Postdischarge prophylactic antibiotics following mastectomy with and without breast reconstruction

Background: Prophylactic antibiotics are commonly prescribed at discharge for mastectomy, despite guidelines recommending against this practice. We investigated factors associated with postdischarge prophylactic antibiotic use after mastectomy with and without immediate reconstruction and the impact on surgical-site infection (SSI). Study design: We studied a cohort of women aged 18–64 years undergoing mastectomy between January 1, 2010, and June 30, 2015, using the MarketScan commercial database. Patients with nonsurgical perioperative infections were excluded. Postdischarge oral antibiotics were identified from outpatient drug claims. SSI was defined using International Classification of Diseases, Ninth Edition, Clinical Modification (ICD-9-CM) diagnosis codes. Generalized linear models were used to determine factors associated with postdischarge prophylactic antibiotic use and SSI. Results: The cohort included 38,793 procedures; 24,818 (64%) with immediate reconstruction. Prophylactic antibiotics were prescribed after discharge after 2,688 mastectomy-only procedures (19.2%) and 17,807 mastectomies with immediate reconstruction (71.8%). The 90-day incidence of SSI was 3.5% after mastectomy only and 8.8% after mastectomy with immediate reconstruction. Antibiotics with anti–methicillin-sensitive Staphylococcus aureus (MSSA) activity were associated with decreased SSI risk after mastectomy only (adjusted relative risk [aRR], 0.74; 95% confidence interval [CI], 0.55–0.99) and mastectomy with immediate reconstruction (aRR, 0.80; 95% CI, 0.73–0.88), respectively. The numbers needed to treat to prevent 1 additional SSI were 107 and 48, respectively. Conclusions: Postdischarge prophylactic antibiotics were common after mastectomy. Anti-MSSA antibiotics were associated with decreased risk of SSI for patients who had mastectomy only and those who had mastectomy with immediate reconstruction. The high numbers needed to treat suggest that potential benefits of postdischarge antibiotics should be weighed against potential harms associated with antibiotic overuse.

Efficacy and Tolerability of Combination Treatments for Major Depression: Antidepressants plus Second-Generation Antipsychotics vs. Esketamine vs. Lithium

Background: Successful treatment of major depressive disorder (MDD) can be challenging, and failures ("treatment-resistant depression" [TRD]) are frequent. Steps to address TRD include increasing antidepressant dose, combining antidepressants, adding adjunctive agents, or using nonpharmacological treatments. Their relative efficacy and tolerability remain inadequately tested. In particular, the value and safety of increasingly employed second-generation antipsychotics (SGAs) and new esketamine, compared to lithium as antidepressant adjuncts remain unclear. Methods: We reviewed randomized, placebo-controlled trials and used random-effects meta-analysis to compare odds ratio (OR) versus placebo, as well as numbers-needed-to-treat (NNT) and to-harm (NNH), for adding SGAs, esketamine, or lithium to antidepressants for major depressive episodes. Results: Analyses involved 49 drug-placebo pairs. By NNT, SGAs were more effective than placebo (NNT = 11 [CI: 9–15]); esketamine (7 [5–10]) and lithium (5 [4–10]) were even more effective. Individually, aripiprazole, olanzapine+fluoxetine, risperidone, and ziprasidone all were more effective (all NNT < 10) than quetiapine (NNT = 13), brexpiprazole (16), or cariprazine (16), with overlapping NNT CIs. Risk of adverse effects, as NNH for most-frequently reported effects, among SGAs versus placebo was 5 [4–6] overall, and highest with quetiapine (NNH = 3), lowest with brexpiprazole (19), 5 (4–6) for esketamine, and 9 (5–106) with lithium. The risk/benefit ratio (NNH/NNT) was 1.80 (1.25–10.60) for lithium and much less favorable for esketamine (0.71 [0.60–0.80]) or SGAs (0.45 [0.17–0.77]). Conclusions: Several modern antipsychotics and esketamine appeared to be useful adjuncts to antidepressants for acute major depressive episodes, but lithium was somewhat more effective and better tolerated. Limitations: Most trials of adding lithium involved older, mainly tricyclic, antidepressants, and the dosing of adjunctive treatments were not optimized.

Propensity weighted indirect treatment comparison of nivolumab (NIVO) versus placebo (PBO) as adjuvant therapy for resected melanoma: A number needed to treat and overall survival analysis.

