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Aims/Introduction This systematic review and meta‐analysis aimed to investigate the efficacy and safety of acceptance and commitment therapy (ACT) for people with type 2 diabetes mellitus. Materials and Methods Several electronic databases were examined on 16 January 2021, including PubMed, CENTRAL, PsycINFO, International Clinical Trials Registry Platform and ClinicalTrials.gov. Randomized controlled trials were included to compare ACT with usual treatment for people with type 2 diabetes reported in any language. Primary outcome measures were glycated hemoglobin, self‐care ability assessed by the summary of diabetes self‐care activities and all adverse events. The secondary outcome measure was acceptance assessed by the acceptance and action diabetes questionnaire. Results Of 678 publications initially identified, three trials were included in the meta‐analysis. ACT resulted in a reduction in glycated hemoglobin (mean difference −0.62 points lower in the intervention group; 95% confidence interval −1.07 to −0.16; I2 = 0%; low‐quality evidence). In addition, ACT increased the score of the summary of diabetes self‐care activities (mean difference 8.48 points higher in the intervention group; 95% confidence interval 2.16–14.80; high‐quality evidence). Adverse events were not measured in all trials. ACT increased scores of the acceptance and action diabetes questionnaire (mean difference 5.98 points higher in the intervention group; 95% confidence interval, 1.42–10.54; I2 = 43%; low‐quality evidence). Conclusions ACT might reduce glycated hemoglobin, and increase self‐care ability and acceptance among people with type 2 diabetes.

Growing evidence suggests that women born preterm or small have an increased risk of experiencing hypertensive disorders during pregnancy; however, a quantitative summary of the evidence on this issue is unavailable.We aimed to systematically review the literature to describe the association between being born preterm, low birthweight (LBW), or small for gestational age (SGA), and future gestational hypertension, preeclampsia, or eclampsia.We searched the MEDLINE, Embase, CINAHL, ClinicalTrials.gov, and ICTRP databases. We included all cohort and case-control studies examining the association between LBW, preterm birth, or SGA and hypertensive disorders in pregnancy. We pooled the odds ratios and 95% confidence intervals using the DerSimonian and Laird random-effects model. We assessed the certainty of evidence for each outcome using the Grading of Recommendations, Assessment, Development, and Evaluation criteria.Eleven studies were identified, totalling 752 316 participants. Being born preterm, LBW, or SGA was associated with gestational hypertension [pooled odds ratio (OR), 1.31; 95% confidence interval (CI) 1.15-1.50; moderate certainty of evidence] and preeclampsia (pooled OR, 1.35; 95% CI 1.23-1.48; moderate certainty of evidence). No study measured eclampsia as an outcome.Women born preterm, LBW, or SGA have an increased risk of gestational hypertension and preeclampsia. The course of the mother's own birth might be used to identify women at risk of gestational hypertension and preeclampsia.

Predicting pathogenic germline variants (PGVs) in breast cancer patients is important for selecting optimal therapeutics and implementing risk reduction strategies. However, PGV risk factors and the performance of prediction methods in the Japanese population remain unclear. We investigated clinicopathological risk factors using the Tyrer‐Cuzick (TC) breast cancer risk evaluation tool to predict BRCA PGVs in unselected Japanese breast cancer patients (n = 1,995). Eleven breast cancer susceptibility genes were analyzed using target‐capture sequencing in a previous study; the PGV prevalence in BRCA1, BRCA2, and PALB2 was 0.75%, 3.1%, and 0.45%, respectively. Significant associations were found between the presence of BRCA PGVs and early disease onset, number of familial cancer cases (up to third‐degree relatives), triple‐negative breast cancer patients under the age of 60, and ovarian cancer history (all P, Combination of major clinicopathological risk factors and predictive scores could help identify and characterize high‐risk population carrying BRCA1/2 PGVs among Japanese breast cancer patients. Significant associations were found between the presence of PGVs and early disease onset, number of familial cancer cases within third‐degree relatives, triple‐negative breast cancer patients under the age of 60, and ovarian cancer history (all P

Background Previous studies have suggested that metformin might improve survival outcomes in patients with breast cancer. However, findings on the efficacy of metformin with chemotherapy or endocrine therapy are inconsistent. Objective To clarify the efficacy of metformin with chemotherapy or endocrine therapy in breast cancer patients according to the treatment setting, including neoadjuvant, adjuvant, and metastasis/recurrence. Methods We systematically searched for randomized controlled trials (RCTs) in MEDLINE, CENTRAL, and EMBASE from inception through July 2020. Overall survival (OS), progression-free survival (PFS), and hypoglycemia rate were the primary outcomes. Secondary outcomes included severe adverse events (SAEs) and relapse-free survival. We used the Grading of Recommendations Assessment, Development, and Evaluation approach and performed a meta-analysis to evaluate the efficacy and safety of metformin with chemotherapy and endocrine therapy in patients with breast cancer. Results Our systematic review included 412 participants from 5 trials. Metformin showed little to no difference in OS (hazard ratio [HR] = 1.13; 95% CI = 0.71-1.81; certainty of evidence [COE], moderate) and PFS (HR = 1.14; 95% CI = 0.86-1.50; COE, moderate) in patients with metastasis/recurrence. The evidence was very uncertain about the effect of metformin on survival outcomes in patients who received metformin with neoadjuvant or adjuvant treatment. Metformin showed little to no difference in hypoglycemia and SAEs. Conclusion and Relevance Metformin should be discouraged routinely in nondiabetic patients with metastatic/recurrent breast cancer. Further RCTs are needed to verify whether metformin with chemotherapy or endocrine therapy results in significant clinical benefits in the neoadjuvant or adjuvant setting.

Lung cancer is one of the most prevalent and lethal cancers worldwide (1). The traditional treatments include surgery, chemotherapy, radiotherapy and interventional therapy. The survival of lung cancer patients has dramatically been prolonged in recent years with the availability of targeted therapies, antiangiogenic agents and immune checkpoint inhibitors (ICIs). Meanwhile, technologies for the molecular detection of lung cancer have also advanced rapidly: the detection of single driver genes has evolved to cover combined multi-gene analysis, and whole exome sequencing (WES) has increasingly been applied in the clinical setting. In addition, life support technologies, including ventilators, artificial liver, and artificial kidney as well as extracorporeal membrane oxygenation (ECMO), have further matured, providing powerful forms of life support for patients with various acute and critical diseases. However, most clinical studies have only enrolled patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) scores from 0 to 1, with few patients having PS scores of 2; patients with a PS score of 3 or 4 have been typically excluded. Therefore, due to the lack of high-quality evidence, supportive care is recommended for patients with a PS score of 3 to 4 in the current guidelines. In the real-world, however, approximately 25% of lung cancer patients present with PS score of 3 or 4 (2) or attain scores between 3 and 4 during the course of treatment. Certain patients with high PS scores can benefit from individualized anti-tumor treatment plus appropriate life-support techniques. In 2017, the Lung Cancer Research Team at the First Affiliated Hospital of Guangzhou Medical College & Institute of Respiratory Diseases for the first time pioneered the concept of “advanced severe lung cancer” (3) and argued that standardized therapy for chronic obstructive pulmonary disease (COPD) plus anti-tumor therapy can improve both quality of life and prognosis in patients with lung cancer combined with COPD. The authors also found that the early detection of lung cancer driver genes and timely targeted therapy can be successful in treating patients with advanced severe lung adenocarcinoma with a PS score of 4 (4). In 2019, the concept of advanced severe lung cancer was further developed in a featured article (5) that indicated “Advanced severe lung cancer: does not refer to end-stage lung cancer but rather to stage IIIB, IIIC and IV lung cancers with a PS score of 2–4, which can result from a variety of factors related to the disease itself or anti-tumor drugs and which are highly likely to benefit from the currently available systemic anti-tumor therapies”. In recent years, with the advances in lung cancer diagnosis and treatment techniques and life support technologies, more clinical studies have enrolled patients with a PS score of 2, and some real-world studies have enrolled patients with PS scores of 3–4. Even for patients with early-stage lung cancer, studies have shown that patients with poor PS scores and co-morbidities have a reduced chance of undergoing surgery and an increased mortality rate (6); nevertheless, survival benefit may still be obtained through surgical modifications combined with individualized and multidisciplinary treatment (7). Therefore, the concept of severe lung cancer should not be limited to advanced lung cancer, but applied to all lung cancer patients. In particular, due to the increase in treatment options as well as substantially prolonged survival, the majority of patients may have a PS score between 2 and 4 for a certain period of time due to a variety of reasons. How to provide timely and reasonable treatment for these lung cancer patients has become a critically important real-world research topic. Therefore, we invited lung cancer experts at home and abroad to consider this issue, and this group has reached the following consensus.

