Dissociative symptoms may be found in a subset of patients with major depressive disorders (MDD). The Clinician-Administered Dissociative States Scale (CADSS) is a 23-item scale for the measurement of present-state dissociative symptoms with good inter-rater reliability and construct validity that can discriminate patients with dissociative disorders. The total CADSS score is derived by adding the score for each of the 23 items. A score of 4 or more on the CADSS is considered abnormal and clinically meaningful. Uncompetitive N-methyl-d-aspartic acid receptor (NMDAR) channel blockers have been proposed as a treatment for post-traumatic stress disorder (PTSD). REL-1017 is a novel, low potency, NMDAR channel blocker currently in Phase 3 studies for MDD.

This retrospective case series describes a subset of patients from a double-blind, randomized, placebo-controlled, in-patient 7-day, phase 2 trial of oral, once daily, 25 mg (75 mg loading dose on day 1, first dose) and 50 mg REL-1017 (100 mg loading dose on day 1, first dose) as an adjunctive treatment for MDD. This subset of patients was selected based on abnormal CADSS score at baseline, pre-treatment with the study drug. As part of REL-1017 safety evaluation, the CADSS was administered at four timepoints to all study patients: (a) 30 to 60 minutes pre-treatment at baseline on day 1; (b) 2 hours post-treatment on day 1 (after the first dose of study drug); (c) 2 hours post-treatment on day 7 (after the last dose); and (d) prior to discharge on day 9 (2 days after the last dose).

Among the 62 randomized patients, four patients had a CADSS score of at least 4 on day 1 before study drug administration (2 patients in the 25 mg arm [CADSS score 22 and 4]; 1 patient in the 50 mg arm [CADSS score 35]; 1 patient in the placebo arm [CADSS score 6]). Among these 4 patients, starting on day 1, 2 hours post-treatment, the 2 subjects in the 25 mg subgroup (75 mg loading dose) and 1 subject in the 50 mg subgroup (100 mg loading dose) showed a clinically meaningful decrease in their CADSS score, while the single patient in the placebo group showed no change. CADSS scores on Day 1 pre-treatment, day 1 post-treatment, day 7 post last treatment, and on day 9 prior to discharge were 22-2-6-0; 4-0-0-0; 35-14-9-0, and 6-6-n/a-n/a, for the two patients in the 25 mg REL-1017 subgroup, the single patient in the 50 mg REL-1017 subgroup, and the single patient in the placebo group, respectively.

These retrospective case report data potentially signal that REL-1017 may determine rapid and sustained improvement in patients with MDD and concurrent clinically meaningful dissociative symptoms assessed by a CADSS score of 4 or above. Ongoing phase 3 trials with REL-1017 are expected to enroll a total of 1200 outpatients with MDD. These studies will potentially generate additional data that may support the initiation of controlled studies with REL-1017 for the treatment of PTSD.

Relmada Therapeutics

Major depressive disorder (MDD) is the second leading cause of disability and chronic disease burden in the United States. The importance of improving functional outcomes in MDD is increasingly recognized. The Symptoms of Depression Questionnaire (SDQ), a patient-reported measure, was developed to capture the heterogeneity of symptoms of MDD. REL-1017 (esmethadone HCl; d-methadone), is a novel N-methyl-d-aspartate receptor (NMDAR) channel blocker and potential rapid antidepressant currently in Phase 3 development. In a Phase 2a trial, REL-1017 showed robust, rapid, and sustained antidepressant efficacy as adjunctive treatment in patients with MDD. The objective of this study was to assess the effects of REL-1017 on SDQ subscales to better characterize the functional implications of its therapeutic effects.

A double-blind, placebo-controlled, inpatient, two-doses, 25 and 50 mg, three-arm, 1:1:1, randomized, phase 2a trial of REL-1017 was conducted at 10 centers in the United States. Least square (LS) mean scores and Cohen’s effect sizes of the total score of a 44-item of SDQ and its 5 subscales: lassitude, mood, cognitive/social functioning (SDQ-1); anxiety, agitation, anger, and irritability (SDQ-2); desire to be dead (SDQ-3); disruptions in sleep quality (SDQ-4); changes in appetite and weight (SDQ-5) were compared between REL-1017 and placebo.

