Quality improvement strategies for diabetes care: Effects on outcomes for adults living with diabetes.

BACKGROUND: There is a large body of evidence evaluating quality improvement (QI) programmes to improve care for adults living with diabetes. These programmes are often comprised of multiple QI strategies, which may be implemented in various combinations. Decision-makers planning to implement or evaluate a new QI programme, or both, need reliable evidence on the relative effectiveness of different QI strategies (individually and in combination) for different patient populations. OBJECTIVES: To update existing systematic reviews of diabetes QI programmes and apply novel meta-analytical techniques to estimate the effectiveness of QI strategies (individually and in combination) on diabetes quality of care. SEARCH METHODS: We searched databases (CENTRAL, MEDLINE, Embase and CINAHL) and trials registers (ClinicalTrials.gov and WHO ICTRP) to 4 June 2019. We conducted a top-up search to 23 September 2021; we screened these search results and 42 studies meeting our eligibility criteria are available in the awaiting classification section. SELECTION CRITERIA: We included randomised trials that assessed a QI programme to improve care in outpatient settings for people living with diabetes. QI programmes needed to evaluate at least one system- or provider-targeted QI strategy alone or in combination with a patient-targeted strategy. - System-targeted: case management (CM); team changes (TC); electronic patient registry (EPR); facilitated relay of clinical information (FR); continuous quality improvement (CQI). - Provider-targeted: audit and feedback (AF); clinician education (CE); clinician reminders (CR); financial incentives (FI). - Patient-targeted: patient education (PE); promotion of self-management (PSM); patient reminders (PR). Patient-targeted QI strategies needed to occur with a minimum of one provider or system-targeted strategy. DATA COLLECTION AND ANALYSIS: We dual-screened search results and abstracted data on study design, study population and QI strategies. We assessed the impact of the programmes on 13 measures of diabetes care, including: glycaemic control (e.g. mean glycated haemoglobin (HbA1c)); cardiovascular risk factor management (e.g. mean systolic blood pressure (SBP), low-density lipoprotein cholesterol (LDL-C), proportion of people living with diabetes that quit smoking or receiving cardiovascular medications); and screening/prevention of microvascular complications (e.g. proportion of patients receiving retinopathy or foot screening); and harms (e.g. proportion of patients experiencing adverse hypoglycaemia or hyperglycaemia). We modelled the association of each QI strategy with outcomes using a series of hierarchical multivariable meta-regression models in a Bayesian framework. The previous version of this review identified that different strategies were more or less effective depending on baseline levels of outcomes. To explore this further, we extended the main additive model for continuous outcomes (HbA1c, SBP and LDL-C) to include an interaction term between each strategy and average baseline risk for each study (baseline thresholds were based on a data-driven approach; we used the median of all baseline values reported in the trials). Based on model diagnostics, the baseline interaction models for HbA1c, SBP and LDL-C performed better than the main model and are therefore presented as the primary analyses for these outcomes. Based on the model results, we qualitatively ordered each QI strategy within three tiers (Top, Middle, Bottom) based on its magnitude of effect relative to the other QI strategies, where 'Top' indicates that the QI strategy was likely one of the most effective strategies for that specific outcome. Secondary analyses explored the sensitivity of results to choices in model specification and priors.  Additional information about the methods and results of the review are available as Appendices in an online repository. This review will be maintained as a living systematic review; we will update our syntheses as more data become available. MAIN RESULTS: We identified 553 trials (428 patient-randomised and 125 cluster-randomised trials), including a total of 412,161 participants. Of the included studies, 66% involved people living with type 2 diabetes only. Participants were 50% female and the median age of participants was 58.4 years. The mean duration of follow-up was 12.5 months. HbA1c was the commonest reported outcome; screening outcomes and outcomes related to cardiovascular medications, smoking and harms were reported infrequently. The most frequently evaluated QI strategies across all study arms were PE, PSM and CM, while the least frequently evaluated QI strategies included AF, FI and CQI. Our confidence in the evidence is limited due to a lack of information on how studies were conducted.  Four QI strategies (CM, TC, PE, PSM) were consistently identified as 'Top' across the majority of outcomes. All QI strategies were ranked as 'Top' for at least one key outcome. The majority of effects of individual QI strategies were modest, but when used in combination could result in meaningful population-level improvements across the majority of outcomes. The median number of QI strategies in multicomponent QI programmes was three.  Combinations of the three most effective QI strategies were estimated to lead to the below effects:  - PR + PSM + CE: decrease in HbA1c by 0.41% (credibility interval (CrI) -0.61 to -0.22) when baseline HbA1c < 8.3%; - CM + PE + EPR: decrease in HbA1c by 0.62% (CrI -0.84 to -0.39) when baseline HbA1c > 8.3%;  - PE + TC + PSM: reduction in SBP by 2.14 mmHg (CrI -3.80 to -0.52) when baseline SBP < 136 mmHg; - CM + TC + PSM: reduction in SBP by 4.39 mmHg (CrI -6.20 to -2.56) when baseline SBP > 136 mmHg;  - TC + PE + CM: LDL-C lowering of 5.73 mg/dL (CrI -7.93 to -3.61) when baseline LDL < 107 mg/dL; - TC + CM + CR: LDL-C lowering by 5.52 mg/dL (CrI -9.24 to -1.89) when baseline LDL > 107 mg/dL. Assuming a baseline screening rate of 50%, the three most effective QI strategies were estimated to lead to an absolute improvement of 33% in retinopathy screening (PE + PR + TC) and 38% absolute increase in foot screening (PE + TC + Other). AUTHORS' CONCLUSIONS: There is a significant body of evidence about QI programmes to improve the management of diabetes. Multicomponent QI programmes for diabetes care (comprised of effective QI strategies) may achieve meaningful population-level improvements across the majority of outcomes. For health system decision-makers, the evidence summarised in this review can be used to identify strategies to include in QI programmes. For researchers, this synthesis identifies higher-priority QI strategies to examine in further research regarding how to optimise their evaluation and effects. We will maintain this as a living systematic review.

