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Background: The value of rapid reviews in informing health care decisions is more evident since the onset of the coronavirus disease 2019 (COVID-19) pandemic. While systematic reviews can be completed rapidly, rapid reviews are usually a type of evidence synthesis in which components of the systematic review process may be simplified or omitted to produce information more efficiently within constraints of time, expertise, funding or any combination thereof. There is an absence of high-quality evidence underpinning some decisions about how we plan, do and share rapid reviews. We will conduct a modified James Lind Alliance Priority Setting Partnership to determine the top 10 unanswered research questions about how we plan, do and share rapid reviews in collaboration with patients, public, reviewers, researchers, clinicians, policymakers and funders. Methods: An international steering group consisting of key stakeholder perspectives (patients, the public, reviewers, researchers, clinicians, policymakers and funders) will facilitate broad reach, recruitment and participation across stakeholder groups. An initial online survey will identify stakeholders' perceptions of research uncertainties about how we plan, do and share rapid reviews. Responses will be categorised to generate a long list of questions. The list will be checked against systematic reviews published within the past three years to identify if the question is unanswered. A second online stakeholder survey will rank the long list in order of priority. Finally, a virtual consensus workshop of key stakeholders will agree on the top 10 unanswered questions. Discussion: Research prioritisation is an important means for minimising research waste and ensuring that research resources are targeted towards answering the most important questions. Identifying the top 10 rapid review methodology research priorities will help target research to improve how we plan, do and share rapid reviews and ultimately enhance the use of high-quality synthesised evidence to inform health care policy and practice., Competing Interests: Competing interests: Nikita Burke is paid in full from Evidence Synthesis Ireland, which is a capacity-building initiative funded by the Health Research Board (Ireland) and the HSC R&D Division of the Public Health Agency (Northern Ireland). Claire Beecher is paid in part from Evidence Synthesis Ireland, which is a capacity-building initiative funded by the Health Research Board (Ireland) and the HSC R&D Division of the Public Health Agency (Northern Ireland). Declan Devane is paid in part from Evidence Synthesis Ireland, which is a capacity-building initiative funded by the Health Research Board (Ireland) and the HSC R&D Division of the Public Health Agency (Northern Ireland). Andrea C. Tricco is paid in part by a Tier 2 Canada Research Chair in Knowledge Synthesis, (Copyright: © 2021 Beecher C et al.)

Individuals with a social anxiety disorder (SAD) show hypofunctioning of the hypothalamus-pituitary-gonadal (HPG) axis, which is linked to social fear and avoidance behavior. As testosterone administration has been shown to facilitate social-approach behavior in this population, it may enhance the effectiveness of exposure treatment. In this proof-of-concept study, we performed a randomized clinical assay in which 55 women diagnosed with SAD received two exposure therapy sessions. Session 1 was supplemented with either testosterone (0.50 mg) or placebo. Next, transfer effects of testosterone augmentation on within-session subjective fear responses and SAD symptom severity were assessed during a second, unenhanced exposure session (session 2) and at a 1-month follow-up, respectively. The participants having received testosterone showed a more reactive fear pattern, with higher peaks and steeper reductions in fear levels in session 2. Post-hoc exploration of moderating effects of endogenous testosterone levels, revealed that this pattern was specific for women with high basal testosterone, both in the augmented and in the transfer session. In contrast, the participants with low endogenous testosterone showed reduced peak fear levels throughout session 1, again with transfer to the unenhanced session. Testosterone did not significantly affect self-reported anxiety. The effects of testosterone supplementation on fear levels show transfer to non-enhanced exposure, with effects being modulated by endogenous testosterone. These first preliminary results indicate that testosterone may act on important fear mechanisms during exposure, providing the empirical groundwork for further exploration of multi-session testosterone-enhanced exposure treatment for SAD., (© 2021. The Author(s).)

