Regularized parametric survival modeling to improve risk prediction models.

We propose to combine the benefits of flexible parametric survival modeling and regularization to improve risk prediction modeling in the context of time-to-event data. Thereto, we introduce ridge, lasso, elastic net, and group lasso penalties for both log hazard and log cumulative hazard models. The log (cumulative) hazard in these models is represented by a flexible function of time that may depend on the covariates (i.e., covariate effects may be time-varying). We show that the optimization problem for the proposed models can be formulated as a convex optimization problem and provide a user-friendly R implementation for model fitting and penalty parameter selection based on cross-validation. Simulation study results show the advantage of regularization in terms of increased out-of-sample prediction accuracy and improved calibration and discrimination of predicted survival probabilities, especially when sample size was relatively small with respect to model complexity. An applied example illustrates the proposed methods. In summary, our work provides both a foundation for and an easily accessible implementation of regularized parametric survival modeling and suggests that it improves out-of-sample prediction performance.

The relationship between pre-operative hypertension and intra-operative haemodynamic changes known to be associated with postoperative morbidity.

Hypertension is not consistently associated with postoperative cardiovascular morbidity and is therefore not considered a major peri-operative risk factor. However, hypertension may predispose to peri-operative haemodynamic changes known to be associated with peri-operative morbidity and mortality, such as intra-operative hypotension and tachycardia. The objective of this study was to determine whether pre-operative hypertension was independently associated with haemodynamic changes known to be associated with adverse peri-operative outcomes. We performed a five-day multicentre, prospective, observational cohort study which included all adult inpatients undergoing elective, non-cardiac, non-obstetric surgery. We recruited 343 patients of whom 164 (47.8%) were hypertensive. An intra-operative mean arterial pressure of < 55 mmHg occurred in 59 (18.2%) patients, of which 25 (42.4%) were hypertensive. Intra-operative tachycardia (heart rate> 100 beats.min-1 ) occurred in 126 (38.9%) patients, of whom 61 (48.4%) were hypertensive. Multivariable logistic regression did not show an independent association between the stage of hypertension and either clinically significant hypotension or tachycardia, when controlled for ASA physical status, functional status, major surgery, duration of surgery or blood transfusion. There was no association between pre-operative hypertension and peri-operative haemodynamic changes known to be associated with major morbidity and mortality. These data, therefore, support the recommendation of the Joint Guidelines of the Association of Anaesthetists of Great Britain and Ireland (AAGBI) and the British Hypertension Society to proceed with elective surgery if a patient's blood pressure is < 180/110 mmHg.

Is low serum albumin level a significant predictor for the development of heparin-induced thrombocytopenia-thrombosis?

The present study investigates the effect of albumin levels in patients who have developed heparin-induced thrombocytopenia (HIT) and heparin-induced thrombocytopenia-thrombosis (HITT). A retrospective observational cohort study was conducted at King Abudlaziz Medical City (KAMC), a university teaching hospital, on patients diagnosed with HIT between June 2013 and December 2014. Clinical and laboratory findings were used to confirm HIT. Albumin levels were reported on admission as baseline and during HIT occurrence. Twenty-eight patients were identified as HIT positive by enzyme-linked immunosorbent assay (ELISA), with a cutoff value of ≥1 optical density units and pretest probability "4Ts" score of ≥4. Of the 28 patients, nine (32%) developed HITT. Demographic characteristics of the patients who developed HIT and HITT were similar. The mean albumin level for patients who developed HITT was significantly lower than that for patients who developed HIT (p < 0.001). Our findings suggest that patients with low serum albumin levels are at greater risk of developing HITT. This finding awaits confirmation in larger prospective clinical trials.

Mortality outcomes in patients transfused with fresher versus older red blood cells: a meta-analysis.