Background Social determinants of health (SDHs) are social factors that affect human health; loneliness and social isolation are core SDH factors. There is a possibility that SDHs are related to passive decisionmaking. However, few studies have evaluated SDHs, especially social isolation and loneliness, among lung cancer patients. This study aims to investigate the effects of social isolation and loneliness on the diagnosis and treatment of Japanese lung cancer patients. Methods This is a prospective cohort study that was conducted in a tertiary referral hospital in Japan (University Hospital Medical Information Network registration: UMIN000031810). The enrollment period was between April 2018 and March 2020. Patients with clinical and/or pathological diagnosis of lung cancer were enrolled in this study. Exposures were social isolation and loneliness, and main outcomes were diagnosis methods and whether the initial treatment involved active therapy or best supportive care (BSC). The confounding factors were defined as sex, age, smoking status, respiratory symptoms, weight loss, presentation with any symptoms, Eastern Cooperative Oncology Group (ECOG) performance status, tumor nodes metastasis (TNM) classification, driver gene mutations [i.e., epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK)], and programmed death-ligand 1 (PD-L1) tumor proportion score. Results The study enrolled 264 patients who were divided into quartiles according to their loneliness scores and into two groups according to the social isolation level. Univariate analysis, complete case analysis, and multivariate analysis with multiple imputation failed to detect significant differences in diagnostic method or initial treatment strategy according to loneliness or social isolation level. Conclusions Physicians may not need to consider a patient's loneliness and/or social isolation when diagnosing lung cancer and selecting treatment under universal health insurance coverage. Further studies are needed to understand the influences of loneliness and social isolation on the prognosis of lung cancer patients.

Purpose To date, no consensus exists on the effects of systemic steroid use on pneumonic chronic obstructive pulmonary disease (COPD) exacerbation owing to trial design issues in previous trials involving these conditions. This multicenter study aimed to evaluate more precisely the effectiveness of the use of systemic steroids in treating pneumonic COPD exacerbation in a larger sample by adjusting for confounding factors. Patients and methods This multicenter, retrospective, observational study was conducted across five acute general hospitals in Japan. We analyzed the association between parenteral/oral steroid therapy and time to clinical stability in pneumonic COPD exacerbation. We used a validated algorithm derived from the 10th revision of the International Classification of Diseases and Related Health Problems (ICD-10) to include patients with pneumonic COPD exacerbation. We excluded patients with other hypoxia causes (asthma exacerbation, pneumothorax, heart failure) and complicated pneumonia (obstructive pneumonia, empyema), those who required tracheal intubation/vasopressors, and those who were clinically stable on day of admission. The primary outcome was the time to clinical stability. Multiple imputation was used for missing data. Propensity scores within each imputed dataset were calculated using potential confounding factors. The Fine and Gray model was used within each dataset to account for the competing risk of death and hospital discharge without clinical stability, and we combined the results. Results Altogether, 1237 patients were included. Systemic steroid therapy was administered to 658 patients (53%). The pooled estimated subdistribution hazard ratio of time to clinical stability in steroid vs non-steroid users was 0.89 (95% confidence interval, 0.78 to 1.0). Conclusion This study revealed that systemic steroid therapy may not improve the time to clinical stability in patients with pneumonic COPD exacerbation of mild to moderate severity. Further randomized controlled trials including more severe patients will be needed to evaluate the effectiveness of systemic steroid therapy accurately.

Background: Breast cancer risk models are used to predict the risk of carrying a variant, for one of the most common breast cancer susceptibility genes such as BRCA1 and BRCA2, and the lifetime risk of developing breast cancer. The prediction of harboring a germline variant of the BRCA gene and the development of breast or ovarian cancer over time affects the decision-making for undergoing genetic testing and screening using imaging techniques as the common practice. For instance, the American Cancer Society and the National Comprehensive Cancer Network (NCCN) recommends screening using MRI in women with 20% or greater lifetime risk of having breast cancer. We aimed to investigate the prediction of these risks in Japanese women, particularly on the relationship between the presence of pathogenic germline variants and breast cancer susceptibility genes, using a cohort of 1016 primary breast cancer patients. Patients and Methods: We analyzed a cohort of Japanese patients with primary breast cancer who were treated at the Kyoto University Hospital and the related institutions or hospitals from the period of 2011 to 2016. The germline variants were examined for a set of 13 breast cancer susceptibility genes, using targeted-capture sequencing of pooled DNA, and it was found that 66 out of 1016 patients had pathogenic variants. These included 11 functionally well-established genes (BRCA1, BRCA2, TP53, PTEN, CDH1, STK11, NF1, PALB2, ATM, CHEK2, and NBN) and two additional genes (BARD1 and BRIP1), which are recommended for the screening of high-risk patients with hereditary breast cancer in the NCCN guidelines. Using this cohort, we studied the association of the calculated risk of carrying a germline variant of BRCA1/ BRCA2, using the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool, within the laboratory germline test results. Results: Pathogenic germline variants of BRCA1/ BRCA2 were carried by 54 (5.3%) out of the 1016 patients (12 cases of BRCA1 and 42 cases of BRCA2). According to the NCCN guidelines, which focus on Genetic/ Familial High-Risk Assessment: Breast and Ovarian, it was found that 500 out of 1016 (49.2%)patients were categorized for considering germline testing. In fact, 38 (7.6%) of the 500 patients, harbored a pathogenic germline variant of BRCA1/ BRCA2. In the remaining 516 patients, 16 (3.1%) harbored the pathogenic germline variant of BRCA1/ BRCA2. The predictive risks of the Tyrer-Cuzick model Breast Cancer Risk Evaluation Tool were recorded as follows: Area under the ROC curve, BRCA1 (area 0.750, 95% CI- 0.581-0.919), BRCA2 (area 0.741, 95% CI- 0.661-0.820), BRCA1 or BRCA2 (Area 0.749, 95% CI: 0.675-0.822), suggesting that the Tyrer-Cuzick model may be useful for the Japanese population. In the mammography breast density analysis, 484 patients showed almost entirely fat or scattered fibroglandular breast tissue, and 362 cases had heterogeneous or extreme fibroglandular breast tissue. In this study, the correlations of breast tissue density with age and breast or ovarian cancer familial history have been reported in greater detail. Discussion and Conclusions: In a retrospective cohort of 1016 Japanese patients with primary breast cancer, 5.3% had pathogenic germline variants of BRCA1/ BRCA2. In a group recommended by NCCN guidelines for considering genetic testing, the BRCA1/ BRCA2 variant rate was 7.6%. Predictive risks calculated by the Tyrer-Cuzick model similar with the known data. Further data are reported. Citation Format: Noriko Senda, Nobuko Kawaguchi-Sakita, Masahiro Kawashima, Yukiko Inagaki-Kawata, Kenichi Yoshida, Tomomi Nishimura, Masahiro Takada, Eiji Suzuki, Yuki Kataoka, Fumiaki Sato, Yoshiaki Matsumoto, Masae Torii, Hiroshi Yoshibayashi, Kazuhiro Yamagami, Shigeru Tsuyuki, Akira Yamauchi, Nobuhiko Shinkura, Hironori Kato, Yoshio Moriguchi, Ryuji Okamura, Norimichi Kan, Hirofumi Suwa, Shingo Sakata, Susumu Mashima, Fumiaki Yotsumoto, Tsuyoshi Tachibana, Mitsuru Tanaka, Takashi Inamoto, Masahiro Sugimoto, Seishi Ogawa, Masakazu Toi. Relationship between predicted risks of carrying breast cancer susceptibility genes and the presence of germline variants in Japanese patients with primary breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-10-12.