Background: Risk of cancer in multiple sclerosis (MS) patients compared to their siblings is unknown., Objective: The objective was to prospectively investigate the risk of cancer among MS patients compared to siblings without MS and to population controls., Methods: We retrieved data on MS patients born between 1930 and 1979 from the Norwegian Multiple Sclerosis Registry and population studies and on cancer diagnosis from the Cancer Registry of Norway. We used adjusted Cox proportional hazard regression to estimate cancer risk among 6883 MS patients, 8918 siblings without MS, and 37,919 population controls., Results: During 65 years of follow-up, cancer risk among MS patients was higher than that among population controls (hazard ratio (HR) = 1.14, 95% confidence interval (CI): 1.05-1.23) in respiratory organs (HR = 1.66, 95% CI: 1.26-2.19), urinary organs (HR = 1.51, 95% CI: 1.12-2.04), and the central nervous system (HR = 1.52, 95% CI: 1.11-2. 09). Siblings had higher risk of hematological cancers compared with MS patients (HR = 1.82, 95% CI: 1.21-2.73) and population controls (HR = 1.72, 95% CI: 1.36-2.18)., Conclusion: MS patients were associated with increased risk of cancer compared to population controls. Siblings had increased risk of hematological cancer. This indicates that MS and hematological cancer could share a common etiology.

Stepped-care (SC) models for anxiety disorders are implemented on a large scale and are assumed to be as effective for the greater majority of patients as more intensive treatment schemes. To compare the outcomes of SC and international guideline-based treatment (Treatment as Usual: TAU) for panic disorder, a total of 128 patients were randomized to either SC or TAU (ratio 2: 1, respectively) using a computer generated algorithm. They were treated in four mental health care centres in the Netherlands after therapists had been trained in SC by a senior expert therapist. SC comprised 10-week guided self-help (pen-and-paper version) followed, if indicated, by 13-week manualized face-to-face cognitive behavioural therapy (CBT), with medication- if prescribed- kept constant. TAU consisted of 23-week regular face-to-face CBT (RCBT) with medication -when prescribed- also kept constant. The means of the attended sessions in the SC condition was 5.9 (SD = 4.8) for ITT and 9.6 (SD = 9.6) for the RCBT condition. The difference in the number of attended sessions between the conditions was significant (t(126) = -3.87, p < .001). Remission rates between treatment conditions did not differ significantly (SC: 44.5%; RCBT: 53.3%) and symptom reduction was similar. Stepping up SC treatment to face-to-face CBT showed a minimal additional effect. Importantly, drop-out rates differed significantly for the two conditions (SC: 48.2%; RCBT: 26.7%). SC was effective in the treatment of panic disorder in terms of symptom reduction and remission rate, but dropout rates were twice as high as those seen in RCBT, with the second phase of SC not substantially improving treatment response. However, SC required significantly less therapist contact time compared to RCBT, and more research is needed to explore predictors of success for guided self-help interventions to allow treatment intensity to be tailored to patients' needs and preferences., Competing Interests: Although at the time of the study one of the authors (MV) was a member of the board HSK Groep as well as an employee of the Behavioural Science Institute of Radboud University, his affiliation with HSK Groep does not alter our adherence to PLOS ONE policies on sharing data and materials. The authors have declared that no competing interests exist.

Background: Comorbid personality disorders are assumed to negatively interfere with the treatment outcome of affective disorders. Data on late-life panic disorder remain unknown. We examined the association of personality pathology and treatment outcome related to age and treatment modality., Methods: An observational study on the effectiveness of cognitive-behavioral therapy (CBT) for panic disorder with agoraphobia among patients 18 to 74 years of age and randomized controlled comparison of paroxetine and CBT in older patients (60 y of age or older) were performed. The diagnosis of panic disorder was confirmed by the Anxiety Disorder Interview Schedule-Revised (ADIS-IV) and personality features were assessed with the Personality Diagnostic Questionnaire. The impact of personality features on either agoraphobic cognitions (Agoraphobic Cognitions Questionnaire) or avoidance behavior (Mobility Inventory Avoidance Scale) was examined by multiple linear regression analyses adjusted for sex, level of education, duration of illness, comorbid psychopathology, and baseline severity. The interaction between personality and age was examined among those treated with CBT (n=90); the interaction between personality and treatment modality was examined among the older subgroup (n=34)., Results: Cluster B personality pathology (evaluated on the basis of either Diagnostic and Statistical Manual of Mental Disorders, Third Edition, Revised (DSM-III-R) or Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) criteria depending on the date of assessment) was negatively associated with outcomes of CBT in both younger and older adults with panic disorder and agoraphobia. Older adults with a higher number of features of any personality pathology or cluster A pathology had worse treatment outcomes when treated with paroxetine compared with CBT., Conclusions: Cluster B pathology had a detrimental effect on CBT treatment outcome for panic disorder in both age groups. In late-life panic disorder with comorbid personality pathology, CBT may be preferred over treatment with paroxetine.

