Citations

AbstractThe set of guidelines for good clinical research practice in pharmacodynamic studies of neuromuscular blocking agents was developed following an international consensus conference in Copenhagen in 1996 (Viby‐Mogensen et al., Acta Anaesthesiol Scand 1996, 40, 59–74); the guidelines were later revised and updated following the second consensus conference in Stockholm in 2005 (Fuchs‐Buder et al., Acta Anaesthesiol Scand 2007, 51, 789–808). In view of new devices and further development of monitoring technologies that emerged since then, (e.g., electromyography, three‐dimensional acceleromyography, kinemyography) as well as novel compounds (e.g., sugammadex) a review and update of these recommendations became necessary. The intent of these revised guidelines is to continue to help clinical researchers to conduct high‐quality work and advance the field by enhancing the standards, consistency, and comparability of clinical studies.There is growing awareness of the importance of consensus‐based reporting standards in clinical trials and observational studies. Such global initiatives are necessary in order to minimize heterogeneous and inadequate data reporting and to improve clarity and comparability between different studies and study cohorts. Variations in definitions of endpoints or outcome variables can introduce confusion and difficulties in interpretation of data, but more importantly, it may preclude building of an adequate body of evidence to achieve reliable conclusions and recommendations. Clinical research in neuromuscular pharmacology and physiology is no exception.

Abstract Amyotrophic lateral sclerosis (ALS) therapeutic development has largely relied on staff-administered functional rating scales to determine treatment efficacy. We sought to determine if mobile applications (apps) and wearable devices can be used to quantify ALS disease progression through active (surveys) and passive (sensors) data collection. Forty ambulatory adults with ALS were followed for 6-months. The Beiwe app was used to administer self-entry ALS functional rating scale-revised (ALSFRS-RSE) and the Rasch Overall ALS Disability Scale (ROADS) surveys every 2-4 weeks. A wrist-worn activity monitor (ActiGraph's Insight Watch) or an ankle-worn activity monitor (Modus' StepWatch) was used continuously by each participant. Wearable device wear and app survey compliance were adequate. ALSFRS-R highly correlated with ALSFRS-RSE. Several wearable data daily physical activity measures demonstrated statistically significant change over time and associations with ALSFRS-RSE and ROADS. Active and passive digital data collection hold promise for novel ALS trial outcomes development.

OBJECTIVES: To determine the association of prior use of renin-angiotensin-aldosterone system inhibitors (RAASIs) with mortality and outcomes in hospitalized patients with COVID-19. DESIGN: Retrospective observational study. SETTING: Multicenter, international COVID-19 registry. Subjects: Adult hospitalized COVID-19 patients on antihypertensive agents (AHAs) prior to admission, admitted from March 31, 2020, to March 10, 2021. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Data were compared between three groups: patients on RAASIs only, other AHAs only, and those on both medications. Multivariable logistic and linear regressions were performed after controlling for prehospitalization characteristics to estimate the effect of RAASIs on mortality and other outcomes during hospitalization. Of 26,652 patients, 7,975 patients were on AHAs prior to hospitalization. Of these, 1,542 patients (19.3%) were on RAASIs only, 3,765 patients (47.2%) were on other AHAs only, and 2,668 (33.5%) patients were on both medications. Compared with those taking other AHAs only, patients on RAASIs only were younger (mean age 63.3 vs 66.9 yr; p < 0.0001), more often male (58.2% vs 52.4%; p = 0.0001) and more often White (55.1% vs 47.2%; p < 0.0001). After adjusting for age, gender, race, location, and comorbidities, patients on combination of RAASIs and other AHAs had higher in-hospital mortality than those on RAASIs only (odds ratio [OR] = 1.28; 95% CI [1.19–1.38]; p < 0.0001) and higher mortality than those on other AHAs only (OR = 1.09; 95% CI [1.03–1.15]; p = 0.0017). Patients on RAASIs only had lower mortality than those on other AHAs only (OR = 0.87; 95% CI [0.81–0.94]; p = 0.0003). Patients on ACEIs only had higher mortality compared with those on ARBs only (OR = 1.37; 95% CI [1.20–1.56]; p < 0.0001). CONCLUSIONS: Among patients hospitalized for COVID-19 who were taking AHAs, prior use of a combination of RAASIs and other AHAs was associated with higher in-hospital mortality than the use of RAASIs alone. When compared with ARBs, ACEIs were associated with significantly higher mortality in hospitalized COVID-19 patients.