Duloxetine has some effect against cancer neuropathic pain (CNP); however, predictors of duloxetine response are unclear. This study sought to identify predictors of duloxetine response in patients with CNP. Patients (N = 70) with CNP unresponsive to or intolerant of opioid–pregabalin combination therapy, with a brief pain inventory-short form (BPI-SF) Item 5 score (average pain) ≥ 4, and with a total hospital anxiety and depression scale score < 20, were randomized to a duloxetine or a placebo group. Multiple linear regression analysis was conducted to identify predictors of duloxetine response as a secondary analysis with the change in the average pain score on day 10 from day 0 as the dependent variable, and the following five covariates; baseline (day 0) average pain score, baseline opioid dose, continuation/discontinuation of pregabalin, and items 20 and 21 score of the short-form McGill pain questionnaire 2 (SF-MPQ-2) as independent variables. Of the four domains (continuous pain, intermittent pain, neuropathic pain, and affective descriptors) score of SF-MPQ-2 on day 0, significant differences were observed in the neuropathic pain domain (p = 0.040) in change on the average pain between day 10 and day 0 in the duloxetine group. Multiple linear regression analysis revealed that patients with a high score for SF-MPQ-2 Item 21 (tingling pain) on day 0 had a significantly greater change in average pain between day 10 and day 0 (p = 0.046). Patients with a high score for SF-MPQ-2 Item 21 might benefit more from duloxetine.

We performed a systematic review and meta-analysis to re-evaluate the effectiveness of angiotensin-converting enzyme inhibitors (ACE-I) in the reduction of pneumonia risk. We searched relevant publications in five databases. All studies included patients older than 18 years, who had used ACE-I as an intervention, and had assessed pneumonia. Seven RCTs (n = 8704) and 38 observational studies (n = 1,705,030) were included. The overall risk of bias was high. ACE-I-treated patients were associated with a slightly lower risk of pneumonia, both from pooled estimates of RCTs [pooled odds ratio (OR), 0.75; 95% confidence interval (CI), 0.62–0.90; low certainty of evidence] and observational studies (pooled OR, 0.85; 95% CI, 0.78–0.92; very low certainty of evidence). Considering the small effect size of ACE-I in preventing pneumonia and the low quality of the evidence, routine use of ACE-I for pneumonia prevention is not recommended.

Although frequent chronic obstructive pulmonary disease (COPD) exacerbation has been associated with the isolation of Pseudomonas aeruginosa (PA) in sputum cultures, it remains unknown whether the empirical use of anti-pseudomonal antibiotics can improve outcomes in patients with frequent COPD exacerbations. This multicenter retrospective cohort study evaluated whether the empirical use of anti-pseudomonal antibiotics improves the length of the hospital stay in patients with recurrent COPD exacerbation (≥ 2 admissions from April 1, 2008 to July 31, 2020). For statistical analysis, a log-linked Gamma model was used. Parameters were estimated using a generalized estimating equation model with an exchangeable correlation structure accounting for repeated observations from a single patient. Covariates included age, body mass index, home oxygen therapy use, respiratory rate, heart rate, oxygen use on admission, mental status, systemic steroid use, activities of daily living, and the number of recurrences. Hospital-specific effects were specified as fixed effects. In total, 344 patients and 965 observations of recurrent COPD exacerbations were selected. Anti-pseudomonal antibiotics were used in 173 patients (18%). The estimated change in the length of the hospital stay between anti-pseudomonal and non-anti-pseudomonal antibiotics groups was 0.039 days [95% confidence interval; − 0.083, 0.162]. Anti-pseudomonal antibiotics could not shorten the length of the hospital stay.

Purpose: Pneumonic acute exacerbation of chronic obstructive pulmonary disease (COPD-AE) is associated with worse outcomes compared with non-pneumonic COPD-AE. Currently, only one study has been evaluated the prognostic factors of pneumonic COPD-AE; the study is limited by sample size, and ignoring heterogeneity of the treatment strategy. Thus, we aimed to include more patients and explore the more focused prognostic factors of patients with pneumonic COPD-AE who were treated with systemic steroids. Patients and methods: This multicentered retrospective cohort study was conducted across five acute hospitals in Japan. Hospitalized patients ≥ 40 years of age with pneumonic COPD-AE who were administered systemic corticosteroids during hospitalization were included. Patients with other causes of respiratory failure (heart failure, pneumothorax, asthma exacerbation, and obstructive pneumonia), daily systemic steroids users, and patients who were not treated with systemic steroids were excluded. The following potential prognostic factors were selected in advance based on the existing clinical prediction models: age (> 70 years), eosinophilic count ( ≥ 0.05 × 109 /L), blood urea nitrogen (> 7 mmol/L), respiratory rate (≥ 30/min), diastolic blood pressure (≤ 60 mmHg), and altered mental status. Multivariate logistic regression was conducted to determine whether the potential prognostic factors were associated with in-hospital death.Results: After excluding 897 patients based on the exclusion criteria, 669 patients with pneumonic COPD-AE who were administered systemic corticosteroids were included. The in-hospital mortality rate was 5.1 %; the median age was 78.0; 15 patients were intubated; and the median length of hospital was 12 days. Altered mental status was associated with mortality (odds ratio, 4.47; 95% confidence intervals, 2.00 to 10.00]) and a high eosinophil count was associated with a lower risk of mortality (odds ratio, 0.19; 95% confidence intervals: 0.06 to 0.56).Conclusion: Altered mental status may be the prognostic factor of in-hospital death among patients with pneumonic COPD-AE who are receive systemic corticosteroids. Moreover, high eosinophilia may be a prognostic factor for lower in-hospital mortality in hospital among these patients.

Background The main goal of enteral nutrition (EN) is to manage malnutrition in order to improve clinical outcomes. However, EN may increase the risks of vomiting or aspiration pneumonia during gastrointestinal dysfunction. Consequently, monitoring of gastric residual volume (GRV), that is, to measure GRV periodically and modulate the speed of enteral feeding according to GRV, has been recommended as a management goal in many intensive care units. Yet, there is a lack of robust evidence that GRV monitoring reduces the level of complications during EN. The best protocol of GRV monitoring is currently unknown, and thus the precise efficacy and safety profiles of GRV monitoring remain to be ascertained. Objectives To investigate the efficacy and safety of GRV monitoring during EN. Search methods We searched electronic databases including CENTRAL, MEDLINE, Embase, and CINAHL for relevant studies on 3 May 2021. We also checked reference lists of included studies for additional information and contacted experts in the field. Selection criteria We included randomized controlled trials (RCTs), randomized cross-over trials, and cluster-RCTs investigating the effects of GRV monitoring during EN. We imposed no restrictions on the language of publication. Data collection and analysis Two review authors independently screened the search results for eligible studies and extracted trial-level information from each included study, including methodology and design, characteristics of study participants, interventions, and outcome measures. We assessed risk of bias for each study using Cochrane's risk of bias tool. We followed guidance from the GRADE framework to assess the overall certainty of evidence across outcomes. We used a random-effects analytical model to perform quantitative synthesis of the evidence. We calculated risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous and mean difference (MD) with 95% CIs for continuous outcomes. Main results We included eight studies involving 1585 participants. All studies were RCTs conducted in ICU settings. Two studies (417 participants) compared less-frequent (less than eight hours) monitoring of GRV against a regimen of more-frequent (eight hours or greater) monitoring. The evidence is very uncertain about the effect of frequent monitoring of GRV on mortality rate (RR 0.91, 95% CI 0.60 to 1.37; I² = 8%; very low-certainty evidence), incidence of pneumonia (RR 1.08, 95% CI 0.64 to 1.83; heterogeneity not applicable; very low-certainty evidence), length of hospital stay (MD 2.00 days, 95% CI -2.15 to 6.15; heterogeneity not applicable; very low-certainty evidence), and incidence of vomiting (RR 0.14, 95% CI 0.02 to 1.09; heterogeneity not applicable; very low-certainty evidence). Two studies (500 participants) compared no GRV monitoring with frequent (12 hours or less) monitoring. Similarly, the evidence is very uncertain about the effect of no monitoring of GRV on mortality rate (RR 0.87, 95% CI 0.62 to 1.23; I² = 51%; very low-certainty evidence), incidence of pneumonia (RR 0.70, 95% CI 0.43 to 1.13; heterogeneity not applicable; very low-certainty evidence), length of hospital stay (MD -1.53 days, 95% CI -4.47 to 1.40; I² = 0%; very low-certainty evidence), and incidence of vomiting (RR 1.47, 95% CI 1.13 to 1.93; I² = 0%; very low-certainty evidence). One study (322 participants) assessed the impact of GRV threshold (500 mL per six hours) on clinical outcomes. The evidence is very uncertain about the effect of the threshold for GRV at time of aspiration on mortality rate (RR 1.01, 95% CI 0.74 to 1.38; heterogeneity not applicable; very low-certainty evidence), incidence of pneumonia (RR 1.03, 95% CI 0.72 to 1.46; heterogeneity not applicable; very low-certainty evidence), and length of hospital stay (MD -0.90 days, 95% CI -2.60 to 4.40; heterogeneity not applicable; very low-certainty evidence). Two studies (140 participants) explored the effects of returning or discarding the aspirated/drained GRV. The evidence is uncertain about the effect of discarding or returning the aspirated/drained GRV on the incidence of vomiting (RR 1.00, 95% CI 0.06 to 15.63; heterogeneity not applicable; very low-certainty evidence) and volume aspirated from the stomach (MD -7.30 mL, 95% CI -26.67 to 12.06, I² = 0%; very low-certainty evidence) We found no studies comparing the effects of protocol-based EN strategies that included GRV-related criteria against strategies that did not include such criteria. Authors' conclusions The evidence is very uncertain about the effect of GRV on clinical outcomes including mortality, pneumonia, vomiting, and length of hospital stay.

