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The United States Government (USG) public-private partnership “Accelerating COVID-19 Treatment Interventions and Vaccines” (ACTIV) was launched to identify safe, effective therapeutics to treat patients with Coronavirus Disease 2019 (COVID-19) and prevent hospitalization, progression of disease, and death. Eleven original master protocols were developed by ACTIV, and thirty-seven therapeutic agents entered evaluation for treatment benefit. Challenges encountered during trial implementation led to innovations enabling initiation and enrollment of over 26,000 participants in the trials. While only two ACTIV trials continue to enroll, the recommendations here reflect information from all the trials as of May 2023. We review clinical trial implementation challenges and corresponding lessons learned to inform future therapeutic clinical trials implemented in response to a public health emergency and the conduct of complex clinical trials during “peacetime,” as well.
Auditory verbal hallucinations (AVHs) in schizophrenia have been suggested to arise from failure of corollary discharge mechanisms to correctly predict and suppress self-initiated inner speech. However, it is unclear whether such dysfunction is related to motor preparation of inner speech during which sensorimotor predictions are formed. The contingent negative variation (CNV) is a slow-going negative event-related potential that occurs prior to executing an action. A recent meta-analysis has revealed a large effect for CNV blunting in schizophrenia. Given that inner speech, similar to overt speech, has been shown to be preceded by a CNV, the present study tested the notion that AVHs are associated with inner speech-specific motor preparation deficits.
Objectives
The present study aimed to provide a useful framework for directly testing the long-held idea that AVHs may be related to inner speech-specific CNV blunting in patients with schizophrenia. This may hold promise for a reliable biomarker of AVHs.
Methods
Hallucinating (n=52) and non-hallucinating (n=45) patients with schizophrenia, along with matched healthy controls (n=42), participated in a novel electroencephalographic (EEG) paradigm. In the Active condition, they were asked to imagine a single phoneme at a cue moment while, precisely at the same time, being presented with an auditory probe. In the Passive condition, they were asked to passively listen to the auditory probes. The amplitude of the CNV preceding the production of inner speech was examined.
Results
Healthy controls showed a larger CNV amplitude (p = .002, d = .50) in the Active compared to the Passive condition, replicating previous results of a CNV preceding inner speech. However, both patient groups did not show a difference between the two conditions (p > .05). Importantly, a repeated measure ANOVA revealed a significant interaction effect (p = .007, ηp2 = .05). Follow-up contrasts showed that healthy controls exhibited a larger CNV amplitude in the Active condition than both the hallucinating (p = .013, d = .52) and non-hallucinating patients (p < .001, d = .88). No difference was found between the two patient groups (p = .320, d = .20).
Conclusions
The results indicated that motor preparation of inner speech in schizophrenia was disrupted. While the production of inner speech resulted in a larger CNV than passive listening in healthy controls, which was indicative of the involvement of motor planning, patients exhibited markedly blunted motor preparatory activity to inner speech. This may reflect dysfunction in the formation of corollary discharges. Interestingly, the deficits did not differ between hallucinating and non-hallucinating patients. Future work is needed to elucidate the specificity of inner speech-specific motor preparation deficits with AVHs. Overall, this study provides evidence in support of atypical inner speech monitoring in schizophrenia.
This study aimed to analyse surgical outcomes of paediatric patients with congenital cholesteatoma according to age.
Method
This was a retrospective study reviewing the records of 186 children (136 boys and 50 girls) from August 1993 to January 2016. Patients were divided into three age groups (equal to or less than 3 years, over 3 and less than 7 years, and 7 to 15 years).
Results
There were significant differences in chief complaints, location of cholesteatoma in the middle ear, computed tomography findings, operation methods, ossicular erosion and type of cholesteatoma sac among the three groups. In addition, older age, open type cholesteatoma, ossicular erosion and mastoid invasion of cholesteatoma increased the recurrence rate after surgery. However, despite higher pre-operative air–bone gap in older children, hearing can be improved enough after proper surgery with ossicular reconstruction.
