Web-Based Post-Bereavement Survey System in Specialized Palliative Care: A Feasibility Pilot Study.

Web-based post-bereavement survey systems for specialized palliative care will enable obtaining timely results on the care quality from more participants at a lower cost. The primary aim of the study was to develop a web-based post-bereavement survey system and to compare response rates for different number of items. The secondary aim was to examine response bias between web-based and mail survey in post-bereavement surveys. Between January and April 2019, two cross-sectional web-based questionnaire surveys were conducted among the bereaved families from six inpatient palliative care units in Japan. Measurements included structure and process of end-of-life (EOL) care, overall care satisfaction, achievement of a good death, depression, grief status, web survey usability, and participant and bereaved family member characteristics. The long survey included 34 items, and the short survey included 16 items. There were no significant differences in the response rates between the long and short surveys (24% and 27%, respectively, p = 0.376). Compared with a previous nationwide post-bereavement mail survey, more children responded; however, the quality rating scores was unchanged. Despite low response rate, no apparent response bias was observed, indicating its feasibility. This survey method is low-cost, less burdensome to the institution, and allows for ongoing quality assurance.

Antibodies against Serum Anti-Melanoma Differentiation-Associated Gene 5 in Rheumatoid Arthritis Patients with Chronic Lung Diseases.

Chronic lung diseases (CLD), including interstitial lung disease (ILD) and airway diseases (ADs), are common complications of rheumatoid arthritis (RA). Rheumatoid factor (RF) and anti-citrullinated peptide antibodies are reported to be associated with CLD in RA patients. The presence of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies (Abs) is associated with clinically amyopathic dermatomyositis developing into rapidly progressive ILD. However, few studies on anti-MDA5 Abs in RA have been published. Here, we analyzed the association of anti-MDA5 Abs with CLD complications in RA. Anti-MDA5 Abs were quantified in sera from RA patients with or without CLD. Anti-MDA5 Ab levels were higher in RA patients with ADs than without (mean ± SDM, 4.4 ± 2.4 vs. 4.0 ± 4.2, p = 0.0001). AUC values of anti-MDA5 Ab and RF ROC curves were similar in RA patients with or without CLD (0.578, 95%CI 0.530-0.627 and 0.579, 95%CI 0.530-0.627, respectively, p = 0.9411). Multiple logistic regression analysis of anti-MDA5 Abs and clinical characteristics yielded an MDA5-index with a higher AUC value than anti-MDA5 Ab alone (0.694, 95%CI 0.648-0.740, p = 5.08 × 10-5). Anti-MDA5 Abs were associated with ADs in RA patients and could represent a biomarker for CLD, similar to RF. The involvement of anti-MDA5 Abs in the pathogenesis of ADs in RA is proposed.

Comprehensive Steroid Assay with Non-Targeted Analysis Using Liquid Chromatography Ion Mobility Mass Spectrometry.

Aldosterone-producing adenomas (APAs) have different steroid profiles in serum, depending on the causative genetic mutation. Ion mobility is a separation technique for gas-phase ions based on their m/z values, shapes, and sizes. Human serum (100 µL) was purified by liquid-liquid extraction using tert-butyl methyl ether/ethyl acetate at 1/1 (v/v) and mixed with deuterium-labeled steroids as the internal standard. The separated supernatant was dried, re-dissolved in water containing 20% methanol, and injected into a liquid chromatography-ion mobility-mass spectrometer (LC/IM/MS). We established a highly sensitive assay system by separating 20 steroids based on their retention time, m/z value, and drift time. Twenty steroids were measured in the serum of patients with primary aldosteronism, essential hypertension, and healthy subjects and were clearly classified using principal component analysis. This method was also able to detect phosphatidylcholine and phosphatidylethanolamine, which were not targeted. LC/IM/MS has a high selectivity for known compounds and has the potential to provide information on unknown compounds. This analytical method has the potential to elucidate the pathogenesis of APA and identify unknown steroids that could serve as biomarkers for APA with different genetic mutations.

