Which patients should be considered for gene therapy.

Gene therapy for haemophilia, utilizing adeno-associated viral vectors (AAVs) and coagulation factor genes, have demonstrated promising results, leading to recent approvals and introduction of the first gene therapy products into clinical practice. For successful and safe use, there are predefined inclusion and exclusion criteria, and the treatment process and associated risks should be thoroughly understood and long-term safety and efficacy carefully evaluated during follow up. As gene therapy becomes more accessible outside of clinical study centers, continuous evaluation of patient eligibility for subsequent AAV-based treatments becomes essential. Thorough evaluation of factors such as liver condition, anti-AAV status, and medical history ensures that gene therapy maximizing benefits while minimizing risks. Apart from fulfilling the established inclusion and exclusion criteria, the success of gene therapy is greatly influenced by the motivation and willingness of patients to accept temporary constraints, such as regular laboratory monitoring, potential use of immunosuppressants, and thorough documentation. Furthermore, various patient-related factors play a significant role in the management and outcomes of gene therapy, making a comprehensive evaluation essential. With the accumulation of more data, there is potential for the expansion of certain inclusion criteria, which may allow for a larger number of eligible patients to benefit from gene therapy. Empowering patients through shared decision-making enables them to thoroughly consider the therapy's potential benefits and risks.

The American Association of Tissue Banks tissue donor screening for Mycobacterium tuberculosis-Recommended criteria and literature review.

After two multistate outbreaks of allograft tissue-transmitted tuberculosis (TB) due to viable bone, evidence-based donor screening criteria were developed to decrease the risk of transmission to recipients. Exclusionary criteria, commentary, and references supporting the criteria are provided, based on literature search and expert opinion. Both exposure and reactivation risk factors were considered, either for absolute exclusion or for exclusion in combination with multiple risk factors. A criteria subset was devised for tissues containing viable cells. Risk factors for consideration included exposure (e.g., geographic birth and residence, travel, homelessness, incarceration, healthcare, and workplace) and reactivation (e.g., kidney disease, liver disease, history of transplantation, immunosuppressive medications, and age). Additional donor considerations include the possibility of sepsis and chronic illness. Donor screening criteria represent minimal criteria for exclusion and do not completely exclude all possible donor TB risks. Additional measures to reduce transmission risk, such as donor and product testing, are discussed but not included in the recommendations. Careful donor evaluation is critical to tissue safety.

Eligibility for Substance Use Clinical Trials Among Emergency Psychiatry Patients: The Impact of Exclusion Criteria.

Objective: The first objective was to identify common exclusion criteria used in clinical trials. The second objective was to quantify the degree to which these criteria exclude emergency psychiatry patients. Methods: Qualitative Content Analysis was used for the first objective, identifying common exclusion criteria used in recent high-impact substance use clinical trials. A retrospective record review was used for the second objective, which examined the frequency of these exclusion criteria in a 1-month sample of adults receiving psychiatric evaluation in an emergency department. Results: Most trials had exclusions for co-occurring psychiatric problems (76.6%), medical problems (74.0%), prior or current treatment (72.7%), motivation for change (61.1%), pregnancy or lactation (57.1%), or using other specified substances of abuse (54.6%). In the clinical sample, exclusions for co-occurring psychiatric problems would make 94.7% of patients ineligible. Other exclusions had a combined effect of making 76% of patients ineligible. Conclusions: Clinical trials using typical exclusion criteria exclude nearly all emergency psychiatry patients with substance use problems.

Eligibility criteria in clinical trials in breast cancer: a cohort study.