BackgroundThis study aimed to develop criteria for identifying patients with acute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) from Japanese administrative data and validate the pre-existing criteria.MethodsThis retrospective, multi-center validation study was conducted at eight institutes in Japan to verify the diagnostic accuracy of the disease name for AE-IPF. We used the Japanese Diagnosis Procedure Combination data to identify patients with a disease name that could meet the diagnostic criteria for AE-IPF, who were admitted to the eight institutes from January 2016 to February 2019. As a reference standard, two respiratory physicians performed a chart review to determine whether the patients had a disease that met the diagnostic criteria for AE-IPF. Furthermore, two radiologists interpreted the chest computed tomography findings of cases considered AE-IPF and confirmed the diagnosis. We calculated the positive predictive value (PPV) for each disease name and its combination.ResultsWe included 830 patients; among them, 216 were diagnosed with AE-IPF through the chart review. We combined the groups of disease names and yielded two criteria: the criteria with the highest PPV (0.72 [95% confidence interval 0.62 to 0.81]) and that with a slightly less PPV (0.61 [0.53 to 0.68]) but more true positives. Pre-existing criteria showed a PPV of 0.40 (0.31 to 0.49).ConclusionThe criteria derived in this study for identifying AE-IPF from Japanese administrative data show a fair PPV. Although these criteria should be carefully interpreted according to the target population, our findings could be utilized in future database studies on AE-IPF.

Background Osimertinib, the third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), has become the standard treatment in cases where rebiopsy reveals T790M mutation after the first-line EGFR-TKI treatment. However, the prognosis of patients after rebiopsy, the most important outcome for cancer patients, has not been described sufficiently. This systematic review aimed to clarify whether rebiopsy contributes to improved prognosis in the first- or second-generation EGFR-TKI refractory patients. Methods Using free word and control terms related to “non-small cell lung cancer” and “rebiopsy,” we searched studies from Medical Literature Analysis and Retrieval System Online via PubMed, Embase, Cochrane Central Register of Controlled Trials, and World Health Organization International Clinical Trials Registry Platform. We included cohort studies and case reports written in English and judged whether each study answers our research questions. Results Of the 144 studies included, only one reported the prognosis of patients with/without rebiopsy showing that in EGFR-TKI refractory non-small cell lung cancer patients, the post-progression survival (PPS) was significantly longer in patients who received rebiopsy and treatment based on a resistant mechanism (median PPS 24.2 months) than those who received rebiopsy and salvage regimen (median PPS 15.2 months, p = 0.002) and who did not receive rebiopsy (median PPS 9.7 months, p

Background: Although frequent chronic obstructive pulmonary disease (COPD) exacerbation has been associated with the isolation of Pseudomonas aeruginosa (PA) in sputum cultures, it remains unknown whether the empirical use of anti-pseudomonal antibiotics can improve outcomes in patients with frequent COPD exacerbations. Research Question: Does empirical use of anti-pseudomonal antibiotics improve the length of the hospital stay in patients with recurrent COPD exacerbation?Study Design and Methods: This multicenter retrospective cohort study was conducted in seven hospitals in Japan. We included patients aged ≥40 years who were admitted to the hospital with COPD exacerbation more than twice during the study period (April 1, 2008 to July 31, 2020). The primary outcome was the length of the hospital stay. For statistical analysis, a log-linked Gamma model was used. Parameters were estimated using a generalized estimating equation model with an exchangeable correlation structure accounting for repeated observations from a single patient. Covariates included age, body mass index, home oxygen therapy use, respiratory rate, heart rate, oxygen use on admission, mental status, systemic steroid use, activities of daily living, and number of recurrences. Hospital-specific effects were specified as fixed effects.Results: Among 1573 patients with COPD exacerbation, 344 patients and 965 observations of recurrent COPD exacerbations were selected. Anti-pseudomonal antibiotics were used in 173 patients (18%). The estimated change in the length of the hospital stay between the anti-pseudomonal and non-anti-pseudomonal antibiotics groups was 0.044 days [95% confidence interval; -0.077, 0.166]. Interpretation: Use of empirical anti-pseudomonal antibiotics based only on recurrence may not be necessary. Further large-scale studies are needed to more precisely evaluate the effectiveness of empirical anti-pseudomonal antibiotics.

Background: The sensitivity and specificity of anti-glomerular basement membrane (GBM) antibodies have not been systematically analyzed. In this systematic review, we aimed to evaluate the diagnostic accuracy of anti-GBM antibodies for anti-GBM disease. Summary: Potential studies were searched using MEDLINE, Embase, the Cochrane Library, and the International Clinical Trials Registry Platform based on the index test and target condition. The inclusion criteria were prospective or retrospective cohort studies or case-control studies assessing the sensitivity and specificity of anti-GBM antibodies, and the reference standard was clinical diagnosis including biopsy results. The exclusion criteria were review articles, case reports, animal studies, and in vitro studies. Quality assessment was conducted based on the Quality Assessment of Diagnostic Accuracy Studies-2. The pooled estimates of sensitivity and specificity were calculated using a bivariate random-effects model. The overall quality was evaluated using the Grades of Recommendation, Assessment, Development, and Evaluation. Six studies (1,691 patients) and 11 index tests were included in our systematic review. A high risk of bias and concerns regarding the applicability of patient selection were noted because of the case-control design in 67% of the included studies. The pooled sensitivity and specificity were 93% (95% CI: 84–97%) and 97% (95% CI: 94–99%), respectively. The certainty of evidence was low because of the high risk of bias and indirectness. Key Messages: Anti-GBM antibodies may exhibit high sensitivity and specificity in the diagnosis of anti-GBM disease. Further cohort studies are needed to confirm their precise diagnostic accuracy and compare diagnostic accuracies among different immunoassays.

The diagnosis of plasmablastic lymphoma (PBL), plasmablastic myeloma (PBM), and plasmablastic neoplasm (PBN) may be arbitrary in some cases because these entities can be indistinct. We conducted this scoping review to investigate heterogeneity in diagnostic criteria used in previous studies and validate the diagnostic results of previous diagnostic algorithms and the algorithm we developed, which also includes diagnosis of PBN. Using the PRISMA Extension for Scoping Reviews, we analyzed literature published between September 2017 and April 2020. We identified a total of 163 cases (128 PBL, 32 PBM, and 3 PBN) from 77 case reports and 8 case series. We found that diagnostic criteria in the literature varied for PBL but were consistent for PBM. Our algorithm was the first attempt to include PBN in a complete structure. The results of the three diagnostic algorithms varied significantly. Hematologists and pathologists should pay more attention to the differential diagnosis of PBL, PBM, and PBN.