Conclusion
Delayed detection of paediatric cholesteatoma can lead to extensive disease and the need for an aggressive operation, which can result in worse hearing outcomes and an increased recurrence risk.
At least half of the local galaxies reside in galaxy groups, which indicates that the group is the common environment where galaxies evolve. Therefore, it is important to probe how significantly galaxies are affected by group environmental processes, in order to obtain a better understanding of galaxy evolution. We carried out a new CO imaging survey for 31 galaxies in the IC 1459 and NGC 4636 groups, using the Atacama Compact Array, to study the effect of the group environment on the molecular gas properties and the star formation activity. With our resolved CO data, combined with high-resolution H i images, we find asymmetric CO and H i distributions in the group galaxies. Compared to isolated galaxies, group members have relatively low molecular gas fraction and low star formation rate. These results suggest that the group environment can change the properties of cold gas components and star formation in group galaxies.
This SHEA white paper identifies knowledge gaps and challenges in healthcare epidemiology research related to coronavirus disease 2019 (COVID-19) with a focus on core principles of healthcare epidemiology. These gaps, revealed during the worst phases of the COVID-19 pandemic, are described in 10 sections: epidemiology, outbreak investigation, surveillance, isolation precaution practices, personal protective equipment (PPE), environmental contamination and disinfection, drug and supply shortages, antimicrobial stewardship, healthcare personnel (HCP) occupational safety, and return to work policies. Each section highlights three critical healthcare epidemiology research questions with detailed description provided in supplementary materials. This research agenda calls for translational studies from laboratory-based basic science research to well-designed, large-scale studies and health outcomes research. Research gaps and challenges related to nursing homes and social disparities are included. Collaborations across various disciplines, expertise and across diverse geographic locations will be critical.
We aimed to investigate the heterogeneity of seasonal suicide patterns among multiple geographically, demographically and socioeconomically diverse populations.
Methods
Weekly time-series data of suicide counts for 354 communities in 12 countries during 1986–2016 were analysed. Two-stage analysis was performed. In the first stage, a generalised linear model, including cyclic splines, was used to estimate seasonal patterns of suicide for each community. In the second stage, the community-specific seasonal patterns were combined for each country using meta-regression. In addition, the community-specific seasonal patterns were regressed onto community-level socioeconomic, demographic and environmental indicators using meta-regression.
Results
We observed seasonal patterns in suicide, with the counts peaking in spring and declining to a trough in winter in most of the countries. However, the shape of seasonal patterns varied among countries from bimodal to unimodal seasonality. The amplitude of seasonal patterns (i.e. the peak/trough relative risk) also varied from 1.47 (95% confidence interval [CI]: 1.33–1.62) to 1.05 (95% CI: 1.01–1.1) among 12 countries. The subgroup difference in the seasonal pattern also varied over countries. In some countries, larger amplitude was shown for females and for the elderly population (≥65 years of age) than for males and for younger people, respectively. The subperiod difference also varied; some countries showed increasing seasonality while others showed a decrease or little change. Finally, the amplitude was larger for communities with colder climates, higher proportions of elderly people and lower unemployment rates (p-values < 0.05).
Conclusions
Despite the common features of a spring peak and a winter trough, seasonal suicide patterns were largely heterogeneous in shape, amplitude, subgroup differences and temporal changes among different populations, as influenced by climate, demographic and socioeconomic conditions. Our findings may help elucidate the underlying mechanisms of seasonal suicide patterns and aid in improving the design of population-specific suicide prevention programmes based on these patterns.