Abstract Background Guidelines recommend that all patients with upper gastrointestinal bleeding (UGIB) undergo endoscopy within 24 h. It is unclear whether a subgroup may benefit from an urgent intervention. We aimed to evaluate the influence of endoscopic hemostasis and urgent endoscopy on mortality in UGIB patients with high-risk stigmata (HRS). Methods Consecutive patients with suspected UGIB were enrolled in three Japanese hospitals with a policy to perform endoscopy within 24 h. The primary outcome was 30-day mortality. Endoscopic hemostasis and endoscopy timing (urgent, ≤6 h; early, &gt;6 h) were evaluated in a regression model adjusting for age, systolic pressure, heart rate, hemoglobin, creatinine, and variceal bleeding in multivariate analysis. A propensity score of 1:1 matched sensitivity analysis was also performed. Results HRS were present in 886 of 1966 patients, and 35 of 886 (3.95%) patients perished. Median urgent-endoscopy time (n = 769) was 3.0 h (interquartile range [IQR], 2.0–4.0 h) and early endoscopy (n = 117) was 12.0 h (IQR, 8.5–19.0 h). Successful endoscopic hemostasis and urgent endoscopy were significantly associated with reduced mortality in multivariable analysis (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.09–0.52; P = 0.0006, and OR, 0.37; 95% CI, 0.16–0.87; P = 0.023, respectively). In a propensity-score-matched analysis of 115 pairs, adjusted comparisons showed significantly lower mortality of urgent vs early endoscopy (2.61% vs 7.83%, P &lt; 0.001). Conclusions A subgroup of UGIB patients, namely those harboring HRS, may benefit from endoscopic hemostasis and urgent endoscopy rather than early endoscopy in reducing mortality. Implementing triage scores that predict the presence of such lesions is important.

IMPORTANCE: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.

OBJECTIVES: To describe the outcomes of hospitalized patients in a multicenter, international coronavirus disease 2019 registry. DESIGN: Cross-sectional observational study including coronavirus disease 2019 patients hospitalized with laboratory-confirmed severe acute respiratory syndrome coronavirus-2 infection between February 15, 2020, and November 30, 2020, according to age and type of organ support therapies. SETTING: About 168 hospitals in 16 countries within the Society of Critical Care Medicine’s Discovery Viral Infection and Respiratory Illness University Study coronavirus disease 2019 registry. PATIENTS: Adult hospitalized coronavirus disease 2019 patients who did and did not require various types and combinations of organ support (mechanical ventilation, renal replacement therapy, vasopressors, and extracorporeal membrane oxygenation). INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Primary outcome was hospital mortality. Secondary outcomes were discharge home with or without assistance and hospital length of stay. Risk-adjusted variation in hospital mortality for patients receiving invasive mechanical ventilation was assessed by using multilevel models with hospitals as a random effect, adjusted for age, race/ethnicity, sex, and comorbidities. Among 20,608 patients with coronavirus disease 2019, the mean (± sd ) age was 60.5 (±17), 11,1887 (54.3%) were men, 8,745 (42.4%) were admitted to the ICU, and 3,906 (19%) died in the hospital. Hospital mortality was 8.2% for patients receiving no organ support ( n = 15,001). The most common organ support therapy was invasive mechanical ventilation ( n = 5,005; 24.3%), with a hospital mortality of 49.8%. Mortality ranged from 40.8% among patients receiving only invasive mechanical ventilation ( n =1,749) to 71.6% for patients receiving invasive mechanical ventilation, vasoactive drugs, and new renal replacement therapy ( n = 655). Mortality was 39% for patients receiving extracorporeal membrane oxygenation ( n = 389). Rates of discharge home ranged from 73.5% for patients who did not require organ support therapies to 29.8% for patients who only received invasive mechanical ventilation, and 8.8% for invasive mechanical ventilation, vasoactive drugs, and renal replacement; 10.8% of patients older than 74 years who received invasive mechanical ventilation were discharged home. Median hospital length of stay for patients on mechanical ventilation was 17.1 days (9.7-28 d). Adjusted interhospital variation in mortality among patients receiving invasive mechanical ventilation was large (median odds ratio 1.69). CONCLUSIONS: Coronavirus disease 2019 prognosis varies by age and level of organ support. Interhospital variation in mortality of mechanically ventilated patients was not explained by patient characteristics and requires further evaluation.