We performed this study to provide the latest evidence of the diagnostic accuracy of all Aspergillus antibodies for chronic pulmonary aspergillosis (CPA). In this meta-analysis, we searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, and other databases, until 19 March 2020, for studies that examined the diagnostic accuracy of each Aspergillus-specific antibody for CPA and assessed the risk of bias using the revised Quality Assessment of Diagnostic Accuracy Studies-2 tool. We integrated the results using a hierarchical summary receiver operating characteristic (HSROC) model and calculated the point estimates of specificity with sensitivity fixed at 0.90 using the HSROC curve. We identified 32 published and one unpublished studies, including 75 studies on five antibody test types: 18 of precipitin test (2810 participants), 46 of IgG (8197), three of IgA (283), six of IgM (733) and two of combined IgG and IgM (IgG + IgM) (920). The results of specificity with sensitivity fixed at 0.90 were as follows: precipitin test, 0.93 (95% credible intervals: 0.86, 1.00); IgG, 0.90 (0.86, 0.95); IgA, 0.74 (0.00, 1.00); IgM, 0.50 (0.37, 0.53); IgG + IgM, 0.47 (0.00, 1.00). However, the precipitin test showed imprecision and instability in the sensitivity analysis. Most studies had a high risk of bias due to the case-control design. Although there is lack of applicability for malignancy or immunosuppressive patients, our study suggests a preference for IgG over other antibody tests in CPA screening. Particularly, IgG should be used as an adjunct when ruling out CPA.

Introduction: There is no consensus on steroid use in patients with exacerbation of chronic obstructive pulmonary disease (COPD) and pneumonia as a comorbidity. Aims and Objectives: The aim of this study was to evaluate the effectiveness of steroids for patients with COPD exacerbation and pneumonia. Methods: This multicenter retrospective observational study was performed at three acute general hospitals in Japan. We analyzed the association between parenteral or oral steroid therapy and the time to clinical stability in COPD exacerbation complicated by community-onset pneumonia. We included patients with COPD and pneumonia who were admitted to the three hospitals. We excluded patients who had other causes of hypoxia, those who required tracheal intubation or vasopressors on the day of admission, and those who were clinically stable on the day of admission. The primary outcome was the time to clinical stability. We calculated crude subdistribution hazard ratio (sHR) between steroid users and non-steroid users. In addition, we used the Fine–Gray model accounting for the competing risk of death with adjustment for potential confounders. Results: We included 1038 patients (mean age, 80.0 years; 938 [90.4%] male, 595 [57.3%] steroid users). The number of deaths in steroid users and non-steroid users were 41 (6.9%) and 25 (5.6%). The crude and adjusted sHR of the time to clinical stability in steroid users to that in non-steroid users was 3.1 (P = 0.08) and 0.93 (P = 0.40), respectively. Conclusions: Steroid therapy for COPD exacerbation with pneumonia could not significantly improve the time to clinical stability.

Highlights • This study investigated the difference between COVID-19 RCT in medRxiv and in PubMed. • SPIN in the conclusion was more frequently seen in reports in medRxiv than PubMed. • Readers should pay attention to the overstatements in preprints of COVID-19 RCT.

Background and study aims We aimed to assess the efficacy and safety of the starting position during colonoscopy. Patients and methods We searched CENTRAL, MEDLINE, EMBASE, and the WHO International Clinical Trials Registry Platform through February 2019 to identify studies reporting the comparison between the right/supine/prone/tilt-down and left lateral starting position during colonoscopy. The primary outcomes were mean cecal insertion time and adverse events requiring medication. Two reviewers performed study selection and risk of bias assessment. We determined the quality of evidence using the Grading of Recommendations, Assessment, Development, and Evaluation method. This study was registered in PROSPERO (CRD42019124360). Results We identified 10 randomized controlled trials (RCTs) (2083 participants), including three trials on right/tilt-down versus left, two trials on supine/prone versus left, respectively. Mean difference in mean cecal insertion time in supine versus left was –41.0 s (95 % confidence interval [CI] –57.3 to –24.7) in one study and in tilt-down versus left was – 37.3 s (95 % CI –72.1 to –2.4; I2 = 58 %) in three studies; however, there were no statistically significant differences in prone/right versus left position (very low certainty of evidence). Four of eight studies noted adverse effects requiring medication (moderate certainty of evidence). One RCT applying the tilt-down position was terminated because of increased occurrence of oxygen desaturation. Conclusion We could not conclusively determine the efficacy and safety of the starting position during colonoscopy because of low certainty of evidence. Further studies are needed to confirm the efficacy and safety of the starting potion during colonoscopy.

Background Acute kidney injury (AKI) is a major comorbidity in hospitalised patients. Patients with severe AKI require continuous renal replacement therapy (CRRT) when they are haemodynamically unstable. CRRT is prescribed assuming it is delivered over 24 hours. However, it is interrupted when the extracorporeal circuits clot and the replacement is required. The interruption may impair the solute clearance as it causes under dosing of CRRT. To prevent the circuit clotting, anticoagulation drugs are frequently used. Objectives To assess the benefits and harms of pharmacological interventions for preventing clotting in the extracorporeal circuits during CRRT. Search methods We searched the Cochrane Kidney and Transplant Register of Studies up to 12 September 2019 through contact with the Information Specialist using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov. Selection criteria We selected randomised controlled trials (RCTs or cluster RCTs) and quasi-RCTs of pharmacological interventions to prevent clotting of extracorporeal circuits during CRRT. Data collection and analysis Data were abstracted and assessed independently by two authors. Dichotomous outcomes were calculated as risk ratio (RR) with 95% confidence intervals (CI). The primary review outcomes were major bleeding, successful prevention of clotting (no need of circuit change in the first 24 hours for any reason), and death. Evidence certainty was determined using the Grading of Recommendation Assessment, Development, and Evaluation (GRADE) approach. Main results A total of 34 completed studies (1960 participants) were included in this review. We identified seven ongoing studies which we plan to assess in a future update of this review. No included studies were free from risk of bias. We rated 30 studies for performance bias and detection bias as high risk of bias. We rated 18 studies for random sequence generation, six studies for the allocation concealment, three studies for performance bias, three studies for detection bias, nine studies for attrition bias, 14 studies for selective reporting and nine studies for the other potential source of bias, as having low risk of bias. We identified eight studies (581 participants) that compared citrate with unfractionated heparin (UFH). Compared to UFH, citrate probably reduces major bleeding (RR 0.22, 95% CI 0.08 to 0.62; moderate certainty evidence). Citrate may have little or no effect on death at 28 days (RR 1.06, 95% CI 0.86 to 1.30, moderate certainty evidence), while citrate versus UFH may have little or no effect on successful prevention of clotting (RR 1.01, 95% CI 0.77 to 1.32; moderate certainty evidence). Citrate versus UFH may reduce the number of participants who drop out of treatment due to adverse events (RR 0.47, 95% CI 0.15 to 1.49; low certainty evidence). Compared to UFH, citrate may make little or no difference to the recovery of kidney function (RR 0.95, 95% CI 0.66 to 1.36; low certainty evidence). Compared to UFH, citrate may reduce thrombocytopenia (RR 0.39, 95% CI 0.14 to 1.03; low certainty evidence). It was uncertain whether citrate reduces a cost to health care services because of inadequate data. For low molecular weight heparin (LMWH) versus UFH, six studies (250 participants) were identified. Compared to LMWH, UFH may reduce major bleeding (0.58, 95% CI 0.13 to 2.58; low certainty evidence). It is uncertain whether UFH versus LMWH reduces death at 28 days or leads to successful prevention of clotting. Compared to LMWH, UFH may reduce the number of patient dropouts from adverse events (RR 0.29, 95% CI 0.02 to 3.53; low certainty evidence). It was uncertain whether UFH versus LMWH leads to the recovery of kidney function because no included studies reported this outcome. It was uncertain whether UFH versus LMWH leads to thrombocytopenia. It was uncertain whether UFH reduces a cost to health care services because of inadequate data. For the comparison of UFH to no anticoagulation, one study (10 participants) was identified. It is uncertain whether UFH compare to no anticoagulation leads to more major bleeding. It is uncertain whether UFH improves successful prevention of clotting in the first 24 hours, death at 28 days, the number of patient dropouts due to adverse events, recovery of kidney function, thrombocytopenia, or cost to health care services because no study reported these outcomes. For the comparison of citrate to no anticoagulation, no completed study was identified. Authors' conclusions Currently, available evidence does not support the overall superiority of any anticoagulant to another. Compared to UFH, citrate probably reduces major bleeding and probably has little or no effect on preventing clotting or death at 28 days. For other pharmacological anticoagulation methods, there is no available data showing overall superiority to citrate or no pharmacological anticoagulation. Further studies are needed to identify patient populations in which CRRT should commence with no pharmacological anticoagulation or with citrate.