Background: An adequate frequency of treatment might be a prerequisite for a favorable outcome. Unfortunately, there is a diversity of factors that interfere with an adequate frequency of sessions. This occurs especially in the first phase of treatment, while the first phase seems vital for the rest of treatment. The aim of this naturalistic study was to explore the impact of the initial frequency of treatment sessions on treatment outcome in a diverse mental health care population., Methods: Anonymized data were analyzed from 2,634 patients allocated for anxiety disorders, depressive disorders, and personality disorders to outpatient treatment programs in a large general mental health care facility. Patients' treatment outcome was routinely monitored with the Outcome Questionnaire-45 (OQ-45.2), every 12 weeks. Frequency of sessions was assessed for the first three months of treatment. Using Cox-proportional-hazard models, we explored the associations between initial frequency and improvement (reliable significant change) and recovery (reliable and clinically significant change)., Results: Improvement and recovery were associated with symptom severity and functional impairment at start of treatment, the year the treatment started, number of measurements, the treatment program (anxiety disorders, depressive disorders, and personality disorders) and receiving group therapy other than psychotherapy. In all diagnostic groups, both improvement and recovery were associated with a higher frequency of sessions during the first three months of treatment. For improvement, this effect diminished after three years in treatment; however, for recovery this association was sustained., Conclusions: In addition to severity at start of treatment and other predictors of outcome, a low frequency of initial treatment sessions might lead to a less favorable outcome and a more chronic course of the mental disorder. This association seems not to be limited to a specific diagnostic group, but was found in a large group of patients with common mental disorders (depression and anxiety disorders) and patients with a personality disorder. Despite organizational obstacles, more effort should be made to start treatment quickly by an effective frequency of session.

Approximately 40% of adolescents with obsessive-compulsive disorder (ocd) do not improve sufficiently from standard cognitive behavioral therapy, and are at risk for a chronic course of the symptomatology as well as stagnation in their development. There has hardly been any research into next step evidence-based treatments for adolescents with persevering ocd. We treated three adolescents with persevering ocd with an eight-day intensive, therapist-assisted exposure and response prevention (erp) in which family members were involved. Two out of the three patients showed an improvement in ocd-symptoms and for one of these two patients the symptoms went in full remission. These outcomes are promising, and these case studies prove that short erp therapy, which is more intensive and provides assisted erp, can be a possible second step in the treatment.

Objectives: Patients with head and neck cancer (HNC) frequently encounter weight loss with multiple negative outcomes as a consequence. Adequate treatment is best achieved by early identification of patients at risk for critical weight loss. The objective of this study was to detect predictive factors for critical weight loss in patients with HNC receiving (chemo)radiotherapy ((C)RT)., Materials and Methods: In this cohort study, 910 patients with HNC were included receiving RT (±surgery/concurrent chemotherapy) with curative intent. Body weight was measured at the start and end of (C)RT. Logistic regression and classification and regression tree (CART) analyses were used to analyse predictive factors for critical weight loss (defined as >5%) during (C)RT. Possible predictors included gender, age, WHO performance status, tumour location, TNM classification, treatment modality, RT technique (three-dimensional conformal RT (3D-RT) vs intensity-modulated RT (IMRT)), total dose on the primary tumour and RT on the elective or macroscopic lymph nodes., Results: At the end of (C)RT, mean weight loss was 5.1±4.9%. Fifty percent of patients had critical weight loss during (C)RT. The main predictors for critical weight loss during (C)RT by both logistic and CART analyses were RT on the lymph nodes, higher RT dose on the primary tumour, receiving 3D-RT instead of IMRT, and younger age., Conclusion: Critical weight loss during (C)RT was prevalent in half of HNC patients. To predict critical weight loss, a practical prediction tree for adequate nutritional advice was developed, including the risk factors RT to the neck, higher RT dose, 3D-RT, and younger age., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background: Digital technology (e-health or 'blended' care), combined with evidence-based face-to-face CBT, is becoming increasingly implemented into mental health care and is expected to result in improved effectiveness and efficiency., Aim: To explore the feasibility of blended CBT for patients with a panic disorder., Method: Nine face-to-face sessions of blended CBT (n = 18), supplemented with the digital support of a tabletcomputer and three e-mail contacts, were compared with 12 weekly sessions of regular CBT (n = 18). Primary outcomes were panic frequency and avoidance behaviour; the secondary outcome was general functioning. Patients' experiences of the treatment were collected in the form of a structured interview., Results: The effect sizes found in both the regular and the blended CBT were medium to high (Cohen's d 0.42-1.60). In both types of treatment there was a significant reduction in patients' symptoms. There were no big differences in patient satisfaction regarding the treatment received. The therapists registered 39 face-to-face minutes in the blended treatment but they registered in total 41 fewer face-to-face minutes; this represented a time reduction of 4%., Conclusion: Blended CBT with help of a tablet computer seems to be a suitable method for treating panic disorder psychologically, although the time saved is only moderate. Much more research is needed to ascertain the feasibility and the cost effectiveness of blended CBT.