BACKGROUND: Breast cancer (BC) is the most common cancer type in women. The purpose of this study was to assess the eligibility criteria in recent clinical trials in BC, especially those that can limit the enrollment of older patients as well as those with comorbidities and poor performance status. METHODS: Data on clinical trials in BC were extracted from ClinicalTrials.gov. Co-primary outcomes were proportions of trials with different types of the eligibility criteria. Associations between trial characteristics and the presence of certain types of these criteria (binary variable) were determined with univariate and multivariate logistic regression. RESULTS: Our analysis included 522 trials of systemic anticancer treatments started between 2020 and 2022. Upper age limits, strict exclusion criteria pertaining to comorbidities, and those referring to inadequate performance status of the patient were used in 204 (39%), 404 (77%), and 360 (69%) trials, respectively. Overall, 493 trials (94%) had at least one of these criteria. The odds of the presence of each type of the exclusion criteria were significantly associated with investigational site location and trial phase. We also showed that the odds of the upper age limits and the exclusion criteria involving the performance status were significantly higher in the cohort of recent trials compared with cohort of 309 trials started between 2010 and 2012 (39% vs 19% and 69% vs 46%, respectively; p < 0.001 for univariate and multivariate analysis in both comparisons). The proportion of trials with strict exclusion criteria was comparable between the two cohorts (p > 0.05). Only three of recent trials (1%) enrolled solely patients aged 65 or 70 and older. CONCLUSIONS: Many recent clinical trials in BC exclude large groups of patients, especially older adults, individuals with different comorbidities, and those with poor performance status. Careful modification of some of the eligibility criteria in these trials should be considered to allow investigators to assess the benefits and harms of investigational treatments in participants with characteristics typically encountered in clinical practice.

A Note on Cherry-Picking in Meta-Analyses.

We study selection bias in meta-analyses by assuming the presence of researchers (meta-analysts) who intentionally or unintentionally cherry-pick a subset of studies by defining arbitrary inclusion and/or exclusion criteria that will lead to their desired results. When the number of studies is sufficiently large, we theoretically show that a meta-analysts might falsely obtain (non)significant overall treatment effects, regardless of the actual effectiveness of a treatment. We analyze all theoretical findings based on extensive simulation experiments and practical clinical examples. Numerical evaluations demonstrate that the standard method for meta-analyses has the potential to be cherry-picked.

Exclusion criteria of breast cancer clinical trial protocols: a descriptive analysis.

PURPOSE: 3-8% of US adults with cancer are enrolled in a clinical trial due to various barriers to enrollment. The purpose of this study is to evaluate the variability of eligibility criteria, which currently have no standard guidelines. METHODS: This descriptive analysis utilized all therapeutic breast protocols offered at the University of Alabama at Birmingham between 2004 and 2020. Exclusion criteria were abstracted using OnCore and ClinicalTrials.gov. Laboratory values included liver function tests and hematologic labs. Comorbid conditions included congestive heart failure, cardiovascular disease, central nervous system (CNS) metastases, and prior cancer history. Comorbid conditions were further analyzed by amount of time protocols required participants to be from diagnosis or exacerbation-free. RESULTS: 102 protocols were eligible. Among liver laboratory values, bilirubin (78%) was included in most protocols ranging from institutional upper limit of normal (ULN) (9%) to 3xULN (2%), with 1.5xULN (56%) being most common. Similar variability was observed in alanine transaminase and aspartate transaminase. Among hematological labs, 82% of protocols defined a lower limit of acceptable absolute neutrophil count ranging from 500 µL (1%) to 1800 µL (1%), with 1500 µL (64%) being most common. Of the comorbid conditions, exclusion criteria varied for congestive heart failure (49%), an acute exacerbation of cardiovascular disease (80%), CNS metastases (59%), and a prior cancer (66%). The allowable timeframe varied between protocols for cardiovascular disease and prior cancer. CONCLUSION: Substantial heterogeneity was observed across laboratory values and comorbid variables among protocols. Future research should focus on defining standardized eligibility criteria while allowing for deviation based on drug specificity.

An updated systematic review on heart failure treatments for patients with renal impairment: the tide is not turning.