Few studies have delineated the real-world, long-term trends of prescription patterns of antidepressants for patients with major depressive disorder (MDD). This study aims to describe their vicissitudes in the nationally representative sample of the US from 1996 to 2015 and explore their characteristics. We used the Medical Expenditure Panel Survey, a nationally representative database of the US population, between 1996 and 2015. We estimated the prevalence of MDD among adults, calculated the proportions of those on antidepressant treatment as well as those on specific drugs through the two decades, and determined their dosages in 2015. We conducted multivariable regression to find possible factors related to their suboptimal prescriptions. The prevalence of adults diagnosed with MDD increased from 6.1% (95% CI, 5.7–6.6%) in 1996 to 10.4% (9.7–11.1%) in 2015. The proportion of patients without any antidepressant therapy decreased but still accounted for 30.6% (28.3–33.1%) in 2015. Sertraline and fluoxetine were among the most frequently prescribed antidepressants throughout the 20 years, while the trend for some new drugs changed dramatically. 16.1% (12.5–20.2%) of patients of MDD on antidepressant monotherapy were prescribed with suboptimal doses in 2015; the risk was lower for those who had higher Body Mass Index (OR 0.94 [0.90–0.99]), longer-term prescriptions (OR 0.92 [0.87–0.97]), and the risk was higher for those who were prescribed with tricyclic antidepressants (OR 11.21 [2.12–59.34], compared with serotonin reuptake inhibitors (SSRIs)), and antidepressants other than SSRIs and serotonin and norepinephrine reuptake inhibitors (OR 4.12 [1.95, 8.73], compared with SSRIs). This study confirmed the growing numbers of patients with MDD and the increase in the antidepressant prescriptions among them. However, the existence of patients without any antidepressant prescriptions or with suboptimal prescriptions and the variable prescription patterns through the decades might suggest some unresolved gaps between evidence and practice.

Introduction Nivolumab has been shown to be effective and safe in previously treated patients with advanced non-small cell lung cancer (NSCLC). However, little is known regarding its performance in real-world (i.e., non-trial) settings. Furthermore, nivolumab efficacy is unknown in patients who are ineligible for clinical trials or who are categorized into small subgroups in such trials. Methods We conducted a 15-center, observational, retrospective cohort study of patients with advanced NSCLC who received nivolumab monotherapy between January and December 2016. Results Of 613 patients included in our study, 141 had poor performance status (PS) and 106 were EGFR mutation – or ALK rearrangement-positive. The response and disease control rates were 20% and 44%, respectively; the estimated 1-year progression-free survival (PFS) was 18%. Multivariate analysis identified never smoking, poor PS, and EGFR mutation/ALK rearrangement as independent negative predictors of PFS. The most frequently reported grade ≥3 adverse event was pneumonitis (5% of patients). Severe pneumonitis (grade ≥3) occurred significantly earlier than mild pneumonitis (1.6 vs. 2.3 months, P = 0.031). Patients with pneumonitis achieved higher response rates and longer PFS than those without (37% vs. 18%, and 5.8 vs. 2.1 months, respectively; P = 0.002). Conclusions Smoking status, PS, and EGFR mutation/ALK rearrangement were independent predictors of PFS. Our study elucidated nivolumab's efficacy in previously underreported patient populations; i.e., those with poor PS and/or with driver oncogenes. We also found that pneumonitis is not infrequent, and carries key implications for outcomes. These data should be useful for improving the clinical courses of nivolumab-treated patients with NSCLC.

Phlebosclerotic colitis presents with ischemic bowels and calcification of the mesenteric veins. Owing to its rarity, we have little information on the complications of this disease. Herein, we report on a 77-year-old woman with phlebosclerotic colitis and interstitial lung disease. She was diagnosed as having phlebosclerotic colitis by CT and colonoscopy. At the same time, chest CT also showed interstitial lung disease. After 4 years, she experienced exacerbation of interstitial lung disease. She recovered without treatment. The occurrence of interstitial lung disease may have been associated with her phlebosclerotic colitis.

Background & Aims The accuracy of ultrasound for evaluation of individual colorectal segments in patients with inflammatory bowel diseases (IBD) has not been evaluated in a systematic review. We evaluated the diagnostic accuracy of ultrasound in different colorectal segments of patients with IBD. Methods We searched publication databases from inception through March 2019 for studies that assessed the accuracy of ultrasound in detection of inflammation in right, transverse, and left colon and in rectum in patients with IBD, using findings from colonoscopy as the reference standard. Subgroup analyses were performed including IBD type, patient age, body mass index, and study design. The risk of bias was assessed with the Quality Assessment of Diagnostic Accuracy Studies-2 tool. Results Nineteen studies (1101 patients) were included in the qualitative synthesis. After we assessed the risk of bias, 7 studies (comprising 84 patients with Crohn’s disease and 420 patients with ulcerative colitis) were included in the meta-analysis. Bowel wall thickness ≥ 3 mm identified colorectal segments with inflammation with 86.4% pooled sensitivity (95% CI, 76.1%–92.7%) and 88.3% pooled specificity (95% CI, 58.1%–97.6%). In rectum only, bowel wall thickness ≥ 3 mm identified inflammation with 74.5% sensitivity (95% CI, 53.0%–88.3%) and 69.5% specificity (95% CI, 33.6%–91.1%). Diagnostic accuracy was comparable among subgroups. Increased bowel wall flow and loss of stratification had higher true-positive odds ratios. Conclusions Based on meta-analysis of patient-level data, ultrasound has higher diagnostic accuracy for detecting inflammation in colon than rectum in patients with IBD. Studies are needed to increase the accuracy of ultrasound detection of inflammation in rectum.

Collagenous colitis is a cause of chronic diarrhea. We report an atypical case of collagenous colitis, presenting with an acute onset, and associated with protein‐losing enteropathy. An 82‐year‐old woman was admitted with a 1 week history of nausea, appetite loss, and diarrhea. Serum albumin level was low. Protein leakage from the small intestine was found by a Technetium‐99m human serum albumin scintigraphy. We diagnosed the patient with collagenous colitis from pathology findings of multiple biopsies taken from the colon. This case implies that collagenous colitis should be considered in acute watery diarrhea, and that it can cause protein‐losing enteropathy.

Approximately 10% of patients with T1 colorectal cancer have lymph node metastases (LNM), requiring node dissection along with surgical resection. Patient gender was recently reported to affect the occurrence of LNM. The aim of the present study was to assess whether patient gender was predictive of LNM in T1 colorectal cancer. Public databases, including PubMed, EMBASE and the Cochrane Central Register of Controlled Trials were searched, using key terms related to ‘T1 colorectal cancer’ and ‘lymph node’. All relevant studies reporting the adjusted odds ratio or risk ratio of LNM in relation to patient gender were included. The quality of the studies was classified according to the Quality in Prognostic Studies tool. A random-effects model was used and the quality of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation approach. The initial database search identified 2,492 publications; of those, 36 studies reported unadjusted results. Of the 36 studies, 4 reported adjusted results and fulfilled the inclusion criteria for this meta-analysis: 3 studies were graded as having a moderate risk of bias, and 1 had a low risk of bias. The present meta-analysis demonstrated that female gender was associated with increased risk of LNM (risk ratio=2.45, 95% confidence interval: 1.03–3.88). The I2 statistic was 0.901, classified as very low (+OOO) and was downgraded by the risk of bias, inconsistency and publication bias. In conclusion, female gender was found to be correlated with LNM in patients with T1 colorectal cancer.