Apixaban to Prevent Venous Thromboembolism in Patients with Cancer.

BACKGROUND: Patients with active cancer have an increased risk of venous thromboembolism, which results in substantial morbidity, mortality, and health care expenditures. The Khorana score (range, 0 to 6, with higher scores indicating a higher risk of venous thromboembolism) has been validated to identify patients with cancer at elevated risk for this complication and may help select those who could benefit from thromboprophylaxis. METHODS: We conducted a randomized, placebo-controlled, double-blind clinical trial assessing the efficacy and safety of apixaban (2.5 mg twice daily) for thromboprophylaxis in ambulatory patients with cancer who were at intermediate-to-high risk for venous thromboembolism (Khorana score, ≥2) and were initiating chemotherapy. The primary efficacy outcome was objectively documented venous thromboembolism over a follow-up period of 180 days. The main safety outcome was a major bleeding episode. RESULTS: Of the 574 patients who underwent randomization, 563 were included in the modified intention-to-treat analysis. Venous thromboembolism occurred in 12 of 288 patients (4.2%) in the apixaban group and in 28 of 275 patients (10.2%) in the placebo group (hazard ratio, 0.41; 95% confidence interval [CI], 0.26 to 0.65; P<0.001). In the modified intention-to-treat analysis, major bleeding occurred in 10 patients (3.5%) in the apixaban group and in 5 patients (1.8%) in the placebo group (hazard ratio, 2.00; 95% CI, 1.01 to 3.95; P = 0.046). During the treatment period, major bleeding occurred in 6 patients (2.1%) in the apixaban group and in 3 patients (1.1%) in the placebo group (hazard ratio, 1.89; 95% CI, 0.39 to 9.24). CONCLUSIONS: Apixaban therapy resulted in a significantly lower rate of venous thromboembolism than did placebo among intermediate-to-high-risk ambulatory patients with cancer who were starting chemotherapy. The rate of major bleeding episodes was higher with apixaban than with placebo. (Funded by the Canadian Institutes of Health Research and Bristol-Myers Squibb-Pfizer Alliance; AVERT ClinicalTrials.gov number, NCT02048865.).

Systemic interventions for treatment of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome.

BACKGROUND: Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN), and SJS/TEN overlap syndrome are rare, severe cutaneous adverse reactions usually triggered by medications. In addition to tertiary-level supportive care, various systemic therapies have been used including glucocorticoids, intravenous immunoglobulins (IVIGs), cyclosporin, N-acetylcysteine, thalidomide, infliximab, etanercept, and plasmapheresis. There is an unmet need to understand the efficacy of these interventions. OBJECTIVES: To assess the effects of systemic therapies (medicines delivered orally, intramuscularly, or intravenously) for the treatment of SJS, TEN, and SJS/TEN overlap syndrome. SEARCH METHODS: We searched the following databases up to March 2021: the Cochrane Skin Specialised Register, CENTRAL, MEDLINE, and Embase. We also searched five clinical trial registers, the reference lists of all included studies and of key review articles, and a number of drug manufacturer websites. We searched for errata or retractions of included studies. SELECTION CRITERIA: We included only randomised controlled trials (RCTs) and prospective observational comparative studies of participants of any age with a clinical diagnosis of SJS, TEN, or SJS/TEN overlap syndrome. We included all systemic therapies studied to date and permitted comparisons between each therapy, as well as between therapy and placebo. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures as specified by Cochrane. Our primary outcomes were SJS/TEN-specific mortality and adverse effects leading to discontinuation of SJS/TEN therapy. Secondary outcomes included time to complete re-epithelialisation, intensive care unit length of stay, total hospital length of stay, illness sequelae, and other adverse effects attributed to systemic therapy. We rated the certainty of the evidence for each outcome using GRADE. MAIN RESULTS: We included nine studies with a total of 308 participants (131 males and 155 females) from seven countries. We included two studies in the quantitative meta-analysis. We included three RCTs and six prospective, controlled observational studies. Sample sizes ranged from 10 to 91. Most studies did not report study duration or time to follow-up. Two studies reported a mean SCORe of Toxic Epidermal Necrosis (SCORTEN) of 3 and 1.9. Seven studies did not report SCORTEN, although four of these studies reported average or ranges of body surface area (BSA) (means ranging from 44% to 51%). Two studies were set in burns units, two in dermatology wards, one in an intensive care unit, one in a paediatric ward, and three in unspecified inpatient units. Seven studies reported a mean age, which ranged from 29 to 56 years. Two studies included paediatric participants (23 children). We assessed the results from one of three RCTs as low risk of bias in all domains, one as high, and one as some concerns. We judged the results from all six prospective observational comparative studies to be at a high risk of bias. We downgraded the certainty of the evidence because of serious risk of bias concerns and for imprecision due to small numbers of participants. The interventions assessed included systemic corticosteroids, tumour necrosis factor-alpha (TNF-alpha) inhibitors, cyclosporin, thalidomide, N-acetylcysteine, IVIG, and supportive care. No data were available for the main comparisons of interest as specified in the review protocol: etanercept versus cyclosporin, etanercept versus IVIG, IVIG versus supportive care, IVIG versus cyclosporin, and cyclosporin versus corticosteroids. Corticosteroids versus no corticosteroids It is uncertain if there is any difference between corticosteroids (methylprednisolone 4 mg/kg/day for two more days after fever had subsided and no new lesions had developed) and no corticosteroids on disease-specific mortality (risk ratio (RR) 2.55, 95% confidence interval (CI) 0.72 to 9.03; 2 studies; 56 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. IVIG versus no IVIG It is uncertain if there is any difference between IVIG (0.2 to 0.5 g/kg cumulative dose over three days) and no IVIG in risk of disease-specific mortality (RR 0.33, 95% CI 0.04 to 2.91); time to complete re-epithelialisation (mean difference (MD) -2.93 days, 95% CI -4.4 to -1.46); or length of hospital stay (MD -2.00 days, 95% CI -5.81 to 1.81). All results in this comparison were based on one study with 36 participants, and very low-certainty evidence. Adverse effects leading to discontinuation of therapy were not reported. Etanercept (TNF-alpha inhibitor) versus corticosteroids Etanercept (25 mg (50 mg if weight > 65 kg) twice weekly "until skin lesions healed") may reduce disease-specific mortality compared to corticosteroids (intravenous prednisolone 1 to 1.5 mg/kg/day "until skin lesions healed") (RR 0.51, 95% CI 0.16 to 1.63; 1 study; 91 participants; low-certainty evidence); however, the CIs were consistent with possible benefit and possible harm. Serious adverse events, such as sepsis and respiratory failure, were reported in 5 of 48 participants with etanercept and 9 of 43 participants with corticosteroids, but it was not clear if they led to discontinuation of therapy. Time to complete re-epithelialisation and length of hospital stay were not reported. Cyclosporin versus IVIG  It is uncertain if there is any difference between cyclosporin (3 mg/kg/day or intravenous 1 mg/kg/day until complete re-epithelialisation, then tapered off (10 mg/day reduction every 48 hours)) and IVIG (continuous infusion 0.75 g/kg/day for 4 days (total dose 3 g/kg) in participants with normal renal function) in risk of disease-specific mortality (RR 0.13, 95% CI 0.02 to 0.98, 1 study; 22 participants; very low-certainty evidence). Time to complete re-epithelialisation, length of hospital stay, and adverse effects leading to discontinuation of therapy were not reported. No studies measured intensive care unit length of stay. AUTHORS' CONCLUSIONS: When compared to corticosteroids, etanercept may result in mortality reduction. For the following comparisons, the certainty of the evidence for disease-specific mortality is very low: corticosteroids versus no corticosteroids,  IVIG versus no IVIG and cyclosporin versus IVIG. There is a need for more multicentric studies, focused on the most important clinical comparisons, to provide reliable answers about the best treatments for SJS/TEN.