Imprinting, characterized by unequal expression of the offspring's genes in a parent-of-origin dependent manner, has been functionally implicated in brain development and in psychiatric disorders. In this study, unambiguous distortion in paternal but not maternal transmission of the disease-associated single-nucleotide polymorphism (SNP) rs6556547 (T/G) clearly indicated the presence of parent-of-origin effect (POE) in the GABAA receptor β2 subunit gene (GABRB2). ‘Flipping’ of allelic mRNA expression in heterozygotes of SNP rs2229944 (C/T) and the observed two-tiered distribution of mRNA expression levels in heterozygotes of the disease-associated SNP rs1816071 (G/A) furnished important support for the occurrence of imprinting at GABRB2. Imprinting in effect introduced heterozygotes from different parents-of-origin endowed with dissimilar mRNA expression capabilities. The deficit of upper-tiered expressions accounted for the lowered mRNA expression levels in the schizophrenic heterozygotes. This pointed to the necessity of differentiating between two kinds of heterozygotes of different parental origins in disease association studies on GABRB2. Bisulfite sequencing revealed hypermethylation in the neighborhood of SNP rs1816071, and methylation differences between controls and schizophrenia patients. Notably, allele-specific methylation was observed at the disease-associated SNPs rs6556547 and rs1816071. These findings raised the possibility that CpG methylation status of these sites could have an impact on the expression of GABRB2 and the risk of schizophrenia. Furthermore, the occurrence of imprinting and allele-specific methylation in the schizophrenia candidate gene GABRB2 was compatible with the epigenetic hypothesis for schizophrenia pathophysiology, thereby calling for the need to explore the role of epigenetic factors in mediating susceptibility to schizophrenia.
We report a case of a 27-year-old Iraq War veteran with no previous psychiatric history who sustained severe traumatic brain injury (TBI) following a blast injury from an improvised explosive device. The patient subsequently suffered severe anxiety symptoms controlled only with combined therapy with benzodiazepines and venlafaxine. Even more disabling, the patient also experienced intractable headache and shoulder pain unresponsive to non-steroidal anti-inflammatory agents, tramadol, gabapentin, or NMDA-receptor antagonists. Given the risk of respiratory depression with his current medications, opioid analgesics were not favored for the management of his pain. The patient was started on sublingual buprenorphine at a dose of 8mg three times daily with significant improvement. This dose was maintained and the patient was able to function relatively pain-free.
Conclusion:
Chronic pain is a significant complication in patients with TBI and is reported by a majority of patients with TBI, regardless of the severity of the injury. The treatment of chronic pain among individuals can be challenging. Patients with TBI may be on other medications for impulse control, such as anticonvulsants and benzodiazepines. Further treatment with narcotic analgesics may therefore increase the risk of respiratory depression. Buprenorphine is a partial mu agonist whose effects plateau at higher doses, at which time it begins to act like an antagonist. It is this property at higher doses that limits its dose-dependent respiratory depression. Buprenorphine thus has the advantage of effective analgesia with minimal sedation and may be useful to treat chronic pain among TBI patients already taking benzodiazepines.
Speculation exists that bone pain crises among sickle cell disease (SCD) patients are not adequately treated. We counter this assertion with the case of a 17 year-old African American woman receiving narcotics while malingering SCD.
There are various complications of SCD with the most common resulting from ischemia of the bone marrow. While depression, anxiety, and post-traumatic stress disorder have been described, psychiatric complications are not well documented in SCD.
A 17 year old African American female entered the emergency room (ER) with right tibia and fibula fractures. She admitted to having SCD with bone pain crises previously treated with Ketorolac and Meperidine.
On this occasion, radiological studies did not confirm sickle cell changes. A subsequent immunoglobulin electrophoresis came back hemoglobin AA. After the patient received notification she did not have SCD, she attempted to leave against medical advice. Her fractures were treated and she was discharged.
DSM IV defines malingering as “the intentional production of false or grossly exaggerated physical or psychological symptoms”. One previous report of malingering sickle cell crises exists.1 This case demonstrates that the motivation to gain narcotic analgesics is a determining factor for malingering vis-à-vis factitious disorder, in which the primary goal is to assume the sick role.1
Clinicians may assume the validity of a self-reported SCD history. In this case, ER physicians prescribed narcotics without objective evidence of SCD pathology. We suggest verification of SCD diagnosis in order to prevent unnecessary prescription of narcotics.