BACKGROUND: Among transfused patients, the effect of the duration of red blood cell storage on mortality remains unclear. This study aims to compare the mortality of patients who were transfused with fresher versus older red blood cells. METHODS: We performed an updated systematic search in the CENTRAL, MEDLINE, EMBASE and CINAHL databases, from January 2015 to October 2016. RCTs of hospitalized patients of any age comparing transfusion of fresher versus older red blood cells were eligible. We used a random-effects model to calculate pooled risk ratios (RRs) with corresponding 95% confidence interval (CI). RESULTS: We identified 14 randomized trials that enrolled 26 374 participants. All-cause mortality occurred in 1219 of 9531 (12·8%) patients who received a transfusion of fresher red blood cells and 1810 of 16 843 (10·7%) in those who received older red blood cells (RR: 1·04, 95% CI: 0·98-1·12, P = 0·90, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). In six studies, in-hospital death occurred in 691 of 7479 (9·2%) patients receiving fresher red cells and 1291 of 14 757 (8·8%) receiving older red cells (RR: 1·06, 95% CI: 0·97-1·15, P = 0·81, I2 = 0%, high certainty for ruling out benefit of fresh blood, moderate certainty for ruling out harm of fresh blood). CONCLUSION: Transfusion of fresher red blood cells does not reduce overall or in-hospital mortality when compared with older red blood cells. Our results support the practice of transfusing patients with the oldest red blood cells available in the blood bank.

Evaluation of the appropriateness of frozen plasma usage after introduction of prothrombin complex concentrates: a retrospective study.

BACKGROUND: Prothrombin complex concentrates (PCCs) can be used instead of frozen plasma (FP) transfusion to reverse the effect of warfarin. Audits have demonstrated over usage of FP transfusions even before the introduction of PCC. The objective of this study was to determine the appropriateness of current FP transfusion practice in the current era since the introduction of PCCs. METHODS: A retrospective cohort study of consecutive patients receiving FP over 3 months was carried out. Each episode of FP use over a 24-h period was adjudicated independently by two reviewers as appropriate (consistent with Canadian/AABB guidelines), appropriate but inconsistent with guidelines or inappropriate. Discrepancies were resolved by a third reviewer. Use of FP to reverse warfarin was considered inappropriate. FP usage from previous years was assessed as baseline. RESULTS: During the study period, 111 FP transfusions were administered. 74.8% of FP usage occurred in the ICU. The proportion of FP transfusions that were deemed appropriate, inconsistent yet appropriate or inappropriate were 33/89 (37.1%), 16/89 (18.0%) and 40/89 (44.9%), respectively, when use of FP for therapeutic plasma exchange was excluded. The most common reasons for inappropriate use were the absence of bleeding with an increased INR or warfarin reversal. CONCLUSION: Our study is the first to audit FP transfusions in the post-PCC era in Canada. FP usage remains inappropriately high in INR prolongation without another indication or to reverse warfarin. Targeted interventions to reduce FP usage in the future should focus on the ICU and on education about warfarin reversal.

Clinical challenges in patients with cancer-associated thrombosis: Canadian expert consensus recommendations.

Venous thromboembolism is a common complication in cancer patients, and thromboembolism is the second most common cause of death after cancer progression. A number of clinical practice guidelines provide recommendations for the management of cancer-associated thrombosis. However, the guidelines lack recommendations covering commonly encountered clinical challenges (for example, thrombocytopenia, recurrent venous thromboembolism, etc.) for which little or no evidence exists. Accordingly, recommendations were developed to provide expert guidance to medical oncologists and other health care professionals caring for patients with cancer-associated thrombosis. The current expert consensus was developed by a team of 21 clinical experts. For each identified clinical challenge, the literature in medline, embase, and Evidence Based Medicine Reviews was systematically reviewed. The quality of the evidence was assessed, summarized, and graded. Consensus statements were generated, and the experts voted anonymously using a modified Delphi process on their level of agreement with the various statements. Statements were progressively revised through separate voting iterations and were then finalized. Clinicians using these recommendations and suggestions should tailor patient management according to the risks and benefits of the treatment options, patient values and preferences, and local cost and resource allocations.

Lethal control of an apex predator has unintended cascading effects on forest mammal assemblages.