Preoperative imaging of gastric GISTs underestimates pathologic tumor size: A retrospective, single institution analysis.

BACKGROUND: How well imaging size agrees with pathologic size of gastric gastrointestinal stromal tumors (GISTs) is unknown. GIST risk stratification is based on pathologic size, location, and mitotic rate. To inform decision making, the size discrepancy between imaging and pathology for gastric GISTs was investigated. METHODS: Imaging and pathology reports were reviewed for 113 patients. Bland-Altman analyses and intraclass correlation (ICC) assessed agreement of imaging and pathology. Changes in clinical risk category due to size discrepancy were identified. RESULTS: Computed tomography (CT) (n = 110) and endoscopic ultrasound (EUS) (n = 50) underestimated pathologic size for gastric GISTs by 0.42 cm, 95% confidence interval (CI): (0.11, 0.73), p = 0.008 and 0.54 cm, 95% CI: (0.25, 0.82), p < 0.001, respectively. ICCs were 0.94 and 0.88 for CT and EUS, respectively. For GISTs ≤ 3 cm, size underestimation was 0.24 cm for CT (n = 28), 95% CI: (0.01, 0.47), p = 0.039 and 0.56 cm for EUS (n = 26), 95% CI: (0.27, 0.84), p < 0.0001. ICCs were 0.72 and 0.55 for CT and EUS, respectively. Spearman's correlation was ≥0.84 for all groups. For GISTs ≤ 3 cm, 6/28 (21.4% p = 0.01) on CT and 7/26 (26.9% p = 0.005) on EUS upgraded risk category using pathologic size versus imaging size. No GISTs ≤ 3 cm downgraded risk categories. Size underestimation persisted for GISTs ≤ 2 cm on EUS (0.39 cm, 95% CI: [0.06, 0.72], p = 0.02, post hoc analysis). CONCLUSION: Imaging, particularly EUS, underestimates gastric GIST size. Caution should be exercised using imaging alone to risk-stratify gastric GISTs, and to decide between surveillance versus surgery.

Techniques for blood loss estimation in major non-cardiac surgery: a systematic review and meta-analysis.

PURPOSE: Estimated blood loss (EBL) is an important tool in clinical decision-making and surgical outcomes research. It guides perioperative transfusion practice and serves as a key predictor of short-term perioperative risks and long-term oncologic outcomes. Despite its widespread clinical and research use, there is no gold standard for blood loss estimation. We sought to systematically review and compare techniques for intraoperative blood loss estimation in major non-cardiac surgery with the objective of informing clinical estimation and research standards. SOURCE: A structured search strategy was applied to Ovid Medline, Embase, and Cochrane Library databases from inception to March 2020, to identify studies comparing methods of intraoperative blood loss in adult patients undergoing major non-cardiac surgery. We summarized agreement between groups of pairwise comparisons as visual estimation vs formula estimation, visual estimation vs other, and formula estimation vs other. For each of these comparisons, we described tendencies for higher or lower EBL values, consistency of findings, pooled mean differences, standard deviations, and confidence intervals. PRINCIPLE FINDINGS: We included 26 studies involving 3,297 patients in this review. We found that visual estimation is the most frequently studied technique. In addition, visual techniques tended to provide lower EBL values than formula-based estimation or other techniques, though this effect was not statistically significant in pooled analyses likely due to sample size limitations. When accounting for the contextual mean blood loss, similar case-to-case variation exists for all estimation techniques. CONCLUSIONS: We found that significant case-by-case variation exists for all methods of blood loss evaluation and that there is significant disagreement between techniques. Given the importance placed on EBL, particularly for perioperative prognostication models, clinicians should consider the universal adoption of a practical and reproducible method for blood loss evaluation. TRIAL REGISTRATION: PROSPERO (CRD42015029439); registered: 18 November 2015.PROSPERO (CRD42015029439); registered: 18 November 2015.