Advanced chronic kidney disease (CKD) frequently aggravates heart failure (HF). However, these patients have inherently been excluded from most HF trials. We aim to provide updated estimates of the representation of patients with advanced CKD and the provision of baseline renal function indices in HF trials with a focused interest on the landmark trials. Updated systematic review was performed from the inception of MEDLINE to 31 December 2019 to identify all chronic HF randomized trials published in the three major cardiology and medical journals, respectively, which included mortality endpoint. The included studies were analysed based on the representativeness of the advanced CKD population and the reporting of baseline renal function. A total of 187 eligible randomized trials with 322,374 participants were included in our analysis. One hundred and six trials (56.7%) had exclusion criteria related to renal function, which remained a continuing trend-55.1% (27/49) from inception-2000, 53.4% (39/73) from 2001-2010 and 61.5% (40/65) from 2011 (P = 0.64). The exclusion criteria, however, have become less restrictive. There was a temporal improvement in the likelihood of HF trials in providing baseline renal function indices (28.6% from inception-2000 versus 53.4% from 2001-2010 and 83.1% from 2011, P < 0.001). Concordant findings were observed in the landmark trials. Patients with advanced CKD remain underrepresented in HF trials in the contemporary era, even though the exclusion criteria have become less restrictive, and the quality of renal function monitoring has improved. The continued underrepresentation of patients with advanced CKD in HF trials merits measured broadening of eligibility in further trial studies.

Investigation of IgG4-positive cells in idiopathic multicentric Castleman disease and validation of the 2020 exclusion criteria for IgG4-related disease.

Patients with plasma cell type idiopathic multicentric Castleman disease (PC-iMCD) often show elevated serum IgG4 levels and IgG4-positive cell infiltration in tissues due to overproduction of interleukin-6, and may meet the diagnostic criteria for IgG4-related disease (IgG4-RD). Although PC-iMCD has been listed as a major exclusion disease for IgG4-RD, distinguishing between these diseases is challenging due to a lack of highly specific diagnostic biomarkers. In 2020, we proposed exclusion criteria of IgG4-RD mimickers. In this paper, we validated the accuracy of the criteria in excluding one of the mimickers, PC-iMCD, from IgG4-RD. Validation was performed on 57 PC-iMCD patients (39 presenting lymph node lesions and 19 with lung lesions) and 29 IgG4-RD patients (22 presenting lymph node lesions and seven with lung lesions). According to our results, 20.5% of the PC-iMCD patients with lymph node lesions and 42.1% of those with lung lesions met the diagnostic criteria for IgG4-RD. All these patients with PC-iMCD were excluded from a diagnosis of IgG4-RD by the proposed criteria. Additionally, 6.9% of IgG4-RD patients met the exclusion criteria. Thus, if the exclusion criteria are met, diagnosis should be made based on a combination of findings including organ distribution of disease, response to steroid therapy, and other pathological findings.

Frequency and characteristics of patient exclusion criteria in Canadian multidisciplinary pain treatment facilities: a cross-sectional study.

PURPOSE: A multidisciplinary approach is recommended for patients with complex chronic pain (CP). Many multidisciplinary pain treatment facilities (MTPFs) use patient exclusion criteria but little is known about their characteristics. The objective of this study was to describe the frequency and characteristics of exclusion criteria in public Canadian MTPFs. METHODS: We conducted a cross-sectional study in which we defined an MPTF as a clinic staffed with professionals from three disciplines or more (including at least one medical specialty) and whose services were integrated within the facility. We disseminated a web-based questionnaire in 2017-2018 to the administrative leads of MPTFs across the country. They were invited to complete the questionnaire about the characteristics of their facilities. Data were analyzed using descriptive statistics and correlation measures. RESULTS: A total of 87 MTPFs were included in the analyses. Half of them (52%) reported using three exclusion criteria or more. There was no significant association between the number of exclusion criteria and wait time for a first appointment or number of new consultations in the past year. Fibromyalgia and migraine were the most frequently excluded pain syndromes (10% and 7% of MPTFs, respectively). More than one MPTF out of four excluded patients with mental health disorders (30%) and/or substance use disorders (29%), including MPTFs with specialists in their staff. CONCLUSIONS: Multidisciplinary pain treatment facility exclusion criteria are most likely to affect CP patients living with complex pain issues and psychosocial vulnerabilities. Policy efforts are needed to support Canadian MPTFs in contributing to equitable access to pain management.