Disruption to species-interaction networks caused by irruptions of herbivores and mesopredators following extirpation of apex predators is a global driver of ecosystem reorganization and biodiversity loss. Most studies of apex predators' ecological roles focus on effects arising from their interactions with herbivores or mesopredators in isolation, but rarely consider how the effects of herbivores and mesopredators interact. Here, we provide evidence that multiple cascade pathways induced by lethal control of an apex predator, the dingo, drive unintended shifts in forest ecosystem structure. We compared mammal assemblages and understorey structure at seven sites in southern Australia. Each site comprised an area where dingoes were poisoned and an area without control. The effects of dingo control on mammals scaled with body size. Activity of herbivorous macropods, arboreal mammals and a mesopredator, the red fox, were greater, but understorey vegetation sparser and abundances of small mammals lower, where dingoes were controlled. Structural equation modelling suggested that both predation by foxes and depletion of understorey vegetation by macropods were related to small mammal decline at poisoned sites. Our study suggests that apex predators' suppressive effects on herbivores and mesopredators occur simultaneously and should be considered in tandem in order to appreciate the extent of apex predators' indirect effects.

Developing a Natural History Model for Duchenne Muscular Dystrophy.

BACKGROUND: The aim of this study was to pool multiple data sets to build a patient-centric, data-informed, natural history model (NHM) for Duchenne muscular dystrophy (DMD) to estimate disease trajectory across patient lifetime under current standard of care in future economic evaluations. The study was conducted as part of Project HERCULES, a multi-stakeholder collaboration to develop tools to support health technology assessments of new treatments for DMD. METHODS: Health states were informed by a review of NHMs for DMD and input from clinicians, patients and caregivers, and defined using common outcomes in clinical trials and real-world practice. The primary source informing the NHM was the Critical Path Institute Duchenne Regulatory Science Consortium (D-RSC) database. This was supplemented with expert input obtained via an elicitation exercise, and a systematic literature review and meta-analysis of mortality data. RESULTS: The NHM includes ambulatory, transfer and non-ambulatory phases, which capture loss of ambulation, ability to weight bear and upper body and respiratory function, respectively. The NHM estimates patients spend approximately 9.5 years in ambulatory states, 1.5 years in the transfer state and the remainder of their lives in non-ambulatory states. Median predicted survival is 34.8 years (95% CI 34.1-35.8). CONCLUSION: The model includes a detailed disease pathway for DMD, including the clinically and economically important transfer state. The NHM may be used to estimate the current trajectory of DMD in economic evaluations of new treatments, facilitating inclusion of a lifetime time horizon, and will help identify areas for further research.

Should relative survival be used with lung cancer data?

BACKGROUND: Under certain assumptions, relative survival is a measure of net survival based on estimating the excess mortality in a study population when compared with the general population. Background mortality estimates are usually taken from national life tables that are broken down by age, sex and calendar year. A fundamental assumption of relative survival methods is that if a patient did not have the disease of interest then their probability of survival would be comparable to that of the general population. It is argued, as most lung cancer patients are smokers and therefore carry a higher risk of smoking-related mortalities, that they are not comparable to a population where the majority are likely to be non-smokers. METHODS: We use data from the Finnish Cancer Registry to assess the impact that the non-comparability assumption has on the estimates of relative survival through the use of a sensitivity analysis. RESULTS: Under realistic estimates of increased all-cause mortality for smokers compared with non-smokers, the bias in the estimates of relative survival caused by the non-comparability assumption is negligible. CONCLUSION: Although the assumption of comparability underlying the relative survival method may not be reasonable, it does not have a concerning impact on the estimates of relative survival, as most lung cancer patients die within the first 2 years following diagnosis. This should serve to reassure critics of the use of relative survival when applied to lung cancer data.

Assessment of von Willebrand disease as a risk factor for primary postpartum haemorrhage.