Background The low data publication rate for Food and Drug Administration (FDA)-approved drugs, and discrepancies between FDA-submitted versus published data, remain a concern. We investigated the publication statuses of sponsor-submitted clinical trials supporting recent anticancer drugs approved by the FDA, with a focus on immune checkpoint inhibitors (ICPis). Methods We identified all ICPis approved between 2011 and 2014, thereby obtaining 3 years of follow-up data. We assessed the clinical trials performed for each drug indication and matched each trial with publications in the literature. The primary benchmark was the publication status 2 years post-approval. We examined the association between time to publication and drug type using a multilevel Cox regression model that was adjusted for clustering within drug indications and individual covariates. Results Between 2011 and 2014, 36 anticancer drugs including 3 ICPis were newly approved by the FDA. Of 19 trials investigating the 3 ICPis, 11 (58%) were published within 2 years post-approval. We randomly selected 10 of the 33 remaining anticancer drugs; 68 of 101 trials investigating these drugs (67%) were published. Overall, the publication rate was 66% at 2 years post-approval with a median time to publication of 2.3 years. There was no significant difference in the time to trial publication between ICPis and other anticancer drugs (adjusted hazard ratio [HR], 1.1; 95% confidence interval [CI], 0.8–1.7; P = 0.55). However, findings related to non-ICPis investigated specifically in randomized phase 2 or phase 3 trials were significantly more likely to be published earlier than those related to ICPis (adjusted HR, 7.4; 95% CI, 1.8–29.5; P = 0.005). Conclusion One in 3 sponsor-submitted trials of the most recently approved anticancer drugs remained unpublished 2 years post-FDA approval. We found no evidence that the drug type was associated with the time to overall trial publication.

Background Crohn's disease (CD) is a chronic inflammatory disease of the gastrointestinal tract, and immune response modulation is the main treatment strategy to induce remission in active CD. Certolizumab pegol (CZP) is a tumor necrosis factor-alfa (TNF-α) inhibitor which regulates impaired immune response. Objectives The primary objectives were to evaluate the efficacy and safety of CZP for the induction of remission in CD. Search methods We searched MEDLINE, Embase, CENTRAL, the Cochrane IBD group specialized register, trials registers and other sources from inception to 28 January 2019. Moreover, we contacted the pharmaceutical company that manufactures CZP. Selection criteria We included randomized controlled trials comparing CZP with placebo or no treatment in active CD patients. Data collection and analysis We used standard Cochrane methodological procedures. The main outcomes selected for GRADE analysis were clinical remission at week 8 (Crohn's Disease Activity Index [CDAI] ≤150), clinical response at week 8 (CDAI reduction ≥ 100 or clinical remission), and serious adverse events. The Mantel-Haenszel random-effects method was applied for the statistical analyses. For dichotomous outcomes, we calculated the risk ratio (RR) and corresponding 95% confidence interval (95% CI). Main results Four studies involving 1485 participants with moderate to severe CD met the inclusion criteria and were used in the meta-analyses. All studies included active CD patients with CDAI ranging from 220 to 450. Most patients were adults over 18 years of age. One study was identified as high risk of bias due to a non-identical placebo while the other studies were judged to be at low risk of bias.CZP (100 mg to 400 mg every 2 to 4 weeks) was shown to be superior to placebo for achieving clinical remission at week 8 (RR 1.36, 95% CI 1.11 to 1.66; moderate certainty evidence). The raw numbers of participants achieving clinical remission at week 8 were 26.9% (225/835) and 19.8% (129/650) in the CZP and the placebo groups, respectively.CZP was shown to be superior to placebo for achieving clinical response at week 8 (RR 1.29, 95% CI 1.09 to 1.53; moderate certainty evidence). In raw numbers, clinical response at week 8 was achieved in 40.2% (336/835) and 30.9% (201/650) of participants in the CZP and the placebo groups, respectively.In raw numbers, serious adverse events were observed in 8.7% (73/835) and 6.2% (40/650) of participants in the CZP and the placebo groups, respectively (RR 1.35, 95% CI 0.93 to 1.97; moderate certainty evidence). Serious adverse events included worsening Crohn's disease, infections, and malignancy. Authors' conclusions Moderate certainty evidence suggests that CZP is effective for induction of clinical remission and clinical response in participants with active CD patients. It is uncertain whether the risk of serious adverse events differs between CZP and placebo as the 95% CI includes the possibility of a small decrease or doubling of events. Future studies are needed to evaluate the long-term efficacy and safety of CZP in CD patients.

Context Although opioids and pregabalin are widely used for cancer-related neuropathic pain (CNP), no clinical trials exist to determine which medications are effective when an opioid-pregabalin combination therapy fails. Objectives We investigated the efficacy of duloxetine for CNP nonresponsive or intolerant to opioid-pregabalin combination therapy. Methods A multicenter, randomized, double-blind, placebo-controlled trial was performed at 12 specialized palliative care services in Japan. Patients with CNP average pain scores (Brief Pain Inventory [BPI]–Item 5) ≥ 4 in the previous 24 hours and nonresponsive or intolerant to opioid-pregabalin combination therapy were eligible. Patients with chemotherapy-induced peripheral neuropathies were excluded. Patients were administered duloxetine 20 mg/day titrated to 40 mg/day or placebo for 10 days. The primary endpoint was BPI-Item 5 on Day 10. Responder analysis measured proportions of patients with 30% and 50% pain decreases. Results Seventy patients were enrolled. Complete case analysis revealed mean BPI-Item 5 on Day 10 of 4.03 for Group D vs. 4.88 for Group P (P = 0.053). Baseline observation carried forward analysis revealed mean BPI-Item 5 on Day 10 of 4.06 and 4.91 for Groups D and P, respectively (P = 0.048). Clinically meaningful pain improvement (≥30%) was reported by 44.1% (n = 15) of patients in Group D vs. 18.2% (n = 6) in Group P (P = 0.02); 32.4% (n = 11) vs. 3.0% (n = 1) of patients in Groups D and P, respectively, reported pain reduction ≥ 50% (P = 0.002). Conclusion Adding duloxetine to opioid-pregabalin therapy might have clinical benefit in alleviating refractory CNP. Further studies are needed to conclude the efficacy of adding duloxetine.

Objective The risk of atherosclerotic cardiovascular disease (ASCVD) is estimated using the American College of Cardiology (ACC)/American Heart Association (AHA) Pooled Cohort Equations (PCEs). However, the accuracy of this tool remains controversial, particularly among patients who are recommended statin therapy according to the ACC/AHA guidelines. We performed external validation of PCEs among patients eligible for statin therapy using data from the systolic blood pressure intervention trial (SPRINT). Results Our study included 4057 patients from among the 9361 patients in SPRINT. The mean patient age was 64.5 years, and the median predicted 10-year risks of ASCVD were 17.2% and 12.3% for men and women, respectively. Over a median follow-up of 3.3 years, 133 primary events (including 23 cardiovascular deaths) were noted, whereas 304 events were predicted by the PCEs. The PCEs demonstrated poor calibration (Hosmer–Lemeshow test, p

Background: Nonalcoholic fatty liver disease (NAFLD) is associated with poor prognosis after radical breast cancer surgery. Locally advanced breast cancer (LABC) has a higher recurrence rate than early breast cancer does and requires multidisciplinary treatment including cardiotoxic and liver-metabolized anthracycline. The aim of the current study was to investigate the association between NAFLD and the prognosis and morbidity of patients with LABC. Patients and Methods: This single-center, retrospective, cohort study included patients with stage III breast cancer who underwent surgery between July 2015 and December 2018. Hepatic steatosis was defined as a ratio of liver-to-spleen attenuation (L/S) of Results: We analyzed 44 patients, including 6 with NAFLD. The median follow-up time was 852.5 days. On univariate and multivariate analyses, NAFLD was not significantly associated with RFS (hazard ratio [HR], 1.474; 95% confidence interval [CI], 0.324–6.706, and HR, 1.297; 95% CI, 0.263–6.399, respectively). Neither cardiovascular events nor secondary cancers were associated with NAFLD. Known prognostic factors of breast cancer—such as older age, high histological grade, and estrogen receptor negativity—were significantly associated with a shorter RFS. Conclusion: When treating patients with LABC, physicians and patients should not worry much about the prognostic impact of mild NAFLD. Highlights: This single-center, retrospective, cohort study investigated the association between nonalcoholic fatty liver disease (NAFLD) and the prognosis and morbidity of patients with locally advanced breast cancer (LABC). We found that mild NAFLD was not significantly associated with RFS and neither cardiovascular disease nor other cancers occurred. The results of the current study imply that mild NAFLD based on the criteria given by Iwasaki et al. is not a prognostic factor for LABC.