RéSUMé: OBJECTIF: Une approche multidisciplinaire est recommandée pour les patients souffrant de douleur chronique (DC) complexe. De nombreux centres multidisciplinaires de traitement de la douleur (CMTD) utilisent des critères d'exclusion des patients, mais on ne sait que peu de choses sur leurs caractéristiques. L'objectif de cette étude était de décrire la fréquence et les caractéristiques des critères d'exclusion dans les CMTD publics canadiens. MéTHODE: Nous avons mené une étude transversale dans laquelle nous avons défini un CMTD comme une clinique composée de professionnels de trois disciplines ou plus (y compris au moins une spécialité médicale) et dont les services étaient intégrés à l'établissement. En 2017-2018, nous avons fait parvenir un questionnaire en ligne aux responsables administratifs des CMTD partout au pays. Ils ont été invités à remplir le questionnaire sur les caractéristiques de leurs établissements. Les données ont été analysées à l'aide de statistiques descriptives et de mesures de corrélation. RéSULTATS: Au total, 87 CMTD ont été inclus dans les analyses. La moitié d'entre eux (52 %) ont déclaré utiliser trois critères d'exclusion ou plus. Il n'y avait pas d'association significative entre le nombre de critères d'exclusion et le temps d'attente pour un premier rendez-vous ou le nombre de nouvelles consultations au cours de la dernière année. La fibromyalgie et la migraine étaient les syndromes douloureux les plus fréquemment exclus (10 % et 7 % des CMTD, respectivement). Plus d'un CMTD sur quatre excluait les patients atteints de troubles de santé mentale (30 %) et/ou de troubles liés à l'utilisation de substances (29 %), y compris les CMTD comptant des spécialistes dans leur personnel. CONCLUSION: Les critères d'exclusion des centres multidisciplinaires de traitement de la douleur sont plus susceptibles d'affecter les patients atteints de douleur chronique vivant avec des problèmes de douleur complexes et des vulnérabilités psychosociales. Des efforts au niveau des politiques sont nécessaires pour aider les CMTD canadiens à favoriser un accès équitable à la prise en charge de la douleur.

Eligibility Criteria and Representativeness of Randomized Clinical Trials That Include Infants Born Extremely Premature: A Systematic Review.

OBJECTIVE: To assess the eligibility criteria and trial characteristics among contemporary (2010-2019) randomized clinical trials (RCTs) that included infants born extremely preterm (<28 weeks of gestation) and to evaluate whether eligibility criteria result in underrepresentation of high-risk subgroups (eg, infants born at <24 weeks of gestation). STUDY DESIGN: PubMed and Scopus were searched January 1, 2010, to December 31, 2019, with no language restrictions. RCTs with mean or median gestational ages at birth of <28 weeks of gestation were included. The study followed the PRISMA guidelines; outcomes were registered prospectively. Data extraction was performed independently by multiple observers. Study quality was evaluated using a modified Jadad scale. RESULTS: Among RCTs (n = 201), 32 552 infants were included. Study participant characteristics, interventions, and outcomes were highly variable. A total of 1603 eligibility criteria were identified; rationales were provided for 18.8% (n = 301) of criteria. Fifty-five RCTs (27.4%) included infants <24 weeks of gestation; 454 (1.4%) infants were identified as <24 weeks of gestation. CONCLUSIONS: The present study identifies sources of variability across RCTs that included infants born extremely preterm and reinforces the critical need for consistent and transparent policies governing eligibility criteria.

The Association of ICH Exclusion Criteria With Mortality and Disability Rates in ICH Patients Receiving 4F-PCC for Anticoagulation Reversal.