Electroconvulsive therapy (ECT) remains irreplaceable in the treatment of several psychiatric conditions. However, evidence derived using data from a national database to support its safety is limited. The aim of this study was to investigate in-hospital mortality among patients with psychiatric conditions treated with and without ECT.
Methods
Using data from the Taiwan National Health Insurance Research Database from 1997 to 2013, we identified 828,899 inpatients with psychiatric conditions, among whom 0.19% (n = 1571) were treated with ECT.
Results
We found that ECT recipients were more frequently women, were younger and physically healthier, lived in more urbanized areas, were treated in medical centers, and had longer hospital stays. ECT recipients had lower odds of in-hospital mortality than did those who did not receive ECT. Moreover, no factor was identified as being able to predict mortality in patients who underwent ECT. Among all patients, ECT was not associated with in-hospital mortality after controlling for potential confounders.
Conclusion
ECT was indicated to be safe and did not increase the odds of in-hospital mortality. However, ECT appeared to be administered only on physically healthy but psychiatrically compromised patients, a pattern that is in opposition with the scientific evidence supporting its safety. Moreover, our data suggest that ECT is still used as a treatment of last resort in the era of modern psychiatry.
Sleep disturbances are common among cancer patients. Especially during hospitalization, not only adverse medical conditions but also ward environments can affect sleep. We have developed a program of sleep-hygiene education and sleeping pill reduction for inpatients (the i-sleep program) and applied it to cancer patients. This study aimed to explore the effect of the program.
Methods
In a general hospital with 2,715 beds, we estimated the proportion of inpatients prescribed hypnotics at admission to and discharge from the department of oncology before (2014) and after (2015) the program. In addition, we estimated the proportion of inpatients prescribed hypnotics among all inpatients in the department of oncology on the first day of each month of 2014 and 2015.
Results
A total of 12,382 patients (2014, before) and 12,313 patients (2015, after) were admitted to oncology department of Asan Medical Center. The proportion of inpatients prescribed hypnotics as discharge medication among inpatients who had been prescribed them at the time of admission decreased significantly, from 76.0% (2014) to 69.8% (2015), after the program (RR = 0.92, 95% CI: 0.87–0.98). The proportion of inpatients newly prescribed sleeping pills after admission to the hospital did not significantly decrease (4.03% to 3.98%; RR = 0.99, 95% CI: 0.87–1.12). The mean prescription rate of sleeping pills per day was 10.02% in 2014 and 7.99% in 2015 (P = 0.03).
Conclusions
Although the i-sleep program did not reduce the prescription rate of sleeping pills per day, it effectively reduced the proportion of cancer patients who continued to take sleeping pills from admission until discharge.
Disclosure of interest
The authors have not supplied their declaration of competing interest.
Background: Previous post-hoc analysis of three 12-week, double-blind, placebo-controlled trials of adjunctive brivaracetam (BRV) in patients with focal seizures demonstrated similar efficacy over placebo regardless of previous carbamazepine (CBZ), lamotrigine (LTG), levetiracetam (LEV), or topiramate (TPM) failure. This analysis explored long-term retention of adjunctive BRV in patients with previous CBZ/LTG/LEV/TPM. Methods: Post-hoc analysis of double-blind, placebo-controlled trial (N01358 [NCT01261325]) and open-label extension (N01379 [NCT01339559]; cut-off 15-March-2017) of adjunctive BRV in patients (≥16 years) with focal seizures. Outcomes were assessed in patients randomized to BRV (100 or 200 mg/day) who had previous CBZ/LTG/LEV/TPM (stopped ≥90 days before BRV initiation). Results: 503 patients were analyzed. Baseline characteristics were generally similar in subgroups with previous CBZ/LTG/LEV/TPM (n=209/162/256/182). Overall, Kaplan-Meier-estimated BRV retention at 1-, 3-, and 5-years was 71.0%, 50.9%, and 32.4%. Across previous antiepileptic drug (AED) subgroups, Kaplan-Meier-estimated BRV retention (1-year: 64.8%–73.2%; 3-year: 41.9%–49.9%; 5-year: 31.5%–35.7%), BRV discontinuations (58.4%–63.0%), and most common reasons for discontinuation (lack of efficacy: 23.0%–25.3%; adverse event: 16.7%–22.2%) were generally similar. Conclusions: Post-hoc analysis demonstrated similar long-term retention rates and discontinuation reasons with adjunctive BRV in adults previously treated with CBZ/LTG/LEV/TPM. Adjunctive BRV provides long-term effectiveness in patients who failed common AED treatments, including LEV.