A 33-year-old woman was transferred to our hospital for an unresolving pneumonia, who initially presented with dyspnea. Initially antibiotic therapy was started under the suspicion of community-acquired pneumonia, however, her respiratory status worsened at the previous hospital. Computed tomography (CT) on presentation showed peripheral ground glass opacities in both sides of the upper lobe. Also despite additional prednisolone therapy, her respiratory status worsened. On admission to our hospital, physical examination showed Gottoron's sign in her right elbow. From the nature of the rash, the absence of myositis symptoms and rapid respiratory worsening, we suspected clinically amyopathic dermatomyositis (CADM). After the triple drug therapy, her respiratory status improved.

BACKGROUND: The gut microbiota is involved in the pathophysiology of obesity. It is known that oral antibiotics manipulate the gut microbiota; however, the impact on host metabolism of obese adults without bacterial infection has not been systematically summarized. METHODS: We searched for randomized, placebo-controlled trials that investigated the effects of oral antibiotics on the metabolic status in obese adults via Medline, EMBASE, and the Cochrane Library. Primary outcomes were homeostasis model assessment of insulin resistance (HOMA-IR), body weight, and rate of diarrhea. Additional outcomes included fasting plasma glucose (FPG), plasma glucagon-like peptide-1 (GLP-1), waist circumference, fecal short-chain fatty acid (SCFA) levels, and all adverse events. We assessed the certainty of evidence based on Grading of Recommendations, Assessment, Development and Evaluations. RESULTS: Among 1,762 articles screened, four studies were eligible for quantitative analysis, two of which were applied to meta-analysis. Oral antibiotics had low influence on HOMA-IR [mean difference (MD) 0.09 (95% CI: −0.96 to 1.13)], body weight [MD 4.1 kg (95% CI: −23.77 to 31.97)], FPG [MD −0.12 mmol/L (95% CI: −0.47 to 0.23)], and GLP-1 [MD 0.20 pmol/L (95% CI: −2.36 to 2.76)] compared to placebo. Antibiotics treatment altered fecal acetate and butyrate levels, but resulted in little difference in propionate levels [MD −13.60 µmol/g (95% CI: −22.43 to −4.77), MD −7.60 µmol/g (−10.97 to −4.23), MD −1.10 µmol/g (95% CI: −4.18 to 1.98), respectively]. Several adverse events, such as sun sensitivity and gastrointestinal discomfort, were reported following antibiotics treatment, but no diarrhea. The certainty of evidence for most outcomes was very low to low, except for fecal SCFAs. CONCLUSIONS: Our results indicate that oral antibiotics treatment is insufficient to ameliorate metabolic parameters in obese adults, suggesting that oral antibiotics treatment may not qualify as a therapeutic approach for obesity.

Nivolumab is effective in the treatment of previously treated patients with advanced NSCLC. However, its radiological evaluation is challenging because of atypical patterns of response such as pseudoprogression. We examined the characteristics and outcomes of previously treated patients with NSCLC who were treated with nivolumab and experienced development of pseudoprogression.We conducted a 15-center retrospective cohort study of previously treated patients with advanced NSCLC who received nivolumab monotherapy. For the patients who showed pseudoprogression, we defined progression-free survival 1 (PFS1) as the time to Response Evaluation Criteria in Solid Tumors-defined first progressive disease and progression-free survival 2 (PFS2) as the time to Response Evaluation Criteria in Solid Tumors-defined second progressive disease or death.Among the 542 patients included, 20% and 53% showed a typical response and progression, respectively. Of the 14 (3%) patients who showed pseudoprogression, most (n = 10) showed a response within 3 months of nivolumab treatment. The median PFS1 and PFS2 were 1.0 and 7.3 months, respectively. The median PFS2 was significantly shorter in the patients who showed pseudoprogression than the PFS of the patients with a typical response (p 0.001). In contrast, patients showing pseudoprogression had significantly longer overall survival than did patients showing typical progression (p = 0.001).Pseudoprogression was uncommon, and the duration of response in patients who showed pseudoprogression was shorter than that in patients who showed a typical response. However, the survival benefit of pseudoprogression was markedly better than that of typical progression. Further research is required to elucidate the characteristics of and mechanisms underlying pseudoprogression.

Background: Serologic assays for specific immunoglobulin G (IgG) antibodies are available for diagnosing the condition of bird fancier’s lung, however, their usefulness is controversial. This systematic review was aimed at investigating the diagnostic accuracy of specific IgG antibodies used for avian antigens. Methods: Medline, Embase, the Cochrane Library, the International Clinical Trials Registry Platform, and the Web of Science were searched for studies performed to evaluate the diagnostic accuracy of the Ouchterlony method, enzyme-linked immunosorbent assays (ELISAs), electrosyneresis, and ImmunoCAP assays for diagnosing bird fancier’s lung. Nine articles were included in the meta-analysis. The pooled sensitivity and specificity were summarized using a bivariate mixed-effects model, and a hierarchical summary receiver operating characteristic curve was rendered to determine the diagnostic accuracy of the antibodies. Results: The pooled sensitivities and specificities of each specific IgG antibody were 82.9% (95% confidence interval, 71.1–90.5%) and 93.0% (95% confidence interval, 74.4–98.4%) for the Ouchterlony method, 92.5% (95% confidence interval, 71.3–98.4%) and 90.8% (95% confidence interval, 72.1–97.4%) for ELISAs, 90.0% (95% confidence interval, 55.5–99.7%) and 84.6% (95% confidence interval, 73.5–92.4%) for the electrosyneresis method, and 43.5% (95% confidence interval, 35.3–52.1%) and 100% (95% confidence interval, 0–100%) for ImmunoCAP assays. The overall quality of the collective evidence was low, primarily due to the high risk of bias, indirectness, and imprecision of the included studies. Conclusions: The Ouchterlony method demonstrated high specificity, the ELISA method showed high sensitivity, and the diagnostic utilities of electrosyneresis and ImmunoCAP assay testing remain unclear.

This is a protocol for a Cochrane Review (Intervention). The objectives are as follows: To assess the effectiveness and safety of third‐line chemotherapy in patients with small cell lung cancer (SCLC), compared to conventional supportive care.

Aim The aim of the present study was to assess the prognostic utility of the pretreatment blood neutrophil-to-lymphocyte ratio (NLR) and the C-reactive protein-to-albumin ratio (CAR) in patients with inoperable malignant pleural mesothelioma (MPM). Materials and methods The medical records of consecutive patients with histologically confirmed MPM from our hospital between January 2007 and August 2017 were retrospectively reviewed. The primary outcome was overall survival (OS). Univariate and multivariate analyses for the prognostic factors were performed using a Cox proportional hazards model. Results A total of 143 patients with inoperable MPM were included. On multivariate analysis, pretreatment CAR was an independent factor associated with worse OS (hazard ratio(HR)=1.72; 95% confidence interval(CI)=1.11-2.67; p=0.016). However, NLR was not associated with OS in any of the analyses. Conclusion CAR appears to be a prognostic factor in patients with inoperable MPM.