BACKGROUND: Intracranial hemorrhage (ICH) exclusion criteria in the landmark four-factor prothrombin complex concentrate (4F-PCC) trial have not been incorporated into clinical practice and incremental predictive ability is unknown. OBJECTIVES: Evaluate the association of meeting at least 1 ICH exclusion criterion with the composite end point in-hospital mortality and modified Rankin Scale [mRS] score 5 or 6. Determine the number and combination of criteria associated with poor outcomes. METHODS: Retrospective review of adult ICH patients who received 4F-PCC for anticoagulant reversal. Patient demographics, ICH exclusion criteria, in-hospital mortality, disability, and disposition were collected. χ2 Analysis and logistic regression were used to assess differences between patients with and without ICH exclusion criteria. RESULTS: Data from 167 patients were analyzed: 103 (61.7%) met at least 1 ICH exclusion criterion. The composite end point occurred more in those with at least 1 ICH exclusion criterion (74.8% vs 39%; P < 0.0001). Presence of 2 or more ICH exclusion criteria was associated with higher odds of the composite end point, higher mRS score, and long-term care facility disposition (P < 0.0001). Glasgow Coma Scale score <7 and at least 1 other ICH exclusion criterion had negative effects on composite end point and mortality: 95% to 100% and 85% to 100%, respectively. CONCLUSION AND RELEVANCE: Patients meeting at least 1 ICH exclusion criterion had greater death/disability compared with those who did not. More ICH exclusion criteria were associated with higher rates of death, disability, and worse disposition. These data may aid in developing optimal 4F-PCC use criteria.

Multiple-Imputation Variance Estimation in Studies With Missing or Misclassified Inclusion Criteria.

In observational studies using routinely collected data, a variable with a high level of missingness or misclassification may determine whether an observation is included in the analysis. In settings where inclusion criteria are assessed after imputation, the popular multiple-imputation variance estimator proposed by Rubin ("Rubin's rules" (RR)) is biased due to incompatibility between imputation and analysis models. While alternative approaches exist, most analysts are not familiar with them. Using partially validated data from a human immunodeficiency virus cohort, we illustrate the calculation of an imputation variance estimator proposed by Robins and Wang (RW) in a scenario where the study exclusion criteria are based on a variable that must be imputed. In this motivating example, the corresponding imputation variance estimate for the log odds was 29% smaller using the RW estimator than using the RR estimator. We further compared these 2 variance estimators with a simulation study which showed that coverage probabilities of 95% confidence intervals based on the RR estimator were too high and became worse as more observations were imputed and more subjects were excluded from the analysis. The RW imputation variance estimator performed much better and should be employed when there is incompatibility between imputation and analysis models. We provide analysis code to aid future analysts in implementing this method.

Effect of Reasons for Screen Failure on Subsequent Treatment Outcomes in Cancer Patients Assessed for Clinical Trials.

INTRODUCTION: The cancer research community increasingly question the rigidity of eligibility criteria in clinical trials. Common reasons for "screen failure" (RFSF) are well documented; however, their effect on subsequent standard therapy (SST) and outcomes is unclear. METHODS: This retrospective study evaluated patients aged ≥18 years with solid malignancy who were listed as ineligible on a screening log between February 2011 and March 2018. Patients screen-failed for biomarker results or incorrect cancer stage/prior treatment profile were excluded. Data were collected from electronic hospital records, including demographics, cancer history, RFSF, subsequent therapy, and outcomes. RESULTS: Overall, 217 patients were eligible. The most common histologies were lung (28%), melanoma, colon, and pancreatic (all 11%); 90% were metastatic. The most common RFSF were rapid disease progression (PD; 16%), performance status (PS) ≥2 (12%), and abnormal liver function tests (aLFT; 12%). After screen failure, 129/217 (59%) had SST; 9 were dose-reduced. Treatment-naïve or phase III trial-ineligible patients were more likely to receive SST than those pre-treated or phase I trial-ineligible (72/104 vs. 52/113, p = 0.0006; 71/109 vs. 15/42, p = 0.00013), respectively. RFSF stabilised/improved in 104/217 (48%); the main RFSF was co-morbidity (19/104). The most common RFSF to deteriorate were rapid PD (27/72), PS ≥2 (20/72), and aLFT with liver metastases (LM; 13/72). CONCLUSIONS: RFSF related to organ function rarely deteriorate unless directly involved with underlying malignancy. Most RFSF do not prevent patients from having SST, nor increase dose reductions, especially in treatment-naïve/phase III trial-ineligible patients. Those with RFSF of poor PS, rapid PD, and aLFT from LM are less suitable for SST. Careful broadening of trial eligibility is warranted.