RéSUMé: OBJECTIF: Les pertes sanguines estimées constituent un outil important dans la prise de décision clinique et la recherche sur les pronostics chirurgicaux. Elles guident la pratique transfusionnelle périopératoire et servent de prédicteur clé des risques périopératoires à court terme ainsi que des devenirs oncologiques à long terme. Malgré l'utilisation répandue de cette modalité en clinique et en recherche, il n'existe pas de référence absolue pour l'estimation des pertes sanguines. Nous avons tenté de passer systématiquement en revue et de comparer les techniques d'estimation des pertes sanguines peropératoires dans les chirurgies non cardiaques majeures, avec pour objectif d'informer l'évaluation clinique et les normes de recherche. SOURCE: Une stratégie de recherche structurée a été appliquée aux bases de données Ovid Medline, Embase et Cochrane Library de leur création à mars 2020 afin d'identifier les études comparant les méthodes d'estimation des pertes sanguines peropératoires chez des patients adultes subissant une chirurgie non cardiaque majeure. Nous avons résumé la concordance entre des groupes de comparaisons par paires en tant qu'estimation visuelle vs estimation par formule, estimation visuelle vs autre, et estimation par formule vs autre. Pour chacune de ces comparaisons, nous avons décrit les tendances vers des valeurs d'estimations des pertes sanguines plus élevées ou plus basses, la cohérence des résultats, les différences moyennes combinées, les écarts type et les intervalles de confiance. CONSTATATIONS PRINCIPALES: Dans ce compte rendu, 26 études portant sur 3297 patients ont été examinées. L'estimation visuelle est la technique la plus fréquemment étudiée. En outre, les techniques visuelles avaient tendance à donner des valeurs d'estimation des pertes sanguines plus basses que les estimations fondées sur des formules ou d'autres techniques, bien que cet effet n'ait pas eu de signification statistique dans les analyses combinées, probablement en raison des limites liées aux tailles d'échantillon. En tenant compte des pertes sanguines moyennes contextuelles, une variation similaire au cas par cas est apparue avec toutes les techniques d'estimation. CONCLUSION: Nous avons observé qu'une variation significative au cas par cas était présente avec toutes les méthodes d'évaluation des pertes sanguines et qu'il y a un désaccord significatif entre les techniques. Étant donné l'importance octroyée à l'estimation des pertes sanguines, particulièrement dans les modèles de pronostication périopératoire, les cliniciens devraient envisager l'adoption universelle d'une méthode pratique et reproductible d'évaluation des pertes sanguines. ENREGISTREMENT DE L'éTUDE: PROSPERO (CRD42015029439); enregistrée le : 18 novembre 2015.

Treatment of Low Sexual Desire or Frequency Using a Sexual Enhancement Group Couples Therapy Approach.

BACKGROUND: Sexual desire or frequency problems are exceedingly common, but treatment of them has been less than effective. AIM: The goal of this study was to develop a cost-effective, accessible intervention to deal with sexual desire or frequency problems, including sexual desire discrepancy, by enhancing the quality of couples' erotic intimacy. METHODS: 45 couples (38 heterosexual and 7 same-sex couples) distressed by sexual desire or frequency problems were seen in a 16-hour, group couples therapy intervention. Participants completed the New Sexual Satisfaction Scale (NSSS) at pretest, posttest, and at 6-month follow-up. OUTCOMES: The NSSS plus 3 additional items at pretest, posttest, and at 6-month follow-up and patients' written feedback. RESULTS: Statistically significant differences were found between pre-tests and post-tests in satisfaction with intensity of sexual arousal; creativity; frequency; sexual functioning; partner's sexual availability; partner's initiation of sexual activity; emotional opening up during sex; positive sexual reactions to the partner; communication of sexual wishes, preferences and desires; and balance between giving and receiving during sex. The largest improvement and effect sizes were found in overall satisfaction with one's sex life from pre-test to post-test and 6-month follow-up. CLINICAL IMPLICATIONS: Low sexual desire or frequency problems can be treated effectively by enhancing the quality of the couple's erotic connection, thereby creating desirable sex. STRENGTHS & LIMITATIONS: The strengths include the combination of quantitative and qualitative data. Limitations included the small number of same-sex couples. CONCLUSION: Sexual enhancement group couples therapy provides an effective, accessible, and affordable approach to low desire or frequency complaints in distressed couples. Kleinplatz PJ, Charest M, Paradis N, et al. Treatment of Low Sexual Desire or Frequency Using a Sexual Enhancement Group Couples Therapy Approach. J Sex Med 2020;17:1288-1296.

Canadian-Australasian Randomised trial of screening kidney transplant candidates for coronary artery disease-A trial protocol for the CARSK study.

Transplantation is the preferred treatment for patients with kidney failure, but the need exceeds the supply of transplantable kidneys, and patients routinely wait >5 years on dialysis for a transplant. Coronary artery disease (CAD) is common in kidney failure and can exclude patients from transplantation or result in death before or after transplantation. Screening asymptomatic patients for CAD using noninvasive tests prior to wait-listing and at regular intervals (ie, annually) after wait-listing until transplantation is the established standard of care and is justified by the need to avoid adverse patient outcomes and loss of organs. Patients with abnormal screening tests undergo coronary angiography, and those with critical stenoses are revascularized. Screening is potentially harmful because patients may be excluded or delayed from transplantation, and complications after revascularization are more frequent in this population. CARSK will test the hypothesis that eliminating screening tests for occult CAD after wait-listing is not inferior to regular screening for the prevention of major adverse cardiac events defined as the composite of cardiovascular death, nonfatal myocardial infarction, urgent revascularization, and hospitalization for unstable angina. Secondary outcomes include the transplant rate, safety measures, and the cost-effectiveness of screening. Enrolment of 3,306 patients over 3 years is required, with patients followed for up to 5 years during wait-listing and for 1 year after transplantation. By validating or refuting the use of screening tests during wait-listing, CARSK will ensure judicious use of health resources and optimal patient outcomes.

Can peri-ovulatory putrescine supplementation improve egg quality in older infertile women?