The Pain Catastrophizing Scale (PCS) measures three aspects of catastrophic cognitions about pain—rumination, magnification, and helplessness. To facilitate assessment and clinical application, we aimed to (a) develop a short version on the basis of its factorial structure and the items’ correlations with key pain-related outcomes, and (b) identify the threshold on the short form indicative of risk for depression.
Design:
Cross-sectional survey.
Setting:
Social centers for older people.
Participants:
664 Chinese older adults with chronic pain.
Measurements:
Besides the PCS, pain intensity, pain disability, and depressive symptoms were assessed.
Results:
For the full scale, confirmatory factor analysis showed that the hypothesized 3-factor model fit the data moderately well. On the basis of the factor loadings, two items were selected from each of the three dimensions. An additional item significantly associated with pain disability and depressive symptoms, over and above these six items, was identified through regression analyses. A short-PCS composed of seven items was formed, which correlated at r=0.97 with the full scale. Subsequently, receiver operating characteristic (ROC) curves were plotted against clinically significant depressive symptoms, defined as a score of ≥12 on a 10-item version of the Center for Epidemiologic Studies-Depression Scale. This analysis showed a score of ≥7 to be the optimal cutoff for the short-PCS, with sensitivity = 81.6% and specificity = 78.3% when predicting clinically significant depressive symptoms.
Conclusions:
The short-PCS may be used in lieu of the full scale and as a brief screen to identify individuals with serious catastrophizing.
Many women experience both vasomotor menopausal symptoms (VMS) and depressed mood at midlife, but little is known regarding the prospective bi-directional relationships between VMS and depressed mood and the role of sleep difficulties in both directions.
Methods
A pooled analysis was conducted using data from 21 312 women (median: 50 years, interquartile range 49−51) in eight studies from the InterLACE consortium. The degree of VMS, sleep difficulties, and depressed mood was self-reported and categorised as never, rarely, sometimes, and often (if reporting frequency) or never, mild, moderate, and severe (if reporting severity). Multivariable logistic regression models were used to examine the bi-directional associations adjusted for within-study correlation.
Results
At baseline, the prevalence of VMS (40%, range 13–62%) and depressed mood (26%, 8–41%) varied substantially across studies, and a strong dose-dependent association between VMS and likelihood of depressed mood was found. Over 3 years of follow-up, women with often/severe VMS at baseline were more likely to have subsequent depressed mood compared with those without VMS (odds ratios (OR) 1.56, 1.27–1.92). Women with often/severe depressed mood at baseline were also more likely to have subsequent VMS than those without depressed mood (OR 1.89, 1.47–2.44). With further adjustment for the degree of sleep difficulties at baseline, the OR of having a subsequent depressed mood associated with often/severe VMS was attenuated and no longer significant (OR 1.13, 0.90–1.40). Conversely, often/severe depressed mood remained significantly associated with subsequent VMS (OR 1.80, 1.38–2.34).
Conclusions
Difficulty in sleeping largely explained the relationship between VMS and subsequent depressed mood, but it had little impact on the relationship between depressed mood and subsequent VMS.