Have Treatment Studies of Depression Become Even Less Generalizable? Applying the Inclusion and Exclusion Criteria in Placebo-Controlled Antidepressant Efficacy Trials Published over 20 Years to a Clinical Sample.

BACKGROUND: Antidepressants are amongst the most frequently prescribed medications. More than a decade ago, our clinical research group applied a prototypic set of inclusion/exclusion criteria used in an antidepressant efficacy trial (AET) to patients presenting for treatment in our outpatient practice and found that most patients would not qualify for the trial. In the present report from the Rhode Island Methods to Improve Diagnostic Assessment and Services (MIDAS) project, we apply the psychiatric inclusion/exclusion criteria used in 158 placebo-controlled studies to a large sample of depressed patients who presented for outpatient treatment to determine the range and extent of the representativeness of samples treated in AETs and whether this has changed over time. METHOD: We applied the inclusion and exclusion criteria used in 158 AETs to 1,271 patients presenting to an outpatient practice who received a principal diagnosis of major depressive disorder. The patients underwent a thorough diagnostic evaluation. RESULTS: Across all 158 studies, the percentage of patients that would have been excluded ranged from 44.4 to 99.8% (mean = 86.1%). The percentage of patients that would have been excluded was significantly higher in the studies published in 2010 through 2014 compared to the studies published from 1995 to 2009 (91.4 vs. 83.8%, t(156) = 3.74, p < 0.001). CONCLUSIONS: Only a minority of depressed patients seen in clinical practice are likely to be eligible for most AETs. The generalizability of AETs has decreased over time. It is unclear how generalizable the results of AETs are to patients treated in real-world clinical practice.

Intravenous thrombolysis for ischemic stroke in the Veneto region: the gap between eligibility and reality.

Intravenous thrombolysis (IVT) is the treatment of choice for most patients with acute ischemic stroke. According to the recently updated guidelines, IVT should be administered in absence of absolute exclusion criteria. We aimed to assess the proportion of ischemic strokes potentially eligible and actually treated with IVT, and to explore the reasons for not administering IVT. We prospectively collected and analyzed data from 1184 consecutive ischemic stroke patients admitted to the 22 Stroke Units (SUs) of the Veneto region from September 18th to December 10th 2017. Patients were treated with IVT according to the current Italian guidelines. For untreated patients, the reasons for not administering IVT were reported by each center in a predefined model including absolute and/or relative exclusion criteria and other possible reasons. Out of 841 (71%) patients who presented within 4.5 h of stroke onset, 704 (59%) had no other absolute exclusion criteria and were therefore potentially eligible for IVT according to the current guidelines. However, only 323 (27%) patients were eventually treated with IVT. Among 861 (73%) untreated patients, 480 had at least one absolute exclusion criterion, 283 only relative exclusion criteria, 56 only other reasons, and 42 a combination of relative exclusion criteria and other reasons. Our study showed that only 46% (323/704) of the potentially eligible patients were actually treated with IVT in the SUs of the Veneto region. All healthcare professionals involved in the acute stroke pathway should make an effort to bridge this gap between eligibility and reality.

Reasons for Exclusion from a Smoking Cessation Trial: An Analysis by Race/Ethnicity.