It is not clear whether von Willebrand disease (VWD) is associated with an increased risk of postpartum haemorrhage (PPH). We assessed the effect of VWD on PPH in a case-control study. Logistic regression was used to test for differences in the odds of PPH in deliveries to women with and without VWD, before and after adjustment for known risk factors. A total of 62 deliveries in 33 women with VWD were compared with controls matched for age, year of delivery and parity. Primary PPH was observed in 12/62 (19.4%) deliveries in women with VWD and 16/124 (12.9%) controls. The unadjusted odds ratio (OR) for VWD as a risk factor for PPH was 1.62 (95% CI 0.75-3.49, P = 0.22). After adjustment for other risk factors for PPH, the OR for VWD as a risk factor for PPH was 1.31 (95% CI 0.48-3.60, P = 0.60). PPH was observed in 7/24 (29%) deliveries in women known prepregnancy to have VWD. The unadjusted odds for VWD as a risk factor for PPH in this group was significantly greater than the control group (OR 2.78 (95% CI 1.03-7.49) P = 0.043) and remained significant after adjusting for other significant risk factors (OR 3.41 (95% CI 1.07-10.9) P = 0.038). VWD in itself may not be a significant risk factor for PPH, however, women known to have VWD predelivery may represent an at risk sub-group.

Ustekinumab associated thrombotic thrombocytopenic purpura.

Thrombotic thrombocytopenic purpura (TTP) is a rare disorder. Plasma exchange therapy has been shown to significantly reduce mortality in patients with TTP. Here, we report a case of TTP associated with ustekinumab therapy after a period of 2-3 years. Ustekinumab, a monoclonal antibody that inhibits interleukin 12 and interleukin 23, is one of the newer treatments for psoriasis. Although our patient experienced a prolonged course of TTP requiring 1 month of daily plasma exchange therapy, he recovered and remains in remission after 6 months.

Evidence-based recommendations for the prevention and long-term management of thrombosis in antiphospholipid antibody-positive patients: report of a task force at the 13th International Congress on antiphospholipid antibodies.

The antiphospholipid syndrome (APS) is defined by the presence of thrombosis and/or pregnancy morbidity in combination with the persistent presence of circulating antiphospholipid antibodies: lupus anticoagulant, anticardiolipin antibodies and/or anti-ß2-glycoprotein I antibodies in medium to high titers. The management of thrombosis in patients with APS is a subject of controversy. This set of recommendations is the result of an effort to produce guidelines for therapy within a group of specialist physicians in Cardiology, Neurology, Hematology, Rheumatology and Internal Medicine, with a clinical and research focus on APS.

Quality of early evidence on the pathogenesis, diagnosis, prognosis and treatment of COVID-19.

Since the initial description of the SARS-CoV-2 outbreak and its declaration as a worldwide pandemic, the number of publications on the novel virus has increased rapidly. We studied the trends and quality of evidence in early SARS-CoV-2 publications. A comprehensive search of MEDLINE and EMBASE was performed for papers published between 1 January 2020 and 21 April 2020. Two reviewers independently screened titles and abstracts and subsequently full texts for eligibility in this systematic review. The search yielded 2504 citations published between January and February 2020 or an unspecified date, 109 of which remained for extraction after screening. Data extracted included study design, year of publication, country of basis, journal of publication, impact factor of publishing journal, study sample size, number of citations and topic of investigation. Study design-specific critical appraisal tools were used to evaluate the scientific rigour of all included papers: the Joanna Briggs Institute checklist was used for case series, Scale for the Assessment of Narrative Review Articles scale for narrative reviews, Newcastle-Ottawa scale for cohort studies and AMSTAR 2 for systematic reviews. The overall quality of the literature was low-moderate. Of 541 papers that reported clinical characteristics, 295 were commentaries/expert opinions and 36 were case reports. There were no randomised clinical trials, 45 case series studies, 58 narrative reviews, 1 cohort study and 5 systematic reviews. We encourage clinicians to be attentive to these findings when utilising early SARS-CoV-2 evidence in their practices.

A prospective observational study of preoperative natriuretic peptide testing in adult non-cardiac surgical patients in hospitals in Western Cape Province, South Africa.

