incomplete. It is recognized that extensive hydrostatic testing knowledge exists today in the form of API Recommended Practices, ASME code documents, the body of work of industry consultants, regulatory language and other resources. A key element to implementing the current industry standards is a pipeline operator perspective in practical application on selection of hydrostatic testing as an assessment tool and the subsequent technical design of a hydrostatic test program in order to achieve integrity management goals. This paper discusses hydrostatic testing in the context of selection as an integrity management tool, development of risk-balanced objectives for a hydrostatic test program, and understanding the limitations and potential detrimental effects of hydrostatic testing. This paper summarizes key considerations in guidelines published in 2016 that were developed through a Pipeline Research Council International (PRCI) project. While written to be applicable to all hydrostatic testing, this work is a key element of the multi-year PRCI Electric Resistance Welded (ERW) and Longitudinal Seam Pipe Program which began in 2011 and was formed to comprehensively study and develop strategies for management of factors that contribute to seam failures.

Objective While active smoking is a causal agent in respiratory disease, the independent role of secondhand smoke (SHS) merits further investigation. We investigated associations between lifetime active smoking and exposure to secondhand smoke – studied independently – and current use of 1 or more inhaled medications as a surrogate for prevalent pulmonary disease in post-menopausal women. Study design Information on lifetime active and passive tobacco exposure and inhaled pulmonary medication usage at enrollment was collected from 88,185 postmenopausal women aged 50–79 enrolled in the Women’s Health Initiative Observational Study from 1993 to 1998 at 40 centers in the United States. Participants were recruited from localities surrounding the study centers using a variety of methods, including informational mailings and mass media campaigns. Main outcome measures Multivariate adjusted regression models were used to estimate odds ratios and 95% CI according to levels of active smoking and SHS exposure, and trends were tested across categories. Results Ever active smokers had an overall OR of 1.97 (95% CI 1.58–2.45) for having one or more prescribed inhaled medication compared with never-smoking women not exposed to active or passive smoke. The overall OR for using inhalers for never-smoking women exposed to any SHS compared with the same reference group was 1.33 (95% CI 1.07–1.65). In a quantified analysis of SHS, never-smoking women with the highest levels of lifetime SHS exposure had an estimated risk of inhaled medication usage of 1.74 (95% CI 1.32–2.30). Conclusions The risk of requiring one or more prescribed inhaled medications for pulmonary disease was significantly higher in post-menopausal women who ever smoked or who had lifetime exposure to SHS.

Rapid, high-throughput assays that detect and quantify botulinum neurotoxin (BoNT) activity in diverse matrices are required for environmental, clinical, pharmaceutical, and food testing. The current standard, the mouse bioassay, is sensitive but is low in throughput and precision. In this study, we present three biochemical assays for the detection and quantification of BoNT serotype A, B, and F proteolytic activities in complex matrices that offer picomolar to femtomolar sensitivity with small assay volumes and total assay times of less than 24 h. These assays consist of magnetic beads conjugated with BoNT serotype-specific antibodies that are used to purify BoNT from complex matrices before the quantification of bound BoNT proteolytic activity using the previously described BoTest reporter substrates. The matrices tested include human serum, whole milk, carrot juice, and baby food, as well as buffers containing common pharmaceutical excipients. The limits of detection were below 1 pM for BoNT/A and BoNT/F and below 10 pM for BoNT/B in most tested matrices using 200-μl samples and as low as 10 fM for BoNT/A with an increased sample volume. Together, these data describe rapid, robust, and high-throughput assays for BoNT detection that are compatible with a wide range of matrices.

In subjectively assessed artistic sports, judges sometimes collude. To avoid this, Federations adopt various strategies in their regulations. However, it is evident that these methods are often not sufficient to overcome collusions completely. The problem is especially difficult in cases where the judging panel consists of sub-commissions that deal with particular aspects of each performance and the scores of each sub-commission are summarized as mean values, which, in turn, are combined into a final mark. Therefore, the formulation of anti-collusion indices would be useful to assess judges and take account of such scores, rejecting the less reliable ones. An anti-collusion index and related average, recently introduced, can be applied in fields other than sports. This article presents some useful considerations for the application of such instruments to the field of sport.

Infection with Leishmania parasites results in a range of clinical manifestations and outcomes. Control of Leishmania parasite transmission is extremely difficult due to the large number of vectors and potential reservoirs, and none of the current treatments are ideal. Vaccination could be an effective strategy to provide sustained control. In this review, the current global situation with regard to leishmaniasis, the immunology of Leishmania infection and various efforts to identify second generation vaccine candidates are briefly discussed. The variety of clinical trials conducted using the only current second generation vaccine approved for clinical use, LEISH-F1 + MPL-SE, are described. Given that epidemiological evidence suggests that reducing the canine reservoir also positively impacts human incidence, efforts at providing a vaccine for leishmaniasis in dogs are highlighted. Finally, potential refinements and surrogate markers that could expedite the introduction of a vaccine that can limit the severity and incidence of leishmaniasis are discussed.