Monoblastic leukemia (M5a) with chronic basophilic leukemia in a cat.

A cat was presented with depression and anorexia. The complete blood cell count (CBC) revealed non-regenerative anemia (PCV, 8.5%), marked thrombocytopenia (2,400/µl), and leukocytosis (32,090/µl). In the peripheral blood, proliferation of blast cells (85%; 27,276/µl) and basophils (7.7%; 2,460/µl) was observed. Bone marrow aspirate showed hyperplasia with 8.8% blasts and 90.2% basophils of all nucleated cells. The blast cells were negative for myeloperoxidase staining and positive for alpha-naphthol butyrate esterase staining, indicating the agranular blasts are monoblasts. Thus, acute monoblastic leukemia (M5a) with chronic basophilic leukemia was diagnosed. Basophils accounted for more than 40% of the bone marrow, and we diagnosed secondary basophilic leukemia. Secondary basophilic leukemia should be included in the differential list when abnormal basophil increases are observed in feline bone marrow.

Misleading Reporting (Spin) in Noninferiority Randomized Clinical Trials in Oncology With Statistically Not Significant Results: A Systematic Review.

Importance: Spin, the inaccurate reporting of randomized clinical trials (RCTs) with results that are not statistically significant for the primary end point, distorts interpretation of results and leads to misinterpretation. However, the prevalence of spin and related factors in noninferiority cancer RCTs remains unclear. Objective: To examine misleading reporting, or spin, and the associated factors in noninferiority cancer RCTs through a systematic review. Data Sources: A systematic search of the PubMed database was performed for articles published between January 1, 2010, and December 31, 2019, using the Cochrane Highly Sensitive Search Strategy. Study Selection: Two investigators independently selected studies using the inclusion criteria of noninferiority parallel-group RCTs aiming to confirm effects to cancer treatments published between January 1, 2010, and December 31, 2019, reporting results that were not statistically significant for the primary end points. Data Extraction and Synthesis: Standardized data abstraction was used to extract information concerning the trial characteristics and spin based on a prespecified definition. The main investigator extracted the trial characteristics while both readers independently evaluated the spin. The Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline was followed. Main Outcomes and Measures: The main outcome was spin prevalence in any section of the report. Spin was defined as use of specific reporting strategies, from whatever motive, to highlight that the experimental treatment is beneficial, despite no statistically significant difference for the primary outcome, or to distract the reader from results that are not statistically significant. The associations (prevalence difference and odds ratios [ORs]) between spin and trial characteristics were also evaluated. Results: The analysis included 52 of 2752 reports identified in the PubMed search. Spin was identified in 39 reports (75.0%; 95% CI, 61.6%-84.9%), including the abstract (34 reports [65.4%; 95% CI, 51.1%-76.9%]) and the main text (38 reports [73.1%; 95% CI, 59.7%-83.3%]). Univariate analysis found that the spin prevalence was higher in reports with data managers (prevalence difference, 27%; 95% CI, 1.1%-50.3%), reports without funding from for-profit sources (prevalence difference, 31.2%; 95% CI, 4.8%-53.8%), and reports of novel experimental treatments (prevalence difference, 37.5%; 95% CI, 5.8%-64.7%). Multivariable analysis found that novel experimental treatment (OR, 4.64; 95% CI, 0.98-22.02) and funding only from nonprofit sources only (OR, 5.20; 95% CI, 1.21-22.29) were associated with spin. Conclusions and Relevance: In this systematic review, most noninferiority RCTs reporting results that were not statistically significant for the primary end points showed distorted interpretation and inaccurate reporting. The novelty of an experimental treatment and funding only from nonprofit sources were associated with spin.

Chronic constipation is negatively associated with colonic diverticula.