A total of 62 adult male and female patients (18-65 years of age) diagnosed with MDD participated in the trial. On day 14, the last day of efficacy measurement, the difference from placebo of the LS mean (90% CI) for REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed improvement for both tested doses on SDQ total score (−23.2; P = .0066 [effect size: 0.9]; −26.8 P = .0014 [effect size: 1.1]). Additionally, for SDQ subscales, REL-1017 25 mg and REL-1017 50 mg groups, respectively, showed significant improvement as compared with placebo: SDQ-1 (−13.9; P = .0025 [effect size: 1.0]; −15.0; P = .0009 [effect size: 1.1]), SDQ-2 (−4.6; P = .0398 [effect size: 0.7]; −7.2; P = .0012 [effect size: 1.1]) and SDQ-4 (−2.7; P = .0055 [effect size: 1.0]; −2.8; P = .0029 [effect size: 1.0]). No significant differences were observed between the treated groups and placebo in the SDQ-3 and SDQ-5 subscales.

In patients with MDD, aside from improving the overall CFB compared to placebo in SDQ total score, REL-1017 resulted in clinically meaningful and statistically significant improvements in cognitive/motivational, anxiety/irritability, and sleep-specific domains. The robust, rapid, and sustained efficacy of REL-1017 for MDD is not limited to improving mood, but potentially extends to cognitive, motivational, sleep, and social functions, with potentially meaningful therapeutic and socioeconomic implications. These results may signal disease-modifying effects of esmethadone for MDD that may offer potential advantages over symptomatic treatment with standard antidepressants.

Relmada Therapeutics, Inc.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) disease (COVID-19) has high morbidity and mortality in older adults and people with dementia. Infection control and prevention measures potentially reduce transmission within hospitals.

We aimed to replicate our earlier study of London mental health in-patients to examine changes in clinical guidance and practice and associated COVID-19 prevalence and outcomes between COVID-19 waves 1 and 2 (1 March to 30 April 2020 and 14 December 2020 to 15 February 2021).

We collected the 2 month period prevalence of wave 2 of COVID-19 in older (≥65 years) in-patients and those with dementia, as well as patients’ characteristics, management and outcomes, including vaccinations. We compared these results with those of our wave 1 study.

Sites reported that routine testing and personal protective equipment were available, and routine patient isolation on admission occurred throughout wave 2. COVID-19 infection occurred in 91/358 (25%; 95% CI 21–30%) v. 131/344, (38%; 95% CI 33–43%) P < 0.001 in wave 1. Hospitals identified more asymptomatic carriers (26/91; 29% v. 16/130; 12%) and fewer deaths (12/91; 13% v. 19/131; 15%; odds ratio = 0.92; 0.37–1.81) compared with wave 1. The patient vaccination uptake rate was 49/58 (85%).

Patients in psychiatric in-patient settings, mostly admitted without known SARS-CoV-2 infection, had a high risk of infection compared with people in the community but lower than that during wave 1. Availability of infection control measures in line with a policy of parity of esteem between mental and physical health appears to have lowered within-hospital COVID-19 infections and deaths. Cautious management of vulnerable patient groups including mental health patients may reduce the future impact of COVID-19.

Deficits in emotional intelligence (EI) were detected in patients with bipolar disorder (BD), but little is known about whether these deficits are already present in patients after presenting a first episode mania (FEM). We sought (i) to compare EI in patients after a FEM, chronic BD and healthy controls (HC); (ii) to examine the effect exerted on EI by socio-demographic, clinical and neurocognitive variables in FEM patients.

The Emotional Intelligence Quotient (EIQ) was calculated with the Mayer-Salovey-Caruso Emotional Intelligence Test (MSCEIT). Performance on MSCEIT was compared among the three groups using generalized linear models. In patients after a FEM, the influence of socio-demographic, clinical and neurocognitive variables on the EIQ was examined using a linear regression model.

In total, 184 subjects were included (FEM n = 48, euthymic chronic BD type I n = 75, HC n = 61). BD patients performed significantly worse than HC on the EIQ [mean difference (MD) = 10.09, standard error (s.e.) = 3.14, p = 0.004] and on the understanding emotions branch (MD = 7.46, s.e. = 2.53, p = 0.010). FEM patients did not differ from HC and BD on other measures of MSCEIT. In patients after a FEM, EIQ was positively associated with female sex (β = −0.293, p = 0.034) and verbal memory performance (β = 0.374, p = 0.008). FEM patients performed worse than HC but better than BD on few neurocognitive domains.

Patients after a FEM showed preserved EI, while patients in later stages of BD presented lower EIQ, suggesting that impairments in EI might result from the burden of disease and neurocognitive decline, associated with the chronicity of the illness.

Longitudinal data on the mental health impact of the coronavirus disease 2019 (Covid-19) pandemic in healthcare workers is limited. We estimated prevalence, incidence and persistence of probable mental disorders in a cohort of Spanish healthcare workers (Covid-19 waves 1 and 2) -and identified associated risk factors.