The aging-related decline in fertility is an increasingly pressing medical and economic issue in modern society where women are delaying family building. Increasingly sophisticated, costly, and often increasingly invasive, assisted reproductive clinical protocols and laboratory technologies (ART) have helped many older women achieve their reproductive goals. Current ART procedures have not been able to address the fundamental problem of oocyte aging, the increased rate of egg aneuploidy, and the decline of developmental potential of the eggs. Oocyte maturation, which is triggered by luteinizing hormone (LH) in vivo or by injection of human chorionic gonadotropin (hCG) in an in vitro fertilization (IVF) clinic, is the critical stage at which the majority of egg aneuploidies arise and when much of an egg's developmental potential is established. Our proposed strategy focuses on improving egg quality in older women by restoring a robust oocyte maturation process. We have identified putrescine deficiency as one of the causes of poor egg quality in an aged mouse model. Putrescine is a biogenic polyamine naturally produced in peri-ovulatory ovaries. Peri-ovulatory putrescine supplementation has reduced egg aneuploidy, improved embryo quality, and reduced miscarriage rates in aged mice. In this paper, we review the literature on putrescine, its occurrence and physiology in living organisms, and its unique role in oocyte maturation. Preliminary human data demonstrates that there is a maternal aging-related deficiency in ovarian ornithine decarboxylase (ODC), the enzyme responsible for putrescine production. We argue that peri-ovulatory putrescine supplementation holds great promise as a natural and effective therapy for infertility in women of advanced maternal age, applicable in natural conception and in combination with current ART therapies.

Screening for Occult Cancer in Unprovoked Venous Thromboembolism.

BACKGROUND: Venous thromboembolism may be the earliest sign of cancer. Currently, there is a great diversity in practices regarding screening for occult cancer in a person who has an unprovoked venous thromboembolism. We sought to assess the efficacy of a screening strategy for occult cancer that included comprehensive computed tomography (CT) of the abdomen and pelvis in patients who had a first unprovoked venous thromboembolism. METHODS: We conducted a multicenter, open-label, randomized, controlled trial in Canada. Patients were randomly assigned to undergo limited occult-cancer screening (basic blood testing, chest radiography, and screening for breast, cervical, and prostate cancer) or limited occult-cancer screening in combination with CT. The primary outcome measure was confirmed cancer that was missed by the screening strategy and detected by the end of the 1-year follow-up period. RESULTS: Of the 854 patients who underwent randomization, 33 (3.9%) had a new diagnosis of occult cancer between randomization and the 1-year follow-up: 14 of the 431 patients (3.2%) in the limited-screening group and 19 of the 423 patients (4.5%) in the limited-screening-plus-CT group (P=0.28). In the primary outcome analysis, 4 occult cancers (29%) were missed by the limited screening strategy, whereas 5 (26%) were missed by the strategy of limited screening plus CT (P=1.0). There was no significant difference between the two study groups in the mean time to a cancer diagnosis (4.2 months in the limited-screening group and 4.0 months in the limited-screening-plus-CT group, P=0.88) or in cancer-related mortality (1.4% and 0.9%, P=0.75). CONCLUSIONS: The prevalence of occult cancer was low among patients with a first unprovoked venous thromboembolism. Routine screening with CT of the abdomen and pelvis did not provide a clinically significant benefit. (Funded by the Heart and Stroke Foundation of Canada; SOME ClinicalTrials.gov number, NCT00773448.).

Immunoablation and autologous haemopoietic stem-cell transplantation for aggressive multiple sclerosis: a multicentre single-group phase 2 trial.

BACKGROUND: Strong immunosuppression, including chemotherapy and immune-depleting antibodies followed by autologous haemopoietic stem-cell transplantation (aHSCT), has been used to treat patients with multiple sclerosis, improving control of relapsing disease. We addressed whether near-complete immunoablation followed by immune cell depleted aHSCT would result in long-term control of multiple sclerosis. METHODS: We did this phase 2 single-arm trial at three hospitals in Canada. We enrolled patients with multiple sclerosis, aged 18-50 years with poor prognosis, ongoing disease activity, and an Expanded Disability Status Scale of 3.0-6.0. Autologous CD34 selected haemopoietic stem-cell grafts were collected after mobilisation with cyclophosphamide and filgrastim. Immunoablation with busulfan, cyclophosphamide, and rabbit anti-thymocyte globulin was followed by aHSCT. The primary outcome was multiple sclerosis activity-free survival (events were clinical relapse, appearance of a new or Gd-enhancing lesion on MRI, and sustained progression of Expanded Disability Status Scale score). This study was registered at ClinicalTrials.gov, NCT01099930. FINDINGS: Between diagnosis and aHSCT, 24 patients had 167 clinical relapses over 140 patient-years with 188 Gd-enhancing lesions on 48 pre-aHSCT MRI scans. Median follow-up was 6.7 years (range 3.9-12.7). The primary outcome, multiple sclerosis activity-free survival at 3 years after transplantation was 69.6% (95% CI 46.6-84.2). With up to 13 years of follow-up after aHSCT, no relapses occurred and no Gd enhancing lesions or new T2 lesions were seen on 314 MRI sequential scans. The rate of brain atrophy decreased to that expected for healthy controls. One of 24 patients died of transplantation-related complications. 35% of patients had a sustained improvement in their Expanded Disability Status Scale score. INTERPRETATION: We describe the first treatment to fully halt all detectable CNS inflammatory activity in patients with multiple sclerosis for a prolonged period in the absence of any ongoing disease-modifying drugs. Furthermore, many of the patients had substantial recovery of neurological function despite their disease's aggressive nature. FUNDING: Multiple Sclerosis Scientific Research Foundation.

Low-molecular-weight heparin and recurrent placenta-mediated pregnancy complications: a meta-analysis of individual patient data from randomised controlled trials.