OBJECTIVES: Constipation has been considered the key risk factor for diverticulosis occurrence, but the underlying mechanism is unclear. We investigated the factors associated with diverticulosis, focusing on the association of constipation severity with the localization and number of diverticula. MATERIALS AND METHODS: We analyzed consecutive patients who underwent colonoscopy between March and December 2019. Chronic constipation was diagnosed as constipation meeting Rome IV criteria or as that requiring laxative therapy for more than 6 months. The degree of constipation was scored using the Constipation Scoring System (CSS). RESULTS: We assessed 1014 patients. Multivariate analysis revealed that age, alcohol consumption, and hypertension were positively associated with diverticulosis, whereas chronic constipation was negatively associated with diverticulosis (odds ratio [OR] = 0.74; 95% confidence interval [CI], 0.55-0.99). When assessed according to the location of diverticula, right-sided diverticula were significantly associated with a lower incidence of constipation (OR = 0.94; 95% CI, 0.89-0.98), whereas neither left-sided nor bilateral diverticula was associated with constipation. This negative association of diverticula with constipation was stronger in patients with a high CSS score. In stratified analysis, the number of diverticula decreased with increasing degree of constipation (p for trend <.01), and a high CSS score was associated with a decreased prevalence of ≥3 diverticula (OR = 0.64; 95% CI, 0.44-0.99). CONCLUSIONS: Chronic constipation was negatively associated with colonic diverticulosis. The association increased with the degree of constipation and was strong only in cases with right-sided diverticula and those with ≥3 diverticula.

Endotracheal Tube Obstruction Experienced during an Anterior Cervical Discectomy and Fusion.

During anterior cervical discectomy and fusion (ACDF), endotracheal tube difficulties are anticipated at the operative level but are unexpected elsewhere in the airway. We report the case of a 66-year-old woman who underwent C4/C5 ACDF to treat adjacent segment disease following a previous anterior cervical fixation surgery. Shortly after her lower jaw was elevated and the fusion cage was inserted, a rise in airway pressure was observed, indicating impaired breathing. Subsequent examination revealed a bent endotracheal tube in the oral cavity as the cause of the respiratory impairment. During anterior cervical surgery, elevating the lower jaw can cause the tongue root to press against the endotracheal tube. Reinforced endotracheal tubes, with a spiral-wound wire in the inner wall, would effectively prevent this issue. In the unlikely event of impaired breathing during such an operation, the oral cavity should be inspected for confirmation of an open airway.

Efficacy of celecoxib as preemptive analgesia for patients undergoing laparoscopic inguinal hernia repair: a randomized trial.

PURPOSE: To investigate the efficacy and safety of preemptive analgesia with a transversus abdominis plane (TAP) block versus celecoxib for patients undergoing laparoscopic transabdominal preperitoneal inguinal hernia repair (LTAPP). METHODS: Sixty patients scheduled for LTAPP were randomized into three groups: a celecoxib group, given 200 mg celecoxib 2 h before surgery; a celecoxib/diclofenac group, given 200 mg celecoxib 2 h before surgery and 50 mg rectal diclofenac sodium on recovery from general anesthesia; and a block group, given a TAP block with 60 mL 0.25% levobupivacaine after general anesthesia. We assessed the numerical rating scale (NRS) scores for pain at rest and with movement 24 h after surgery. Postoperative analgesia use and adverse events were also evaluated. RESULTS: The NRS scores for pain at rest and with movement were lower in the celecoxib group than in the block group, 24 h postoperatively. The time to first request for analgesia tended to be longer in the block group than in the celecoxib group. No significant between-group differences were noted in analgesic use or adverse events. CONCLUSIONS: Celecoxib was not inferior to the TAP block as preemptive analgesia. Thus, celecoxib could be given as simple preemptive analgesia for LTAPP by considering a multimodal analgesic strategy in the early postoperative period.

Successful Eradication of Helicobacter pylori Could Prevent Metachronous Gastric Cancer: A Propensity Matching Analysis.