Objective: The exclusion criteria of tobacco cessation randomized clinical trials (RCTs) may have unintended consequences on inclusion and cessation disparities. We examined racial/ethnic differences in: a) exclusion from a group-based cessation RCT; and b) reasons for exclusion. Design: Quasi-experimental. Inclusion criteria were self-identification as African American/Black, non-Hispanic White, or Hispanic (any race), adults, minimum five cigarettes/day or carbon monoxide reading of ≥ 8 parts per million (ppm), interest in quitting, and spoke/read English. Data were obtained from a parent trial, which is ongoing and will be completed in 2019. Analyses for our present study on participant screening and enrollment were conducted in 2018. Main Outcome Measures: Study ineligibility, and reasons for exclusion (contraindications for nicotine patch use, serious mental illness [SMI, eg, bipolar disorder or schizophrenia], alcohol dependence or illicit drug use, current tobacco treatment, attendance barriers [eg, transportation], and other concerns [eg, aggressive, intoxicated, disruptive, visibly ill]). Results: Of 1,206 individuals screened, 36% were ineligible. The most frequent reasons were SMI (28%), alcohol dependence or drug use (10%), and attendance barriers (7%). Ineligibility was greater among African Americans (42%) and Hispanics (37%), compared with Whites (24%; P<.001). Compared with African Americans and Hispanics, Whites were more likely to be excluded for single reasons, including attendance barriers, and medical conditions (P<.05). African Americans were more than twice as likely as Whites to be excluded for 3 or more reasons (12% vs 5% respectively, P<.05). Conclusions: A notable proportion of smokers were ineligible for this RCT, with SMI as the greatest single cause. Racial/ethnic minorities were more likely to be excluded, with African Americans deemed ineligible for multiple reasons. Findings have implications for RCT generalizability, addressing tobacco disparities and health equity.

Open Spina Bifida: Why Not Fetal Surgery?

OBJECTIVE: The majority of patients counseled for prenatal open spina bifida repair (SBR) do not undergo fetal surgery. The aim of this study was to analyze the reasons for this phenomenon. MATERIALS AND METHODS: The data of the first 160 patients seeking counseling or referred to the Zurich Center for Fetal Diagnosis and Therapy for prenatal SBR between December 2010 and March 2017 were retrospectively analyzed. RESULTS: A total of 104 (65%) patients did not undergo prenatal SBR. Of this subgroup, 52% met the exclusion criteria, 35% decided to terminate pregnancy, 4% chose to continue pregnancy without fetal intervention, and 3% sought care in other European centers. In 6%, data about the ensuing course of pregnancy were not recorded. The main exclusion criteria were delayed presentation (30%), absence of hindbrain herniation (28%), and concomitant spinal anomalies (17%). CONCLUSION: The high percentage of patients not qualifying for prenatal SBR underscores the necessity of a standard evaluation of every single patient at a qualified referral center. To allow a higher proportion of women carrying a fetus with open spina bifida to be timely and correctly informed about a potential fetal intervention, much more effort is mandatory to spawn correct, objective, and understandable information among all groups of people potentially exposed to this topic.

Historical precedents for the DSM-III bereavement exclusion criteria for major depression.

BACKGROUND: I review the historical antecedents of the two key features of the bereavement exclusion (BE) for major depression (MD) criteria initially proposed in DSM-III: (i) a context-dependent approach to the evaluation of MD which required that the diagnosis be given only when course, symptoms and signs are 'out of proportion' to experienced adversities, and (ii) bereavement is the sole adversity for which this context-dependent approach should be utilized. METHODS: A review of 49 textbook and review articles on depression or melancholia published 1880-1960. RESULTS: Seventeen (35%) of the 49 texts advocated for a context-dependent approach to the diagnosis of MD. Most advocates relied on an intuitive clinical understanding of when the depressive features were v. were not commensurate with the experienced adversities. Several authors suggested that specific symptoms or course of illness could differentiate MD from 'normative' sadness. Others noted that patient reports of psychological causes of their depression should be treated skeptically. While death of loved ones was the most frequently noted specific adversity associated with MD, no author considered it qualitatively different from other stressors or suggested that it alone should be considered when diagnosing MD in a context-dependent manner. CONCLUSIONS: A key underlying assumption of the BE criteria - a context-dependent approach to the diagnosis of MD- was advocated by a significant minority of earlier psychiatric diagnosticians, although problems in its clinical implementation were sometimes noted. No historical precedent was found for the application of the context-dependent approach only to bereavement, as proposed in DSM-III.