The risk of manifestations of ischaemic heart disease (IHD) in fertile women is elevated during pregnancy and the post-partum period. With increasing maternal age and a higher prevalence of cardiac risk factors, the incidence of IHD during pregnancy is rising. However, information in the literature is scarce. We therefore performed a retrospective cohort study and systematically reviewed the overall (1975-2013) and contemporary (2005-2013) literature concerning IHD presenting during pregnancy or in the post-partum period. We report two cases of IHD with atypical presentation during pregnancy or post-partum. In our review, we describe 146 pregnancies, including 57 contemporary cases (2005-2013). Risk factors for IHD were present in 80 %. Of the cases of IHD, 71 % manifested in the third trimester or the post-partum period, and 95 % presented with chest pain. The main cause was coronary dissection (35 %), or thrombus/emboli (35 %) in the more contemporary group. Maternal mortality was 8 % (6 % in the contemporary group), and the main cardiac complication was ventricular tachycardia (n = 17). Premature delivery rate was 56 %, and caesarean section was performed in 57 %. Perinatal mortality was 4 %. In conclusion, IHD during pregnancy or in the post-partum period has high maternal mortality and morbidity rates. Also, premature delivery and perinatal mortality rates are high.

Background: Older adults with panic disorder and agoraphobia (PDA) are underdiagnosed and undertreated, while studies of cognitive-behavioral therapy (CBT) are lacking. This study compares the effectiveness of CBT for PDA in younger and older adults., Methods: A total of 172 patients with PDA (DSM-IV) received manualized CBT. Primary outcome measures were avoidance behavior (Mobility Inventory Avoidance scale) and agoraphobic cognitions (Agoraphobic Cognitions Questionnaire), with values of the younger (18-60 years) and older (≥ 60 years) patients being compared using mixed linear models adjusted for baseline inequalities, and predictive effects of chronological age, age at PDA onset and duration of illness (DOI) being examined using multiple linear regressions., Results: Attrition rates were 2/31 (6%) for the over-60s and 31/141 (22%) for the under-60s group (χ(2) = 3.43, df = 1, P = .06). Patients in both age groups improved on all outcome measures with moderate-to-large effect sizes. Avoidance behavior had improved significantly more in the 60+ group (F = 4.52, df = 1,134, P = .035), with agoraphobic cognitions showing no age-related differences. Baseline severity of agoraphobic avoidance and agoraphobic cognitions were the most salient predictors of outcome (range standardized betas 0.59 through 0.76, all P-values < .001). Apart from a superior reduction of agoraphobic avoidance in the 60+ participants (β = -0.30, P = .037), chronological age was not related to outcome, while in the older patients higher chronological age, late-onset type and short DOI were linked to superior improvement of agoraphobic avoidance., Conclusions: CBT appears feasible for 60+ PDA-patients, yielding outcomes that are similar and sometimes even superior to those obtained in younger patients., (© 2014 Wiley Periodicals, Inc.)