BACKGROUND AND AIM: Helicobacter pylori is the leading cause of gastric cancer, but it is still uncertain whether eradicating H. pylori in early gastric cancer (EGC) patients who underwent endoscopic resection can prevent metachronous gastric cancer (MGC). This study aimed to investigate the effect of H. pylori eradication to prevent MGC after endoscopic submucosal dissection (ESD). METHODS: In this propensity-matched retrospective observational study, 770 patients with EGC who received ESD were enrolled. The outcome was the incidence of MGC; this was compared between the persistent and eradicated groups. RESULTS: MGC was detected in 27 patients (7.8%) during a median period of 39.0 months (range 26.0-64.0). After propensity matching, 126 pairs of patients in each group were analyzed. The 5-year cumulative incidence rates of MGC were 13.2 and 3.9% in the persistent and eradicated groups, respectively (p= 0.021, log-rank test). On multivariate analysis, H. pylori eradication prevented MGC significantly (hazard ratio [HR] 0.32; p = 0.029). The results remained robust after inverse probability of treatment weighting analysis (HR 0.30; p = 0.020). CONCLUSIONS: Successful H. pylori eradication could prevent MGC after ESD for EGC.

Proteogenomic analysis of granulocyte macrophage colony- stimulating factor autoantibodies in the blood of a patient with autoimmune pulmonary alveolar proteinosis.

Recently, attempts to reveal the structures of autoantibodies comprehensively using improved proteogenomics technology, have become popular. This technology identifies peptides in highly purified antibodies by using an Orbitrap device to compare spectra from liquid chromatography-tandem mass spectrometry against a cDNA database obtained through next-generation sequencing. In this study, we first analyzed granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies in a patient with autoimmune pulmonary alveolar proteinosis, using the trapped ion mobility spectrometry coupled with quadrupole time-of-flight (TIMS-TOF) instrument. The TIMS-TOF instrument identified peptides that partially matched sequences in up to 156 out of 162 cDNA clones. Complementarity-determining region 3 (CDR3) was fully and partially detected in nine and 132 clones, respectively. Moreover, we confirmed one unique framework region 4 (FR4) and at least three unique across CDR3 to FR4 peptides via de novo peptide sequencing. This new technology may thus permit the comprehensive identification of autoantibody structure.

Effect of EP1 Receptor Antagonist on Transient Lower Esophageal Sphincter Relaxations in Humans.

BACKGROUND/AIMS: Transient lower esophageal sphincter relaxations (TLESRs) are the major cause of gastroesophageal reflux. Recently, an EP1 receptor antagonist, ONO-8539, showed the reduction of TLESRs in monkeys. However, its effect on TLESRs in humans remains unclear. This study investigated the effect of ONO-8539 on postprandial TLESRs in healthy male subjects. METHODS: Twenty-seven subjects participated in this placebo-controlled, cross-over study. The subjects received either placebo or ONO-8539 (450 mg) after a standardized breakfast. A 30-min basal recording was performed 4 h after drug administration. Subsequently, TLESR recordings were performed after a high-fat test meal for 3 h. The examination was repeated at least 7 days from the first evaluation for washout. RESULTS: Thirteen patients were ultimately analyzed. The basal lower esophageal sphincter pressure was not different between the 2 groups (16.3 and 18.0 mm Hg for placebo and ONO-8539, respectively; p = 0.88). ONO-8539 significantly reduced the number of TLESRs from 15.0 to 12.0 for 3 h (p < 0.05). The proportion of terminating events of TLESRs was significantly different between the 2 groups (p < 0.05). No events and swallowing terminated more TLESRs with ONO-8539 than with placebo. CONCLUSIONS: ONO-8539 suppressed TLESRs mildly. EP1 receptor may be involved with the mechanism of human TLESRs.

Related factors, increased mortality and causes of death in patients with rheumatoid arthritis-associated interstitial lung disease.