BACKGROUND: International guidelines recommend risk stratification to identify high-risk non-cardiac surgical patients. It is also recommended that all patients aged ≥45 years with significant cardiovascular disease should have preoperative natriuretic peptide (NP) testing. Abnormal preoperative B-type NPs have a strong association with postoperative cardiac complications. In South African hospitals, it is not known how many patients with significant cardiovascular disease scheduled for intermediate- to high-risk surgery will have raised NPs. OBJECTIVES: To determine the prevalence of abnormal (raised) NPs in non-cardiac surgical patients with cardiac clinical risk factors. A secondary objective was to develop a model to identify surgical patients who may benefit from preoperative NP screening. METHODS: The inclusion criteria were patients aged ≥45 years presenting for elective, non-obstetric, intermediate- to high-risk non-cardiac surgery with at least one of the following cardiovascular risk factors: a history of ischaemic heart disease or peripheral vascular disease (coronary equivalent); a history of stroke or transient ischaemic attack; a history of congestive cardiac failure; diabetes mellitus currently on an oral hypoglycaemic agent or insulin; and serum creatinine level >175 µmol/L (>2.0 mg/dL). Blood samples for N-terminal-prohormone B-type NP (NT-proBNP) were collected before induction of anaesthesia. The preoperative prognostic threshold for abnormal (raised) NT-proBNP was ≥300 pg/mL. A generalised linear mixed model was used to determine the association between the risk factors and an abnormal NT-proBNP level. RESULTS: Of 172 patients, 63 (37%) had an elevated preoperative NT-proBNP level. The comorbidities independently associated with elevated preoperative NT-proBNP were coronary artery disease or peripheral vascular disease, congestive cardiac failure, and a creatinine level >175 µmol/L CONCLUSIONS: We strongly recommend that non-cardiac surgical patients aged ≥45 years undergoing intermediate- or high-risk noncardiac surgery with a history of coronary artery disease/peripheral vascular disease, congestive cardiac failure or elevated creatinine have preoperative NP testing as part of risk stratification.

Weight-adjusted tinzaparin for venous thromboembolism prophylaxis in bariatric surgery patients weighing 160 kg or more.

INTRODUCTION: Bariatric surgery patients experience an increased risk of venous thromboembolism (VTE), however, the optimal dose of low-molecular-weight heparin for VTE prophylaxis remains uncertain. Currently, St. Joseph's Healthcare Hamilton utilizes a weight-adjusted tinzaparin dosage (50 to 75 units/kg rounded to nearest pre-filled syringe) for postoperative VTE prophylaxis. OBJECTIVES: This study analyzed the safety of weight-adjusted tinzaparin for VTE prophylaxis in bariatric surgery patients weighing ≥160 kg. METHODS: This was a retrospective study involving patients weighing ≥160 kg that underwent bariatric surgery from September 2015 to September 2019. Patients received a single dose of weight-adjusted subcutaneous unfractionated heparin (UFH) [5000 or 7500 IU] immediately prior to surgery, subcutaneous UFH [5000 IU, 7500 IU, or unspecified] immediately postoperatively, and either 10,000 or 14,000 IU of tinzaparin, beginning on the day after surgery, for 10 days. Intra-operative sequential compression devices could be used at the attending surgeon's discretion. Occurrence of VTE and major bleeding within 30 days of surgery were assessed. RESULTS: A total of 389 patients were included for analysis, all patients received in-hospital follow-up while 349 patients had also 30-day follow-up. For the primary safety and efficacy analysis of in-hospital events, VTE and major bleeding rates were 0.26% [95% CI 0.01%-1.44%] (1/389) and 0.77% [95% CI 0.21%-2.24%] (3/389) respectively. For patients with 30-day follow-up VTE and major bleeding rates were 0.57% [95% CI 0.1%-2.07%] (2/349) and 1.43% [95% CI 0.61%-3.3%] (5/349) respectively. CONCLUSIONS: Weight-adjusted tinzaparin was associated with a low risk of bleeding and VTE events, supporting its use for VTE prophylaxis for patients weighing ≥160 kg.

Jointly modelling longitudinally measured urinary human chorionic gonadotrophin and early pregnancy outcomes.