Objective: This study aims to evaluate the differential predictive values of age, age of onset and duration of illness on paroxetine and cognitive-behavioural therapy (CBT) outcome in late-life panic disorder with agoraphobia., Method: Patients 60 years and older with a confirmed diagnosis of panic disorder with agoraphobia (n = 49) were randomly assigned to paroxetine (40 mg/day) treatment, individual CBT or a waiting-list control condition. Multiple regression analyses were conducted per treatment arm with post-treatment avoidance behaviour and agoraphobic cognitions as the dependent variables., Results: Higher age at onset and shorter duration of illness were predictors of superior outcomes following CBT, although these variables did not influence the treatment effects of paroxetine., Conclusions: In late-life agoraphobic panic disorder, chronological age has no impact on treatment modality outcome. In older patients with a late disease onset or shorter duration of illness, CBT is to be preferred over paroxetine, whereas paroxetine might be the treatment of choice for older people with an early onset and short duration of illness., (Copyright © 2011 John Wiley & Sons, Ltd.)

Aim: To collect empirical evidence concerning the effectiveness of the treatment of anxiety disorders in the elderly., Method: Meta-analysis and randomised controlled trials., Results: Meta-analysis showed that cognitive behavioural therapy (CBT) was more successful than waiting-list control or active control as a treatment for older persons with anxiety disorders. In a direct comparison of the treatment of older persons with panic disorder (PD) both CBT an paroxetine were found to be more effective than waiting-list control. CBT was more successful in reducing avoidance behaviours in older persons with PD. Older persons with reported fewer and less severe agoraphobic cognitions than younger patients, but there was no difference between the severity of agoraphobic avoidance in older patients with PD and younger patients with PD., Conclusion: There is sufficient empirical evidence to support the effectiveness of CBT in the treatment of older persons with anxiety disorders. In assessing the severity of PD in the elderly, one should carefully consider the severity of avoidance behaviours. Because no difference was found between the effectiveness of CBT and paroxetine for the treatment of PD in the elderly and because was more effective in reducing avoidance behaviours in older patients with PD than in younger patients with pd, there seems to be a slight preference for CBT in the case of older patients with PD. Older age is not associated with a poorer outcome of treatment with CBT.

Objectives: To compare the agoraphobic cognitions of younger and older patients suffering from panic disorder with agoraphobia by means of existing questionnaires., Method: Agoraphobic cognitions were assessed using the Agoraphobic Cognitions Questionnaire (ACQ) in 205 patients confirmed with confirmed panic disorder with agoraphobia (Diagnostic and Statistical Manual, Fourth Edition, Text Revision) and analyzed at the item level applying a Bonferroni correction., Results: The 48 patients who were older than 60 years had a significantly lower mean (SD) ACQ total score than their younger counterparts (1.6 [0.5] versus 2.1 [0.6]; t = 5.7, df = 203, p < 0.001), with their scores on the items fear of going crazy, acting foolishly, losing control, passing out, and brain tumors (p < 0.004) being significantly lower., Conclusion: The differential effect at the ACQ item level suggests that some cognitions seem less relevant for agoraphobic panic disorder in later life. Future research should explore whether and which agerelated cognitions are missed in the current questionnaires.

Background: Both cognitive-behavioral therapy and treatment with selective serotonin reuptake inhibitors (SSRIs) have proved to be effective in the treatment of panic disorder. The present study examined the effects of paroxetine added to continued cognitive-behavioral therapy in patients who were unsuccessfully treated with initial cognitive-behavioral therapy alone., Method: 161 patients with panic disorder with or without agoraphobia (DSM-IV criteria) underwent a manual-guided cognitive-behavioral therapy of 15 sessions. Forty-three unsuccessfully treated patients from this group were included in a double-blind, placebo-controlled, next-step treatment study consisting of continued cognitive-behavioral therapy plus adjunctive paroxetine at a dose of 40 mg/day or continued cognitive-behavioral therapy plus placebo., Results: Overall, patients in the cognitive-behavioral therapy plus paroxetine condition improved significantly on agoraphobic behavior (p < .05) and anxiety discomfort (p < .01), whereas patients in the cognitive-behavioral therapy plus placebo condition did not. Effect sizes in the cognitive-behavioral therapy plus paroxetine condition ranged from 1.0 to 1.8 and in the cognitive-behavioral therapy plus placebo condition, from 0.4 to 1.0., Conclusion: Patients with panic disorder who are unsuccessfully treated with initial cognitive-behavioral therapy may benefit from the addition of an SSRI as a second treatment modality. The importance of timely evaluation of treatment results is emphasized.