Objectives: Interstitial lung disease (ILD) is a life-threatening extra-articular manifestation of rheumatoid arthritis (RA). We aimed to clarify the relationship between chronic ILD with a pattern of usual interstitial pneumonia (UIP) or non-UIP and mortality in RA patients.Methods: We retrospectively surveyed information of consecutive RA patients who visited our hospital from 2009 to 2014. The relationship between their mortality and chronic ILD (UIP or non-UIP) detected by high-resolution computed tomography was examined.Results: Of 2702 patients enrolled, 261 (9.7%) had chronic ILD and among these 120 had a UIP pattern. At the onset of RA, the prevalence of chronic ILD was 6%. Patients with chronic ILD had a higher mortality than those without. The most frequent cause of death was pneumonia including acute exacerbation (AE) of chronic ILD. Lung cancer death was frequently identified in deceased patients with chronic ILD with a UIP pattern compared with the other decedents (p=.062). The estimated mortality of lung cancer in patients with chronic ILD with a UIP pattern was five times higher than the general population.Conclusion: RA patients with ILD with a UIP pattern have a high mortality rate and are prone to die of AE or lung cancer.

Serum Metabolomic Profiles of Rheumatoid Arthritis Patients With Acute-Onset Diffuse Interstitial Lung Disease.

OBJECTIVE: Acute-onset diffuse interstitial lung disease (AoDILD) includes acute exacerbation of interstitial lung disease (ILD), drug-induced ILD, and Pneumocystis pneumonia, and frequently occurs in patients with rheumatoid arthritis (RA). Since AoDILD causes a poor prognosis in RA, biomarkers for AoDILD were eagerly desired. Metabolomic analyses were extensively performed in cancer patients and successfully generated better diagnostic biomarkers. In the present study, serum metabolomic profiles of AoDILD in RA were investigated to generate better potential metabolomic biomarkers. METHODS: Serum samples of 10 RA patients with AoDILD were collected on admission and in a stable state, more than 3 months before the admission. Serum metabolomic analyses were conducted on the samples from these RA patients with AoDILD. RESULTS: Apparently distinct serum metabolomic profiles in AoDILD were not observed in univariate or hierarchical cluster analyses. Partial least squares-discriminant analysis (PLS-DA) was performed to select candidate metabolites based on variable importance in projection (VIP) scores. The PLS-DA model generated from the four metabolites with VIP scores more than 2.25 (mannosamine, alliin, kynurenine, and 2-hydroxybutyric acid) could successfully discriminate AoDILD from the stable condition (area under the curve: 0.962, 95% confidence interval: 0.778-1.000). CONCLUSION: It was demonstrated that metabolomic profiling was useful to generate better biomarkers in AoDILD.

Inhaled GM-CSF for Pulmonary Alveolar Proteinosis.

BACKGROUND: Pulmonary alveolar proteinosis is a disease characterized by abnormal accumulation of surfactant in the alveoli. Most cases are autoimmune and are associated with an autoantibody against granulocyte-macrophage colony-stimulating factor (GM-CSF) that prevents clearing of pulmonary surfactant by alveolar macrophages. An open-label, phase 2 study showed some therapeutic efficacy of inhaled recombinant human GM-CSF in patients with severe pulmonary alveolar proteinosis; however, the efficacy in patients with mild-to-moderate disease remains unclear. METHODS: We conducted a double-blind, placebo-controlled trial of daily inhaled recombinant human GM-CSF (sargramostim), at a dose of 125 µg twice daily for 7 days, every other week for 24 weeks, or placebo in 64 patients with autoimmune pulmonary alveolar proteinosis who had a partial pressure of arterial oxygen (Pao2) while breathing ambient air of less than 70 mm Hg (or <75 mm Hg in symptomatic patients). Patients with severe pulmonary alveolar proteinosis (Pao2 <50 mm Hg) were excluded to avoid possible exacerbation of the disease in patients who were assigned to receive placebo. The primary end point was the change in the alveolar-arterial oxygen gradient between baseline and week 25. RESULTS: The change in the mean (±SD) alveolar-arterial oxygen gradient was significantly better in the GM-CSF group (33 patients) than in the placebo group (30 patients) (mean change from baseline, -4.50±9.03 mm Hg vs. 0.17±10.50 mm Hg; P = 0.02). The change between baseline and week 25 in the density of the lung field on computed tomography was also better in the GM-CSF group (between-group difference, -36.08 Hounsfield units; 95% confidence interval, -61.58 to -6.99, calculated with the use of the Mann-Whitney U test and the Hodges-Lehmann estimate of confidence intervals for pseudo-medians). Serious adverse events developed in 6 patients in the GM-CSF group and in 3 patients in the placebo group. CONCLUSIONS: In this randomized, controlled trial, inhaled recombinant human GM-CSF was associated with a modest salutary effect on the laboratory outcome of arterial oxygen tension, and no clinical benefits were noted. (Funded by the Japan Agency for Medical Research and Development and the Ministry of Health, Labor, and Welfare of Japan; PAGE ClinicalTrials.gov number, NCT02835742; Japan Medical Association Center for Clinical Trials number, JMA-IIA00205.).