Botulinum neurotoxin serotype E (BoNT/E) outbreaks in the Great Lakes region cause large annual avian mortality events, with an estimated 17,000 bird deaths reported in 2007 alone. During an outbreak investigation, blood collected from bird carcasses is tested for the presence of BoNT/E using the mouse lethality assay. While sensitive, this method is labor-intensive and low throughput and can take up to 7 days to complete. We developed a rapid and sensitive in vitro assay, the BoTest Matrix E assay, that combines immunoprecipitation with high-affinity endopeptidase activity detection by Förster resonance energy transfer (FRET) to rapidly quantify BoNT/E activity in avian blood with detection limits comparable to those of the mouse lethality assay. On the basis of the analysis of archived blood samples ( n = 87) collected from bird carcasses during avian mortality investigations, BoTest Matrix E detected picomolar quantities of BoNT/E following a 2-h incubation and femtomolar quantities of BoNT/E following extended incubation (24 h) with 100% diagnostic specificity and 91% diagnostic sensitivity.

Healthy Indian adult volunteers, with or without a history of leishmaniasis, were evaluated for evidence of previous infection with Leishmania donovani based on the direct agglutination test (DAT). Three cohorts of 6 DAT-negative and 6 DAT-positive subjects were enrolled in an open-label, dose-escalating, uncontrolled clinical trial and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 5μg, 10μg, or 20μg recombinant Leishmania polyprotein LEISH-F1 antigen+25μg MPL®-SE adjuvant). The study injections were given subcutaneously on days 0, 28, and 56, and the subjects were followed through day 168 for safety and immunological endpoints. The vaccine was safe and well-tolerated in DAT-negative and DAT-positive subjects and induced T-cell production of IFN-γ and other cytokines in response to stimulation with the LEISH-F1 antigen. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without history of previous infection with Leishmania donovani.

The provision of emergency care in the United States, regionalized or not, depends on an adequate workforce. Adequate must be defined both qualitatively and quantitatively. There is currently a shortage of emergency care providers, one that will exist for the foreseeable future. This article discusses what is known about the current emergency medicine (EM) and non-EM workforce, future trends, and research opportunities.

Adult patients with mucosal leishmaniasis (ML) were enrolled in a randomized, double-blind, placebo-controlled, dose-escalating clinical trial and were randomly assigned to receive three injections of either the LEISH-F1+MPL-SE vaccine (consisting of 5, 10, or 20 μg recombinant Leishmania polyprotein LEISH-F1 antigen+25 μg MPL(®)-SE adjuvant) (n=36) or saline placebo (n=12). The study injections were given subcutaneously on Days 0, 28, and 56, and the patients were followed through Day 336 for safety, immunological, and clinical evolution endpoints. All patients received standard chemotherapy with sodium stibogluconate starting on Day 0. The vaccine was safe and well tolerated, and induced both humoral and cell-mediated immune responses. Furthermore, intracellular cytokine staining showed an increase in the proportion of memory LEISH-F1-specific IL-2(+) CD4 T-cells after vaccination, which was associated with clinical cure. This clinical trial shows that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in patients with ML.

Forty-four adult patients with cutaneous leishmaniasis (CL) were enrolled in a randomized, double-blind, controlled, dose-escalating clinical trial and were randomly assigned to receive three injections of either the LEISH-F1 + MPL-SE vaccine (consisting of 5, 10, or 20 μg recombinant Leishmania polyprotein LEISH-F1 antigen + 25 μg MPL®-SE adjuvant) (n = 27), adjuvant alone (n = 8), or saline placebo (n = 9). The study injections were given subcutaneously on Days 0, 28, and 56, and the patients were followed through Day 336 for safety, immunological, and clinical evolution endpoints. All patients received chemotherapy with meglumine antimoniate starting on Day 0. The vaccine was safe and well tolerated. Nearly all vaccine recipients and no adjuvant-alone or placebo recipients demonstrated an IgG antibody response to LEISH-F1 at Day 84. Also at Day 84, 80% of vaccine recipients were clinically cured, compared to 50% and 38% of adjuvant-alone and placebo recipients. The LEISH-F1 + MPL-SE vaccine was safe and immunogenic in CL patients and appeared to shorten their time to cure when used in combination with meglumine antimoniate chemotherapy.