Depression is one of the most common mental disorders and identifying effective treatment strategies is crucial for the control of depression. Well-conducted systematic reviews (SRs) and meta-analyses can provide the best evidence for supporting treatment decision-making. Nevertheless, the trustworthiness of conclusions can be limited by lack of methodological rigour. This study aims to assess the methodological quality of a representative sample of SRs on depression treatments.
Methods.
A cross-sectional study on the bibliographical and methodological characteristics of SRs published on depression treatments trials was conducted. Two electronic databases (the Cochrane Database of Systematic Reviews and the Database of Abstracts of Reviews of Effects) were searched for potential SRs. SRs with at least one meta-analysis on the effects of depression treatments were considered eligible. The methodological quality of included SRs was assessed using the validated AMSTAR (Assessing the Methodological Quality of Systematic Reviews) tool. The associations between bibliographical characteristics and scoring on AMSTAR items were analysed using logistic regression analysis.
Results.
A total of 358 SRs were included and appraised. Over half of included SRs (n = 195) focused on non-pharmacological treatments and harms were reported in 45.5% (n = 163) of all studies. Studies varied in methods and reporting practices: only 112 (31.3%) took the risk of bias among primary studies into account when formulating conclusions; 245 (68.4%) did not fully declare conflict of interests; 93 (26.0%) reported an ‘a priori’ design and 104 (29.1%) provided lists of both included and excluded studies. Results from regression analyses showed: more recent publications were more likely to report ‘a priori’ designs [adjusted odds ratio (AOR) 1.31, 95% confidence interval (CI) 1.09–1.57], to describe study characteristics fully (AOR 1.16, 95% CI 1.06–1.28), and to assess presence of publication bias (AOR 1.13, 95% CI 1.06–1.19), but were less likely to list both included and excluded studies (AOR 0.86, 95% CI 0.81–0.92). SRs published in journals with higher impact factor (AOR 1.14, 95% CI 1.04–1.25), completed by more review authors (AOR 1.12, 95% CI 1.01–1.24) and SRs on non-pharmacological treatments (AOR 1.62, 95% CI 1.01–2.59) were associated with better performance in publication bias assessment.
Conclusion.
The methodological quality of included SRs is disappointing. Future SRs should strive to improve rigour by considering of risk of bias when formulating conclusions, reporting conflict of interests and authors should explicitly describe harms. SR authors should also use appropriate methods to combine the results, prevent language and publication biases, and ensure timely updates.
Extended-spectrum β-lactamase (ESBL) production has been very rare in serotype K1 Klebsiella pneumoniae ST23 strains, which are well-known invasive community strains. Among 92 ESBL-producing strains identified in 218 isolates from nine Asian countries, serotype K1 K. pneumoniae strains were screened. Two ESBL-producing K. pneumoniae isolates from Singapore and Indonesia were determined to be serotype K1 and ST23. Their plasmids, which contain CTX-M-15 genes, are transferable rendering the effective transfer of ESBL resistance plasmids to other organisms.
This study aimed to evaluate the association of chronic rhinosinusitis with sudden sensorineural hearing loss using a population-based database.
Methods:
Sampled subject data were obtained from the Taiwan Longitudinal Health Insurance Database 2000. A total of 3325 patients with sudden sensorineural hearing loss were identified and 9975 controls were randomly selected. A conditional logistic regression was used to calculate the odds ratio for having been previously diagnosed with chronic rhinosinusitis, for cases and controls.
Results and conclusion:
The adjusted odds ratio of having prior chronic rhinosinusitis among cases compared to controls was 1.36 (95 per cent confidence interval = 1.16–1.60). The significant relationship between sudden sensorineural hearing loss and chronic rhinosinusitis was most pronounced among those patients aged 44 years or less (compared to controls) (odds ratio = 2.18; 95 per cent confidence interval = 1.63–2.92). However, the significant relationship between sudden sensorineural hearing loss and prior chronic rhinosinusitis was not sustained for patients older than 60 years compared to controls.