Primary aldosteronism subtype discordance between computed tomography and adrenal venous sampling.

The primary aldosteronism (PA) subtype is usually confirmed by CT and adrenal venous sampling (AVS). However, the subtype diagnosis by AVS is not necessarily consistent with the subtype diagnosis by CT. Patients with PA who show bilateral lesions (normal-appearing adrenals or bilateral adrenal nodules) on CT but unilateral disease on AVS are often found. The aim of this study was to evaluate whether patients with PA subtype discordance between CT and AVS obtain benefits from unilateral adrenalectomy. We retrospectively analyzed 362 consecutive patients with PA who underwent both CT and adrenocorticotropic hormone-unstimulated AVS at Kanazawa University Hospital. Surgical outcomes for unilateral PA were evaluated according to the criteria of the Primary Aldosteronism Surgical Outcome study. In our study, the success rate of AVS in patients with bilateral lesions on CT was 89% (191/214). Furthermore, the discordance rate between CT and AVS in patients with bilateral lesions on CT was 39% (74/191). After surgery, patients with bilateral lesions on CT but unilateral disease on AVS (n = 17) had a lower complete biochemical success rate than those with unilateral lesions on CT and ipsilateral disease on AVS (n = 30) (41% vs. 80%, p = 0.01), but clinical and biochemical benefits (the complete and partial success combined) were not significantly different between them (76% vs. 93% (p = 0.11) and 70% vs. 90% (p = 0.10), respectively). In conclusion, patients with bilateral lesions on CT but unilateral disease on AVS benefited from surgery, and AVS should be performed for patients who pursue surgical management when the CT findings suggest bilateral lesions.

Memory B cell pool of autoimmune pulmonary alveolar proteinosis patients contains higher frequency of GM-CSF autoreactive B cells than healthy subjects.

The IgG-type neutralizing GM-CSF autoantibody (GMAb) is known to be the causative agent for autoimmune pulmonary alveolar proteinosis (APAP). Previous studies report that serum levels of IgG-GMAb are approximately 50-fold higher in APAP patients than in healthy subjects (HS). Serum levels of IgM-GMAb are also higher in APAP patients than in HS, but this has been assumed to be an etiological bystander. However, the mechanism for the excessive production of IgG-GMAb in APAP remains unclear. To investigate this, we detected putative GMAb-producing B cells (PGMPB) by inoculated B cells from the peripheral blood of APAP patients, HS, and umbilical cord blood mononuclear cells (UCBMNs) with Epstein-Barr virus. Both ELISA and ELISPOT assays showed that IgM-type GMAb was consistently and frequently present in all three groups, whereas IgG-type GMAb was high only in APAP patients, in whom it was exclusively produced in memory B cells and not in naive B cells. Since PGMPB in UCBMNs produced IgM-GMAb, but not IgG-GMAb, to the same extent as in HS and APAP patients, most IgM-GMAb reacted with GM-CSF in a non-specific manner. The memory B cell pool of APAP patients contain higher frequency of PGMPB than that of healthy subjects.