BACKGROUND: Placenta-mediated pregnancy complications include pre-eclampsia, late pregnancy loss, placental abruption, and birth of a small-for-gestational-age (SGA) neonate. These complications are leading causes of maternal, fetal, and neonatal morbidity and mortality in high-income countries. Affected women are at high risk of recurrence in subsequent pregnancies; however, effective strategies to prevent recurrence are absent. Findings from our previous study-level meta-analysis suggested that low-molecular-weight heparin reduced the risk of recurrent placenta-mediated pregnancy complications. However, we identified significant heterogeneity in the results, possibly due to trial design or inclusion criteria. To identify which patients benefit from, and which outcomes are prevented by, low-molecular-weight heparin, we did an individual patient data meta-analysis. METHODS: We did a systematic review in May, 2013, which identified eight eligible randomised trials done between 2000 and 2013 of low-molecular-weight heparin to prevent recurrent placenta-mediated pregnancy complications. We excluded studies on the basis of the wrong population, the study being ongoing, inability to confirm eligibility of participants, intervention stopped too early, and no response from the principal investigator. We requested individual patient data from the study authors for eligible women (women pregnant at the time of the study with a history of previous pregnancy that had been complicated by one or more of the following: pre-eclampsia, placental abruption, birth of an SGA neonate [<10th percentile], pregnancy loss after 16 weeks' gestation, or two losses after 12 weeks' gestation) and recoded, combined, and analysed the data for our meta-analysis. The primary outcome was a composite of early-onset (<34 weeks) or severe pre-eclampsia, birth of an SGA neonate (<5th percentile), late pregnancy loss (≥20 weeks' gestation), or placental abruption leading to delivery, assessed on an intention-to-treat basis. We assessed risk of bias with the Cochrane Risk of Bias tool. This study is registered with PROSPERO, number CRD42013006249. FINDINGS: We analysed data from 963 eligible women in eight trials: 480 randomly assigned to low-molecular-weight heparin and 483 randomly assigned to no low-molecular-weight heparin. Overall, the risk of bias was not substantial enough to affect decisions regarding trial inclusion. Participants were mostly white (795/905; 88%) with a mean age of 30·9 years (SD 5·0) and 403/963 (42%) had thrombophilia. In the primary analysis, low-molecular-weight heparin did not significantly reduce the risk of recurrent placenta-mediated pregnancy complications (low-molecular-weight heparin 62/444 [14%] versus no low-molecular-weight heparin 95/443 (22%) absolute difference -8%, 95% CI -17·3 to 1·4, p=0·09; relative risk 0·64, 95% CI 0·36-1·11, p=0·11). We noted significant heterogeneity between single-centre and multicentre trials. In subgroup analyses, low-molecular-weight heparin in multicentre trials reduced the primary outcome in women with previous abruption (p=0·006) but not in any of the other subgroups of previous complications. INTERPRETATION: Low-molecular-weight heparin does not seem to reduce the risk of recurrent placenta-mediated pregnancy complications in at-risk women. However, some decreases in event rates might have been too small for the power of our study to explore. FUNDING: Canadian Institutes of Health Research.

The Non-Inferiority Margins in Migraine Research (NIMM) Survey.

OBJECTIVES: To survey experts in Headache Medicine on their opinions regarding appropriate non-inferiority margins for outcomes commonly used in migraine research. METHODS: Members of the American Headache Society and the Canadian Headache Society were invited to participate in the Non-Inferiority Margins in Migraine Research (NIMM) survey. Adult and child neurologists with expertise in Headache Medicine were eligible to participate. The survey had a multiple choice format and comprised questions on respondent characteristics, eligibility, as well as expert opinion on non-inferiority margins for outcomes commonly used in trials of both prophylactic and acute interventions for migraine. RESULTS: Ninety-nine eligible respondents completed the survey. Most respondents were adult neurologists (84.9%) and 74% reported practicing in the USA. The following were the most commonly selected non-inferiority margins: (1) change in monthly migraine attacks comparing baseline to the treatment period: 1 attack (39.4% selecting), (2) change in monthly migraine days comparing baseline to the treatment period: 1 day (44.4%), (3) change in average migraine intensity on a 4-point scale comparing baseline to the treatment period: 1.0 (31.3%), (4) percentage of participants who are pain-free 2 hours after the intervention: 5% (41.4%), (5) percentage of participants who have a migraine recurrence within 48 hours of treatment: 5% (42.4%), and (6) percentage of participants with sustained pain freedom: 5% (42.4%). CONCLUSIONS: The results of the NIMM survey describe the opinions of a group of experts on appropriate non-inferiority margins for outcomes commonly used in migraine clinical trials. There was significant variability in responses and lack of consensus on the choice of non-inferiority margins. The survey did not incorporate the patient perspective and was not validated prior to distribution. Further work in this area is required in order to explore how to incorporate clinical considerations into the selection of non-inferiority margins for migraine research.

The association of urinary sodium excretion and the need for renal replacement therapy in advanced chronic kidney disease: a cohort study.

BACKGROUND: Restriction of dietary sodium is routinely recommended for patients with chronic kidney disease (CKD). Whether or not sodium intake is associated with the progression of CKD and mortality remains controversial. We evaluated the association of urinary sodium excretion (as a surrogate for sodium intake) on the need for renal replacement therapy and mortality in patients with advanced CKD. METHODS: We conducted a retrospective study of patients followed at a CKD clinic of a tertiary care hospital from January 2010 to December 2012. Adult patients with advanced CKD (estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m(2)) were included. Using a time-to-event analysis, we examined the association of urinary sodium excretion as a continuous and also as a categorical variable (categorized as low sodium diet - LSD (<100 mEq/day), medium sodium diet - MSD (100-150 mEq/day), and high sodium diet - HSD (>150 mEq/day) and the outcomes of interest. The primary outcome was defined as composite of progression to end-stage renal disease requiring any type of renal replacement therapy and mortality. The secondary outcome was change in eGFR/year. RESULTS: 341 patients (82 LSD, 116 MSD and 143 HSD) were included in the study (mean follow up of 1.5 years) with a mean eGFR decline of 2.7 ml/min/1.73 m(2)/year. 105 patients (31 %) required renal replacement therapy and 10 (3 %) died. There was no association between urinary sodium excretion and change in the eGFR or need for renal replacement therapy and mortality in crude or adjusted models (unadjusted HR 1.002; 95%CI 1.000-1.004, adjusted HR 1.001; 95%CI 0.998-1.004). CONCLUSION: In patients with advanced CKD (eGFR < 30 ml/min/1.73 m(2)), sodium intake does not appear to impact the progression of CKD to end-stage renal disease; however, more definitive studies are needed.