9572 Background: The CheckMate 238 trial demonstrated that NIVO improved recurrence free survival (RFS) vs. ipilimumab (IPI). The EORTC 18071 trial demonstrated that IPI improved RFS and overall survival (OS) vs. PBO. The current study pooled data from these two trials to indirectly assess the RFS and OS of NIVO vs. PBO and the numbers needed to treat (NNTs) for one additional recurrence-free survivor and survivor over 4 years. Methods: Patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma from CheckMate 238 (NIVO vs. IPI) and EORTC 18071 (IPI vs. PBO) were pooled together with inverse probability weighting to balance between-trial differences in baseline characteristics. NNTs were calculated for RFS and OS comparing NIVO vs. IPI and PBO over 4 years. To account for improved post-recurrence survival over time, a sensitivity analysis that adjusted for post-recurrence survival in the PBO arm of EORTC 18071 was performed. Results: A total of 278, 643, and 365 patients treated with NIVO, IPI, and PBO, respectively, were included. In the weighted samples, patients treated with NIVO had consistently higher RFS rates than those treated with IPI (HR [95% CI]: 0.69 [0.56, 0.85]) and PBO (HR: 0.49 [0.39, 0.61]). NIVO was associated with similar OS as IPI (HR: 0.80 [0.60, 1.08]) and superior OS compared to PBO (HR: 0.45 [0.33, 0.60]). At 4 years, the weighted RFS rate was 53.1% for NIVO, 41.8% for IPI, and 29.1% for PBO. The NNT to achieve one additional recurrence-free survivor was 4.2 for NIVO vs. PBO and 8.9 for NIVO vs. IPI. The NNT to obtain one additional survivor was 4.8 for NIVO vs. PBO and 22.2 for NIVO vs. IPI. The OS rate for PBO after adjusting for differences in post-recurrence treatments at 4 years was 64.1%, and the corresponding NNT of OS comparing NIVO vs. adjusted PBO was 8.5. Conclusions: In patients with resected AJCC 7th edition stage IIIB/C cutaneous melanoma, this indirect comparison showed that NIVO improved RFS and OS vs placebo, with OS improvement maintained after adjustment for post-recurrence therapy.[Table: see text]

Transporting subgroup analyses of randomized trials for planning implementation of new interventions

Subgroup analyses of randomized controlled trials guide resource allocation and implementation of new interventions by identifying groups of individuals who are likely to benefit most from the intervention. Unfortunately, trial populations are rarely representative of the target populations of public health or clinical interest; unless the relevant differences between trial and target populations are accounted for, subgroup results from trials might not reflect which groups in the target population will benefit most from the intervention. Transportability provides a rigorous framework for applying results derived in potentially highly selected study populations to external target populations. The method requires that researchers measure and adjust for all variables that (1) modify the effect of interest and (2) differ between the target and trial populations. To date, applications of transportability have focused on the external validity of overall study results and understanding within-trial heterogeneity; but this approach has not yet been used for subgroup analyses of trials. Through an example from the iPrEx study of HIV pre-exposure prophylaxis, we illustrate how transporting subgroup analyses can produce target-specific subgroup effect estimates and numbers needed to treat. This approach may lead to more tailored and accurate guidance for resource allocation and cost-effectiveness analyses.

Understanding basic numbers: examples from Brexit, Covid and common medical conditions

The UK Brexit debate and the current Covid pandemic have been fertile grounds for people seeking poor use of statistics, and demonstrate a need to reiterate some basic principles of data presentation. Communicating basic numbers to convey the correct message is a vital skill for a public health professional but even basic numbers can be difficult to understand, and are susceptible to misuse. The first issue is how to understand ‘orphan’ numbers; numbers quoted without comparison or context. This leads on to the problems of understand numbers as proportions and how to make comparisons using proportions. Percentages, and in particular percentage changes, are also a major source of misunderstanding and the baseline percentage should always be given. The use of relative risk can also convey the wrong message and should always be accompanied by a measure of absolute risk. Similarly, numbers needed to treat should also refer to baseline risks. Communicating numbers is often more effective using natural counts or frequencies rather than fractions or proportions, and using pictorial representations of proportions can also be effective. The paper will also examine the problems of using simple ratios to try and adjust one continuous variable by another in particular the use of the BMI and for standardising death rates by institution. The misuse of reporting occurs in primary sources such as academic papers, but even more so in secondary reporting sources such as general media reports. It is natural to try and convey complex messages using a single summary number, but there are assumptions behind these summaries that should be questioned. It is usually better to give the individual numbers rather than a ratio of them.

132 ANTI-REFLUX SURGERY FOR CONTROLLING RESPIRATORY SYMPTOMS OF GASTRO-ESOPHAGEAL REFLUX DISEASE: A SYSTEMATIC REVIEW AND META-ANALYSIS.