Objective Intrahepatic cholangiocarcinoma (ICC)—a rare liver malignancy with limited therapeutic options—is characterised by aggressive progression, desmoplasia and vascular abnormalities. The aim of this study was to determine the role of placental growth factor (PlGF) in ICC progression. Design We evaluated the expression of PlGF in specimens from ICC patients and assessed the therapeutic effect of genetic or pharmacologic inhibition of PlGF in orthotopically grafted ICC mouse models. We evaluated the impact of PlGF stimulation or blockade in ICC cells and cancer-associated fibroblasts (CAFs) using in vitro 3-D coculture systems. Results PlGF levels were elevated in human ICC stromal cells and circulating blood plasma and were associated with disease progression. Single-cell RNA sequencing showed that the major impact of PlGF blockade in mice was enrichment of quiescent CAFs, characterised by high gene transcription levels related to the Akt pathway, glycolysis and hypoxia signalling. PlGF blockade suppressed Akt phosphorylation and myofibroblast activation in ICC-derived CAFs. PlGF blockade also reduced desmoplasia and tissue stiffness, which resulted in reopening of collapsed tumour vessels and improved blood perfusion, while reducing ICC cell invasion. Moreover, PlGF blockade enhanced the efficacy of standard chemotherapy in mice-bearing ICC. Conclusion PlGF blockade leads to a reduction in intratumorous hypoxia and metastatic dissemination, enhanced chemotherapy sensitivity and increased survival in mice-bearing aggressive ICC.

Objective: Gamma knife radiosurgery (GKRS) is commonly used to treat vestibular schwannomas (VSs). The risk of complications from GKRS decreases at lower doses, but it is unknown if long-term tumor control is negatively affected by dose reduction. Study Design: This was a retrospective case review and analysis of patient data. Setting: Tertiary referral center. Patients: Patients with VSs who underwent GKRS between 1990 and 2007 at the authors’ institution. Intervention(s): The subjects were divided into two cohorts based on the prescribed doses of radiation received: a 12 Gy cohort (96 patients) with a follow-up period of 124 months and a >12 Gy cohort (118 patients) with a follow-up period of 143 months. Main Outcome Measures: Tumor control rates at 10 to 15 years, frequency of facial and trigeminal nerve complications, and hearing function. Results: The 10 to 15-year tumor control rates were 95% in the 12 Gy cohort and 88% in the > 12 Gy cohort, but the differences were not significant. Compared with the >12 Gy cohort, facial and trigeminal nerve deficits occurred significantly less frequently in the 12 Gy cohort, with the 10-year cumulative, permanent deficit-free rates being 2% and 0%, respectively. Multivariate analyses revealed that treatment doses exceeding 12 Gy were associated with a significantly higher risk for cranial nerve deficits. The percentage of subjects retaining pure-tone average ≤ 50 dB at the final follow-up did not significantly differ between the cohorts (12 Gy cohort, 30% and >12 Gy cohort, 33%; p = 0.823). Conclusions: Dose reduction to 12 Gy for GKRS to treat VSs decreased facial and trigeminal nerve complications without worsening tumor control rates.

The efficacy of radiosurgery for neurofibromatosis type 2 (NF2)-associated vestibular schwannoma (VS) remains debatable. We retrospectively analyzed radiosurgical outcomes for NF2-associated VS compared to sporadic VS using our database of 422 consecutive VS patients. Twenty-five patients with 30 NF2-associated VSs with a mean follow-up of 121 months were identified. NF2-associated VSs exhibited excellent tumor control (10-year cumulative rate, 92% vs. 92% in sporadic VSs; p = 0.945) and worse overall survival (73% vs. 97%; p = 0.005), mainly due to tumor progression other than the treated VSs. The presence of NF2 was not associated with failed tumor control via multivariate Cox proportional hazard analyses. No difference in radiation-induced adverse events (RAEs) was confirmed between cohorts, and prescription dose (hazard ratio 8.30, 95% confidence interval 3.19–21.62, p < 0.001) was confirmed as a risk for cranial nerve injuries via multivariate analysis. Further analysis after propensity score matching using age, volume, and sex as covariates showed that NF2-associated VSs exhibited excellent local control (100% vs. 93%; p = 0.240) and worse overall survival (67% vs. 100%; p = 0.002) with no significant difference in RAEs. Excellent long-term tumor control and minimal invasiveness may make radiosurgery a favorable therapeutic option for NF2 patients with small to medium VS, preferably with non-functional hearing or deafness in combination with postoperative tumor growth or progressive non-operated tumors, or with functional hearing by patients’ wish.