Implementation of the Canadian Paediatric Society's hyperbilirubinemia guidelines: A survey of Ontario hospitals.

INTRODUCTION: In 2007, the Canadian Paediatric Society (CPS) published guidelines aimed at preventing severe hyperbilirubinemia. OBJECTIVES: To determine whether hospitals had implemented these guidelines; to investigate how guideline-recommended care is organized; and to understand the factors influencing guideline implementation. METHODS: The present study was an online survey conducted from December 2011 to May 2012 of all Ontario hospitals offering maternal-newborn services. RESULTS: A total of 97 of 100 eligible hospitals responded. Seventy-seven of the 97 (79%) respondents reported having implemented universal neonatal bilirubin screening. Among these hospitals, hospital-based postdischarge follow-up was reported more frequently than follow-up at community-based locations: hospital laboratory (n=40 [52%]), mother-baby care unit (n=32 [42%]), outpatient clinic (n=25 [33%]), primary care provider in community (n=19 [25%]) and community laboratory (n=8 [10%]). The CPS guidelines were the most frequently reported factor influencing implementation (n=74 [96%]). DISCUSSION: The survey provides valuable insight into the impact of a complex guideline in Canada's largest province. There was heterogeneity in how hospitals organized services, but there was a notable trend toward hospital-based postdischarge care. The shift to hospital-based care runs counter to current health policy directions and highlights the lack of integration among health care sectors. CONCLUSION: The majority of Ontario hospitals implemented universal bilirubin screening following the release of the CPS guidelines. Further analysis is needed to determine the impact that the guidelines and the differences in implementation have had on clinical outcomes and the utilization of health services.

INTRODUCTION: En 2007, la Société canadienne de pédiatrie (SCP) a publié des lignes directrices afin de prévenir l'hyperbilirubinémie grave. OBJECTIFS: Déterminer si les hôpitaux ont adopté ces lignes directrices, examiner l'organisation des soins recommandée dans les lignes directrices et comprendre les facteurs qui influent sur la mise en œuvre des lignes directrices. MÉTHODOLOGIE: La présente étude rend compte d'une enquête virtuelle menée de décembre 2011 à mai 2012 auprès de tous les hôpitaux ontariens offrant des services mère-enfant. RÉSULTATS: Au total, 97 des 100 hôpitaux admissibles ont répondu à l'enquête. Soixante-dix-sept des 97 répondants (79 %) ont déclaré avoir adopté le dépistage universel de la bilirubine néonatale. Dans ces hôpitaux, le suivi en milieu hospitalier après le congé était plus fréquent que le suivi en milieu communautaire : laboratoire de l'hôpital (n=40 [52 %]), unité de soins mère-enfant (n=32 [42 %]), consultations externes (n=25 [33 %]), dispensateur de soins de première ligne en milieu communautaire (n=19 [25 %]) et laboratoire en milieu communautaire (n=8 [10 %]). Les lignes directrices de la SCP étaient le plus souvent invoquées comme le facteur ayant suscité cette mise en œuvre (n=74 [96 %]). EXPOSÉ: L'enquête donne un aperçu précieux des répercussions de lignes directrices complexes dans la plus grande province canadienne. On a remarqué une organisation hétérogène des services dans les hôpitaux, mais une tendance nette vers des soins en milieu hospitalier après le congé. Le passage à des soins en milieu hospitalier va à l'encontre des directives de santé actuelles et fait ressortir l'absence d'intégration entre les secteurs de soins. CONCLUSION: La majorité des hôpitaux ontariens a adopté le dépistage universel de la bilirubine après la publication des lignes directrices de la SCP. Il faudra effectuer une analyse plus approfondie pour déterminer les répercussions de ces lignes directrices et des divers modes de mise en œuvre sur les résultats cliniques et l'utilisation des services de santé.

Development of a clinical prediction rule for risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism.

BACKGROUND: Long-term low-molecular-weight heparin (LMWH) is the current standard for treatment of venous thromboembolism (VTE) in cancer patients. Whether treatment strategies should vary according to individual risk of VTE recurrence remains unknown. We performed a retrospective cohort study and a validation study in patients with cancer-associated VTE to derive a clinical prediction rule that stratifies VTE recurrence risk. METHODS AND RESULTS: The cohort study of 543 patients determined the model with the best classification performance included 4 independent predictors (sex, primary tumor site, stage, and prior VTE) with 100% sensitivity, a wide separation of recurrence rates, 98.1% negative predictive value, and a negative likelihood ratio of 0.16. In this model, the score sum ranged between -3 and 3 score points. Patients with a score ≤ 0 had low risk (≤ 4.5%) for recurrence and patients with a score >1 had a high risk (≥ 19%) for VTE recurrence. Subsequently, we applied and validated the rule in an independent set of 819 patients from 2 randomized, controlled trials comparing low-molecular-weight heparin to coumarin treatment in cancer patients. CONCLUSIONS: By identifying VTE recurrence risk in cancer patients with VTE, we may be able to tailor treatment, improving clinical outcomes while minimizing costs.

Identification of alpha-1 acid glycoprotein (AGP) as a potential marker of impaired growth in the newborn piglet.