Gastro-esophageal reflux disease (GERD) patients have a higher prevalence of airway symptoms, such as chronic cough, wheezing, and hoarseness. The therapeutic management of patients with these symptoms is controversial. Therefore, this study aims to perform a systematic review and meta-analysis evaluating the efficacy of anti-reflux surgery for controlling respiratory symptoms related to GERD. Methods A systematic review and meta-analysis was performed. Extraction of the data concerning proportions of participants who were not free of respiratory symptoms related to GERD (cough, wheezing, hoarseness) or not substantially improved at follow-ups (failure to cure) was performed. Results Of the screened articles, 61 were included for meta-analysis, with a cumulative sample size of 3,869 patients. Of all the included patients, after anti-reflux surgery, the general symptoms improvement was 80% (95% CI 75.2–84%). The numbers needed to harm (NNH) and the numbers needed to treat (NNT) were 15.21 and 1.23, respectively. Of the included patients, 83.4% (95% CI 78.3–87.5%) patients reported improvement in cough symptoms after surgery. For the wheezing symptom, 71.5% (95% CI 62.9–78.8%) reported improvement after surgery. Moreover, surgery presented better results in improving respiratory symptoms than medical therapy (risk difference: -0.46; 95% CI -0.77, −0.16). Conclusion Physicians should strongly consider surgical anti-reflux procedures for controlling respiratory symptoms in GERD patients after proper patient selection. Anti-reflux surgery has shown high efficacy in improving respiratory symptoms related to GERD, even when compared to medical therapy.

Interplay of IL6 and CRIM1 on thiopurine-induced neutropenia in leukemic patients with wild-type NUDT15 and TPMT

Background: NUDT15 and TPMT variants are strong genetic determinants of thiopurine-induced hematological toxicity. Despite recent discovery of homozygous CRIM1 effect on thiopurine toxicity, many patients with wild-type NUDT15, TPMT, and CRIM1 still suffer from thiopurine toxicity, and therapeutic failure and relapse of acute lymphoblastic leukemia (ALL). Methods: Novel PGx interactions associated with thiopurine toxicity in 320 pediatric ALL patients were investigated using whole-exome sequencing technology for the last-cycle 6-Mercaptopurine dose intensity percentage (DIP) tolerated by pediatric ALL patients. Results: IL6 rs13306435 carriers (N=19) exhibited significantly lower DIP (48.0±27.3%) than non-carriers (N=209, 69.9±29.0%| p=0.0016 and 0.0028 by t-test and multiple linear regression, respectively). Of the 19 carriers, seven with both heterozygous IL6 rs13306435 and CRIM1 rs3821169 showed significantly decreased DIP (24.7±8.9%) than those with IL6 (N=12, 61.6±25.1%) or CRIM1 (N=94, 68.1±28.4%) variant only. Both IL6 and CRIM1 variants showed marked inter-ethnic variability. Significant interplay between IL6 and CRIM1 in thiopurine toxicity was suggested. GVB (Gene-wise Variant Burden)-based four-gene-interplay model showed the best odds ratio (8.06) and potential population impact (i.e., relative risk (5.73), population attributable fraction (58%), numbers needed to treat (3.67) and number needed to genotype (12.50)). Conclusions: Interplay of IL6 rs13306435 and CRIM1 rs3821169 was suggested as independent and/or additive genetic determinant of thiopurine toxicity beyond NUDT15 and TPMT in pediatric ALL.

Physician, know thyself: implicit and explicit decision-making for mechanical thrombectomy in stroke

Few clinical situations in medical practice are as time-sensitive and and have such profound ramifications as selection of patients with acute stroke for mechanical thrombectomy (MT). Emergent large vessel occlusion has become a treatable disease with minimal numbers needed to treat to achieve a functional, long-term neurologic outcome. However, MT carries risk and many patients who are appropriately reperfused continue to have significant neurologic deficits and disability despite a successful procedure. The decision to offer or withhold MT can be complex. Frequently decisions must be made based on incomplete information or emergently while the physician is awoken from sleep or distracted while performing other procedures. A growing number of studies have examined cognitive errors and biases as they pertain to patient diagnosis and treatment in medicine. Dual process theory identifies two decision-making processes as system 1 ('implicit') and system 2 ('explicit') and describes the patterns through which decisions are formulated. The implicit system is the default pathway as it requires little effort or focus, uses mental short cuts, and is rapid; however, this pathway is subject to considerable bias and error. This manuscript reviews the mechanisms underlying the way in which physician decisions about MT are made, specifically highlighting prominent biases that may affect judgment, and reviews other important principles, such as confidence in decisions, aggressiveness to pursue MT, and strategies to improve decisions.