Human chorionic gonadotrophin (hCG) is largely used to confirm pregnancy. Yet evidence shows that longitudinal hCG profiles are distinguishable between healthy and failing pregnancies. We retrospectively fitted a joint longitudinal-survival model to data from 127 (85 healthy and 42 failing pregnancies) US women, aged 18-45, who were attempting to conceive, to quantify the association between longitudinally measured urinary hCG and early miscarriage. Using subject-specific predictions, obtained uniquely from the joint model, we investigated the plausibility of adaptively monitoring early pregnancy outcomes based on updating hCG measurements. Volunteers collected daily early morning urine samples for their menstrual cycle and up to 28 days post day of missed period. The longitudinal submodel for log hCG included a random intercept and slope and fixed linear and quadratic time terms. The survival submodel included maternal age and cycle length covariates. Unit increases in log hCG corresponded to a 63.9% (HR 0.36, 95% CI 0.16, 0.47) decrease in the risk of miscarriage, confirming a strong association between hCG and miscarriage. Outputted conditional survival probabilities gave individualised risk estimates for the early pregnancy outcomes in the short term. However, longer term monitoring would require a larger sample size and prospectively followed up data, focusing on emerging extensions to the joint model, which allow assessment of the specificity and sensitivity.

Predictors of length of stay following shoulder arthroplasty in a high-volume UK centre.

INTRODUCTION: Shoulder arthroplasty rates are increasing in the UK. No data have been published from a UK centre on predictors of length of inpatient stay following shoulder arthroplasty. This study analyses the length of inpatient stay following shoulder arthroplasty in a high-volume UK centre and identifies predictors of prolonged inpatient stay. MATERIALS AND METHODS: All shoulder arthroplasty cases performed between 2012 and 2018 were identified. A review of case notes and electronic patient records was completed to identify demographic data, Charlson comorbidity score, length of inpatient stay and factors associated with length of stay. Multiple linear regression analysis was conducted to determine which factors were independently associated with length of inpatient stay. RESULTS: A total of 640 shoulder arthroplasty cases were performed in 566 patients. Median length of stay was two days. Length of stay was predicted by age, sex, chronic kidney disease, congestive cardiac failure, previous myocardial infarction, intraoperative complication and postoperative transfusion. DISCUSSION: Increasing age, female sex, chronic kidney disease, congestive cardiac failure, previous myocardial infarction, intraoperative complication and transfusion were independent predictors of increased length of stay. Strategies to reduce perioperative complication and transfusion, and to optimise renal and cardiac comorbidities may reduce overall length of stay for shoulder arthroplasty patients.

Predictors of mortality following shoulder arthroplasty.

INTRODUCTION: This study aims to determine 30-day, 90-day and 1 year mortality following shoulder arthroplasty and identify predictors of mortality. MATERIALS AND METHODS: All shoulder arthroplasty cases performed at the host institution, between 2012 and 2018 were included. A review of patient records was completed to identify demographic data, Charlson comorbidity index, date of death and factors associated with mortality.Mortality analysis was undertaken using 1-Kaplan Meier estimates with 95% confidence intervals. Comparative analysis was performed for mortality following shoulder arthroplasty for elective vs. trauma and for primary vs. revision surgery. A multiple regression analysis was conducted to determine which factors were associated with increased mortality risk. RESULTS: 640 shoulder arthroplasty cases were performed in 566 patients. There were 44 deaths, 1 occurred within 90 days and 13 within 1 year. Trauma procedures had a hazard ratio of 5.3 (95% CI 1.9 to 15.0) for mortality compared to elective procedures (5 year survival trauma 78.6% (95% CI 60.7 to 89.0); elective 91.8% (95% CI 88.1 to 94.4). 1-year mortality was predicted by presence of malignancy, liver failure, cardiac failure, peptic ulcer, trauma surgery, revision surgery, intra-operative complication, transfusion and increased length of stay. DISCUSSION: 30-day, 90-day and 1-year mortality following shoulder arthroplasty were 0%, 0.16% and 2%; trauma procedures had a hazard ratio of 5.3 for 1-year mortality when compared to elective surgery. Malignancy, cardiac failure, liver failure, peptic ulcer and trauma surgery are associated with an increased risk of 1-year mortality.