Two studies were conducted to investigate the relationship between circulating levels of haptoglobin and α-1 acid glycoprotein (AGP) and growth in neonatal pigs. Circulating serum AGP, but not haptoglobin, was higher (P<0.001) in newborn runts than average-sized littermates. At 1 and 3 weeks, AGP and haptoglobin were similar among control and runt piglets. To determine the possible association between AGP and growth rate, blood was collected between the first and second day after birth in piglets from 10 average litters. Birthweight was positively correlated with growth rate through 21 days (linear regression correlation coefficient (CC), 0.43 (P<0.006); 0.299 (P<0.003) in males and females, respectively). Plasma AGP at birth was negatively correlated with growth (CC, -0.429 (P<0.006); -0.351 (P<0.01) in males and females, respectively). When AGP was calculated on a per kg birthweight basis, the CC with growth improved by 25 and 34% in males and females, respectively, compared with birthweight alone. Haptoglobin in blood was not correlated with growth. These data suggest that AGP at birth is reflective of growth conditions in utero or fetal maturation and may serve as an early predictive biomarker for pre-weaning growth rate.

Practice patterns in spine radiograph utilization among doctors of chiropractic enrolled in a provider network offering complementary care in the United States.

OBJECTIVE: Nonspecific back pain is associated with high use of diagnostic imaging in primary care, yet current evidence suggests that routine imaging of the spine is unnecessary. The objective of this study is to describe current practice patterns in spine radiograph utilization among doctors of chiropractic enrolled in an American provider network. METHODS: A cross-sectional analysis of administrative claims data from one of the largest providers of complementary health care networks for health plans in the United States was performed. Survey data containing provider demographics were linked with routinely collected data on spine radiograph utilization and patient characteristics aggregated at the provider level. We calculated rates and variations of spine radiographs over 12 months. Negative binomial regression was performed to identify significant predictors of high radiograph utilization and to estimate the associated incidence risk ratio. RESULTS: Complete data for 6946 doctors of chiropractic and 249193 adult patients were available for analyses. In 2010, claims were paid for a total of 91542 new patient examinations and 23369 spine radiographs (including 17511 ordered within 5 days of initial patient examination). The rate of spine radiographs within 5 days of an initial patient visit was 204 per 1000 new patient examinations. Significant predictors of higher radiograph utilization rates included the following: practicing in the Midwest or South US census regions, practicing in an urban or suburban setting, chiropractic school attended, and being a male provider in full-time practice with more than 20 years of experience. CONCLUSION: Chiropractic school attended and practice location were the most influential predictors of spine radiograph utilization among network chiropractors. This information may help to inform the development and evaluation of a tailored intervention to address overuse of radiograph utilization.

Effect of PCC on Thrombin Generation among Patients on Factor Xa Inhibitors with Major Bleeding or Needing Urgent Surgery (GAUGE): Design and Rationale.

Background Direct factor Xa inhibitors (FXaIs) account for most oral anticoagulant use and FXaI-associated bleeding events are common. Clinicians have variable national and regional access to specific FXaI reversal agents such as andexanet alfa. Many centers have adopted the use of prothrombin complex concentrates (PCCs) as hemostatic therapy for FXaI-associated major bleeding events. PCC does not impact circulating FXaI levels and its mechanism of action to achieve hemostasis in FXaI-associated bleeding is uncertain. While PCC increases quantitative thrombin generation assay (TGA) parameters, it does not correct FXaI-altered thrombin generation kinetics, nor does it normalize thrombin generation. Clinical data supporting the use of PCC are based on cohort studies reporting clinical hemostatic efficacy, which is difficult to measure. The benefits of PCC for FXaI-associated bleeding beyond supportive care are uncertain. Objective GAUGE is a prospective observational study designed to measure the effects of four-factor PCC administration (Octaplex) on TGA parameters among patients with FXaI-associated bleeding or needing urgent surgery. Methods Laboratory outcomes will include the mean paired change in TGA parameters from pre- to post-PCC administration and the proportion of participants whose post-PCC TGA values fall within a defined reference range. Clinical outcomes will include hemostatic efficacy, thromboembolic complications, and all-cause death at 30 days post-PCC. Conclusion Development of a viable and universally accessible FXaI bleed management strategy is crucial. GAUGE will provide in vivo data on the effects of PCC among patients with FXaI-associated bleeding.

Weaning transition, but not the administration of probiotic candidate Kazachstania slooffiae, shaped the gastrointestinal bacterial and fungal communities in nursery piglets.

As in-feed antibiotics are phased out of swine production, producers are seeking alternatives to facilitate improvements in growth typically seen from this previously common feed additive. Kazachstania slooffiae is a prominent commensal fungus in the swine gut that peaks in relative abundance shortly after weaning and has beneficial interactions with other bacteriome members important for piglet health. In this study, piglets were supplemented with K. slooffiae to characterize responses in piglet health as well as fungal and bacterial components of the microbiome both spatially (along the entire gastrointestinal tract and feces) and temporally (before, during, and after weaning). Litters were assigned to one of four treatments: no K. slooffiae (CONT); one dose of K. slooffiae 7 days before weaning (day 14; PRE); one dose of K. slooffiae at weaning (day 21; POST); or one dose of K. slooffiae 7 days before weaning and one dose at weaning (PREPOST). The bacteriome and mycobiome were analyzed from fecal samples collected from all piglets at day 14, day 21, and day 49, and from organ samples along the gastrointestinal (GI) tract at day 21 and day 49. Blood samples were taken at day 14 and day 49 for cytokine analysis, and fecal samples were assayed for antimicrobial resistance. While some regional shifts were seen in response to K. slooffiae administration in the mycobiome of the GI tract, no remarkable changes in weight gain or health of the animals were observed, and changes were more likely due to sow and the environment. Ultimately, the combined microbiome changed most considerably following the transition from suckling to nursery diets. This work describes the mycobiome along the piglet GI tract through the weaning transition for the first time. Based on these findings, K. slooffiae administered at this concentration may not be an effective tool to hasten colonization of K. slooffiae in the piglet GI tract around the weaning transition nor support piglet growth, microbial gut health, or immunity. However, diet and environment greatly influence microbial community development.