Treatments for breast cancer, specifically hormonal therapy, accelerate bone loss (BL) among breast cancer survivors, leading to osteoporosis and an increase in fracture risk. Tai Chi Chuan (TCC) is a moderate form of weight-bearing exercise, equivalent to walking, and it has been shown to improve aerobic capacity and strength among breast cancer survivors and might also be effective in slowing bone loss in breast cancer survivors. This pilot study compared the influence of TCC with that of standard support therapy (ST; exercise control) on BL biomarkers among breast cancer survivors.Randomly assigned breast cancer survivors (N = 16; median age, 53 years;30 months after treatment) completed 12 weeks (3 times per week, 60 minutes per session) of TCC or ST. Serum levels of N-telopeptides of type I collagen (NTx), a marker of bone resorption, and bone-specific alkaline phosphatase (BSAP), a marker of bone formation, were determined according to enzyme-linked immunosorbent assay at baseline and after the intervention.Using analysis of covariance, survivors in the TCC group experienced a greater increase in levels of bone formation (BSAP [microg/L]: before, 8.3; after, 10.2; change, 1.9 microg/L and 22.4%), compared with survivors in ST (BSAP [microg/L]: before, 7.6; after, 8.1; change, 0.5 microg/L [6.3%]). Survivors in the TCC group also experienced a significant decrease in bone resorption (NTx [nanomoles bone collagen equivalent; nmBCE]: before, 17.6; after, 11.1; change, -6.5 nmBCE; -36.9%), whereas women in the ST group did not (NTx [nmBCE]: before, 20.8; after, 18.8; change, -2.0 nmBCE; -9.6%).This pilot study suggests that weight-bearing exercise exerts positive effects on BL, through increased bone formation and decreased bone resorption. Further examinations of the influence of TCC on bone health are warranted.

Healthy Colombian adult volunteers with no history of leishmaniasis were evaluated for evidence of previous subclinical infection with Leishmania based on the Montenegro skin test (MST). Twelve MST-positive subjects were enrolled in an open-label, uncontrolled clinical trial (the "MST-positive trial") and received three injections of the LEISH-F1+MPL-SE vaccine (consisting of 10 microg recombinant Leishmania polyprotein LEISH-F1 antigen [TSA+LmSTI1+LeIF]+25 microg MPL-SE adjuvant). Sixty-eight MST-negative subjects were enrolled in a randomized, double-blind, controlled trial (the "MST-negative trial") and were randomly assigned to receive three injections of either the vaccine (n=34), 10 microg LEISH-F1 protein alone (n=17), or saline placebo (n=17). In both trials, the study injections were given subcutaneously on Days 0, 28, and 56, and subjects were followed for safety and immunological endpoints. The LEISH-F1+MPL-SE vaccine was safe and well tolerated in MST-positive and MST-negative subjects. In both trials, an IFN-gamma response to the LEISH-F1 antigen at Day 84 was observed in more than half of the vaccine recipients. In the MST-negative trial, the IFN-gamma response was significantly more frequent and of greater magnitude in vaccine recipients than in protein-alone or placebo recipients. An IgG antibody response to LEISH-F1 was observed in all vaccine recipients. In both trials, delayed-type hypersensitivity (DTH) to LEISH-F1 was observed in most of the vaccine recipients. In the MST-negative trial, DTH was significantly higher in vaccine than placebo recipients. These clinical trials of the first defined vaccine for leishmaniasis show that the LEISH-F1+MPL-SE vaccine is safe and immunogenic in healthy subjects with and without evidence of previous subclinical infection with Leishmania.

Background: The majority of recent, well-designed studies have shown that long-term cigarette smoking increases colorectal cancer risk, but older studies with shorter durations of exposure often found no association. This study aimed to examine colorectal cancer risk by smoking exposure using data collected in the late-1950s and early-1960s. Methods: This case–control study examined colorectal cancer risk by lifetime smoking history. There were 1365 patients who visited Roswell Park Cancer Institute (RPCI) between 1957 and 1965 diagnosed with primary, incident colorectal cancers that were matched to 4096 malignancy-free controls on gender and age. Odds ratios were calculated using separate logistic regression models for each smoking exposure, while controlling for other tobacco use, county of residence, race, age, gender, and body mass index (BMI). Results: The adjusted OR for individuals who reported their greatest level of smoking to be more than 1 pack/day was 0.87 (95% CI = 0.67–1.15). Among those who smoked 42 or more years, the adjusted OR was 0.89 (95% CI = 0.68–1.15) compared to those who never smoked. For individuals who smoked more than 45 pack-years, the OR was 0.92 (95% CI = 0.72–1.19). The results did not differ significantly by gender, although men had considerably greater exposure compared to women. Results also did not differ by colorectal sub-site. Conclusion :N o association was found between long-term cigarette smoking and colorectal cancer risk. These results are in accord with studies that followed cohorts throughout the 1950s and 1960s. Methodological limitations, such as missing data on covariates and the higher incidence of smoking-related illness in a hospital setting, may have contributed to the null results found in this study. Prolonged population exposure to cigarettes and perhaps a changing product may explain why more recent studies have reported a positive association between smoking and colorectal cancer.