8996 healthcare workers evaluated on 5 May–7 September 2020 (baseline) were invited to a second web-based survey (October–December 2020). Major depressive disorder (PHQ-8 ≥ 10), generalised anxiety disorder (GAD-7 ≥ 10), panic attacks, post-traumatic stress disorder (PCL-5 ≥ 7), and alcohol use disorder (CAGE-AID ≥ 2) were assessed. Distal (pre-pandemic) and proximal (pandemic) risk factors were included. We estimated the incidence of probable mental disorders (among those without disorders at baseline) and persistence (among those with disorders at baseline). Logistic regression of individual-level [odds ratios (OR)] and population-level (population attributable risk proportions) associations were estimated, adjusting by all distal risk factors, health care centre and time of baseline interview.

4809 healthcare workers participated at four months follow-up (cooperation rate = 65.7%; mean = 120 days s.d. = 22 days from baseline assessment). Follow-up prevalence of any disorder was 41.5%, (v. 45.4% at baseline, p < 0.001); incidence, 19.7% (s.e. = 1.6) and persistence, 67.7% (s.e. = 2.3). Proximal factors showing significant bivariate-adjusted associations with incidence included: work-related factors [prioritising Covid-19 patients (OR = 1.62)], stress factors [personal health-related stress (OR = 1.61)], interpersonal stress (OR = 1.53) and financial factors [significant income loss (OR = 1.37)]. Risk factors associated with persistence were largely similar.

Our study indicates that the prevalence of probable mental disorders among Spanish healthcare workers during the second wave of the Covid-19 pandemic was similarly high to that after the first wave. This was in good part due to the persistence of mental disorders detected at the baseline, but with a relevant incidence of about 1 in 5 of HCWs without mental disorders during the first wave of the Covid-19 pandemic. Health-related factors, work-related factors and interpersonal stress are important risks of persistence of mental disorders and of incidence of mental disorders. Adequately addressing these factors might have prevented a considerable amount of mental health impact of the pandemic among this vulnerable population. Addressing health-related stress, work-related factors and interpersonal stress might reduce the prevalence of these disorders substantially. Study registration number: NCT04556565

Optimal preoperative therapy regimen in the treatment of resectable retroperitoneal sarcoma (RPS) remains unclear. This study compares the impact of preoperative radiation, chemoradiation and chemotherapy on overall survival (OS) in RPS patients.

The National Cancer Database (NCDB) was queried for patients with non-metastatic, resectable RPS (2006–15). The primary endpoint was OS, evaluated by Kaplan–Meier method, log-rank test, Cox multivariable analysis and propensity score matching.

A total of 1,253 patients met the inclusion criteria, with 210 patients (17%) receiving chemoradiation, 850 patients (68%) receiving radiation and 193 patients (15%) receiving chemotherapy. On Cox multivariable analysis, when compared to preoperative chemoradiation, preoperative radiation was not associated with improved OS (hazards ratio [HR] 0·98, 95% CI 0·76–1·25, p = 0·84), while preoperative chemotherapy was associated with worse OS (HR 1·64, 95% CI 1·24–2·18, p < 0·001). Similar findings were observed in 199 and 128 matched pairs for preoperative radiation and chemotherapy, respectively, when compared to preoperative chemoradiation.

Our study suggested an OS benefit in using preoperative chemoradiation compared to chemotherapy alone, but OS outcomes were comparable between preoperative chemoradiation and radiation alone.

Intensive care unit (ICU)–acquired infections with antibiotic-resistant bacteria have been associated with substantial health and economic costs. Moreover, southern Europe has historically reported high levels of antimicrobial resistance.

We estimated the attributable economic burden of ICU-acquired infections due to resistant bacteria based upon hospital excess length of stay (LOS) in a selected sample of southern European countries.

We studied a cohort of adult patients admitted to the ICU who developed an ICU-acquired infection related to an invasive procedure in a sample of Spanish, Italian, and Portuguese hospitals between 2008 and 2016, using data from The European Surveillance System (TESSy) released by the European Centers for Disease Control (ECDC). We analyzed the association between infections with selected antibiotic-resistant bacteria of public health importance and excess LOS using regression, matching, and time-to-event methods. We controlled for several confounding factors as well as time-dependent biases. We also computed the associated economic burden of excess resource utilization for each selected country.