An emotional Stroop task with four word types (panic threat, obsessive-compulsive threat, general threat, and neutral) and two presentation conditions (supraliminal, subliminal) was used in two experiments. The first experiment involved 21 panic disorder (PD) patients and 20 normal controls; the second experiment 20 PD patients and 20 obsessive-compulsive patients. PD patients, obsessive-compulsive patients, and normal controls did not differ in Stroop interferences. In addition, there were no significant correlations between reduction of PD symptoms and differences between pre- and post-treatment Stroop response latencies.

Hyperammonemia has been suggested to induce enhanced cerebral cortex ammonia uptake, subsequent glutamine synthesis and accumulation, and finally net glutamine release into the blood stream, but this has never been confirmed in liver insufficiency models. Therefore, cerebral cortex ammonia- and glutamine-related metabolism was studied during liver insufficiency-induced hyperammonemia by measuring plasma flow and venous-arterial concentration differences of ammonia and amino acids across the cerebral cortex (enabling estimation of net metabolite exchange), 1 day after portacaval shunting and 2, 4, and 6 h after hepatic artery ligation (or in controls). The intra-organ effects were investigated by measuring cerebral cortex tissue ammonia and amino acids 6 h after liver ischemia induction or in controls. Arterial ammonia and glutamine increased in portacaval-shunted rats versus controls, and further increased during liver ischemia. Cerebral cortex net ammonia uptake, observed in portacaval-shunted rats, increased progressively during liver ischemia, but net glutamine release was only observed after 6 h of liver ischemia. Cerebral cortex tissue glutamine, gamma-aminobutyric acid, most other amino acids, and ammonia levels were increased during liver ischemia. Glutamate was equally decreased in portacaval-shunted and liver-ischemia rats. The observed net cerebral cortex ammonia uptake, cerebral cortex tissue ammonia and glutamine accumulation, and finally glutamine release into the blood suggest that the rat cerebral cortex initially contributes to net ammonia removal from the blood during liver insufficiency-induced hyperammonemia by augmenting tissue glutamine and ammonia pools, and later by net glutamine release into the blood. The changes in cerebral cortex glutamate and gamma-aminobutyric acid could be related to altered ammonia metabolism.

In normal rats, muscle is the major glutamine releasing organ and gut is the major glutamine consuming organ. It has been suggested that enhanced muscle ammonia detoxification and gut ammonia production occurs during liver insufficiency-induced hyperammonemia. Therefore, ammonia and amino acid fluxes across portal-drained viscera and hindquarter, and muscle concentrations were measured in portacaval shunted and acute liver ischemia rats. Arterial ammonia and most amino acids were increased after portacaval shunting and increased progressively during liver ischemia, but net hindquarter ammonia uptake was not observed. Net hindquarter glutamine efflux was increased during portacaval shunting, but it decreased during liver ischemia, while muscle glutamine concentrations increased. The comparable net portal drained viscera glutamine uptake in normal and portacaval shunted rats changed during liver ischemia from net uptake to release, coinciding with release of most other amino acids. These results cast doubt on the ammonia detoxifying role of muscle during acute liver ischemia-induced hyperammonemia in the rat. The portal drained viscera glutamine release during severe hyperammonemia could be due to intestinal damage.

To study the influence of cigarette smoking on blood platelet function, bleeding time was measured in two groups of 14 habitual smokers before and after a 20-minute period during which the subjects either smoked two cigarettes (experimental group) or rested (control group). The second bleeding time appeared to be slightly shortened upon cigarette-smoking (-0.1 min) and was found to be prolonged in the control group (+0.4 min). These changes did not differ significantly from each other (P = 0.38). Consequently, bleeding time of habitual smokers is not affected by smoking two cigarettes.