In total, 13,441 patients with at least 1 ICU-acquired infection were included in the analysis: 4,106 patients (30.5%) were infected with antimicrobial-resistant bacteria, whereas 9,335 patients (69.5%) were infected with susceptible bacteria. The unadjusted association between resistance status and excess LOS was 7 days (95% CI, 6.13–7.87; P < .001). Fully adjusted models yielded significantly lower estimates: 2.76 days (95% CI, 1.98–3.54; P < .001) in the regression model, 2.60 days (95% CI, 1.66–3.55; P < .001) in the genetic matching model, and a hazard ratio of 1.15 (95% CI, 1.11–1.19; P < .001) in the adjusted Cox regression model. These estimates, alongside the prevalence of resistance, translated into direct hospitalization attributable costs per ICU-acquired infection of 5,224€ (95% CI, 3,691–6,757) for Spain, 4,461€ (95% CI, 1,948–6,974) for Portugal, and 4,320€ (95% CI, 1,662–6,977) for Italy.

ICU-acquired infections associated with antibiotic-resistant bacteria are substantially associated with a 15% increase in excess LOS and resource utilization in 3 southern European countries. However, failure to appropriately control for significant confounders inflates estimates by ∼2.5-fold.

Induction chemotherapy (iC) followed by concurrent chemoradiation has been shown to improve overall survival (OS) for locally advanced pancreatic cancer (LAPC). However, the survival benefit of stereotactic body radiation therapy (SBRT) versus conventionally fractionated radiation therapy (CFRT) following iC remains unclear.

The National Cancer Database (NCDB) was queried for primary stage III, cT4N0-1M0 LAPC (2004–15). Kaplan–Meier analysis, Cox proportional hazards method and propensity score matching were used.

Among 872 patients, 738 patients underwent CFRT and 134 patients received SBRT. Median follow-up was 24·3 and 22·9 months for the CFRT and SBRT cohorts, respectively. The use of SBRT showed improved survival in both the multivariate analysis (hazards ratio 0·78, p = 0·025) and 120 propensity-matched pairs (median OS 18·1 versus 15·9 months, p = 0·004) compared to the CFRT.

This NCDB analysis suggests survival benefit with the use of SBRT versus CFRT following iC for the LAPC.

This National Cancer Database (NCDB) analysis was performed to evaluate the outcomes of adjuvant chemotherapy (AC) versus observation for resected pancreatic adenocarcinoma treated with neoadjuvant therapy (NT).

The NCDB was queried for primary stages I–II cT1-3N0-1M0 resected pancreatic adenocarcinoma treated with NT (2004–2015). Baseline patient, tumour and treatment characteristics were extracted. The primary end point was overall survival (OS). With a 6-month conditional landmark, Kaplan–Meier analysis, multivariable Cox proportional hazards method and 1:1 propensity score matching was used to analyse the data.

A total of 1,737 eligible patients were identified, of which 1,247 underwent post-operative observation compared to 490 with AC. The overall median follow-up was 34·7 months. The addition of AC showed improved survival on the multivariate analysis (HR 0·78, p < 0·001). AC remained statistically significant for improved OS, with a median OS of 26·3 months versus 22·3 months and 2-year OS of 63·9% versus 52·9% for the observation cohort (p < 0·001). Treatment interaction analysis showed OS benefit of AC for patients with smaller tumours.

Our findings suggest a survival benefit for AC compared to observation following NT and surgery for resectable pancreatic adenocarcinoma, especially in patients with smaller tumours.

The aims of this study were to examine the efficacy among various vitamin D supplementation regimens on serum 25-hydroxyvitamin D (25(OH)D) concentrations and determine the minimal dose rate required to achieve sufficient serum concentrations (≥75 nmol/l) among older adults in long-term care (LTC).

A 1-year medical history was abstracted from medical records, and a one-time blood draw to measure serum 25(OH)D concentrations was obtained. Individuals were stratified into vitamin D-supplemented and non-supplemented groups. The supplemented group was further categorised into four treatment forms: single-ingredient vitamin D2or3, multivitamin, Ca with vitamin D or combination of the three, and by daily prescribed doses: 0–9·9, 10–19·9, 20–49·9, 50–99·9 and >100 μg/d.

Five LTC communities in Austin, Texas.

One hundred seventy-three older (≥65 years) adults.

Of the participants, 62% received a vitamin D supplement and 55% had insufficient (≤75 nmol/l) 25(OH)D serum concentrations. Individuals receiving single-ingredient vitamin D2or3 supplementation received the highest daily vitamin D mean dose (72·5 μg/d), while combination of forms was the most frequent treatment (44%) with the highest mean serum concentration (108 nmol/l). All supplementation doses were successful at reaching sufficient serum concentrations, except those<20 μg/d. Using a prediction model, it was observed that 0·025 μg/d of vitamin D supplementation resulted in a 0·008 nmol/l increase in serum 25(OH)D concentrations.

Based on the predictive equation, results suggest that supplementation of 37·5 μg/d of vitamin D2or3 or combination of vitamin D is most likely to achieve sufficient serum 25(OH)D concentrations in older adults in LTC.