Predictors of thrombolysis in the telestroke and non telestroke settings for hypertensive acute ischemic stroke patients.

BACKGROUND: In acute ischemic stroke patients, telestroke technology provides sustainable approaches to improve the use of thrombolysis therapy. How this is achieved as it relates to inclusion or exclusion of clinical risk factors for thrombolysis is not fully understood. We investigated this in a population of hypertensive stroke patients. METHODS: Structured data from a regional stroke registry that contained telestroke and non telestroke patients with a primary diagnosis of acute ischemic stroke with history of hypertension were collected between January 2014 and June 2016. Clinical risk factors associated with inclusion or exclusion for recombinant tissue plasminogen activator (rtPA) in the telestroke and non telestroke were identified using multiple regression analysis. Associations between variables and rtPA in the regression models were determined using variance inflation factors while the fitness of each model was determined using the ROC curve to predict the power of each logistic regression model. RESULTS: The non telestroke admitted more patients (62% vs 38%), when compared with the telestroke. Although the telestroke admitted fewer patients, it excluded 11% and administered thrombolysis therapy to 89% of stroke patients with hypertension. In the non telestroke group, adjusted odd ratios showed significant associations of NIH stroke scale score (OR = 1.059, 95% CI, 1.025-1.093, P < 0.001) and coronary artery disease (OR = 2.003, 95% CI, 1.16-3.457, P = 0.013) with inclusion, while increasing age (OR = 0.979, 95% CI, 0.961-0.996, P = 0.017), higher INR (OR = 0.146, 95% CI, 0.032-0.665, P = 0.013), history of previous stroke (OR = 0.39, 95% CI, 0.223-0.68, P = 0.001), and renal insufficiency (OR = 0.153, 95% CI, 0.046-0.508, P = 0.002) were associated with rtPA exclusion. In the telestroke, only direct admission to the telestroke was associated with rtPA administration, (OR = 4.083, 95% CI, 1.322-12.611, P = 0.014). CONCLUSION: The direct admission of hypertensive stroke patients to the telestroke network was the only factor associated with inclusion for thrombolysis therapy even after adjustment for baseline variables. The telestroke technology provides less restrictive criteria for clinical risk factors associated with the inclusion of hypertensive stroke patients for thrombolysis.

Inclusion and exclusion criteria used in non-specific low back pain trials: a review of randomised controlled trials published between 2006 and 2012.

BACKGROUND: Low back pain is a common health complaint resulting in substantial economic burden. Each year, upwards of 20 randomised controlled trials (RCTs) evaluating interventions for non-specific low back pain are published. Use of the term non-specific low back pain has been criticised on the grounds of encouraging heterogeneity and hampering interpretation of findings due to possible heterogeneous causes, challenging meta-analyses. We explored selection criteria used in trials of treatments for nsLBP. METHODS: A systematic review of English-language reports of RCTs in nsLBP population samples, published between 2006 and 2012, identified from MEDLINE, EMBASE, and the Cochrane Library databases, using a mixed-methods approach to analysis. Study inclusion and exclusion criteria were extracted, thematically categorised, and then descriptive statistics were used to summarise the prevalence by emerging category. RESULTS: We included 168 studies. Two inclusion themes (anatomical area, and symptoms and signs) were identified. Anatomical area was most reported as between costal margins and gluteal folds (n = 8, 5%), while low back pain (n = 150, 89%) with or without referred leg pain (n = 27, 16%) was the most reported symptom. Exclusion criteria comprised 21 themes. Previous or scheduled surgery (n = 84, 50%), pregnancy (n = 81, 48%), malignancy (n = 78, 46%), trauma (n = 63, 37%) and psychological conditions (n = 58, 34%) were the most common. Sub-themes of exclusion criteria mostly related to neurological signs and symptoms: nerve root compromise (n = 44, 26%), neurological signs (n = 34, 20%) or disc herniation (n = 30, 18%). Specific conditions that were most often exclusion criteria were spondylolisthesis (n = 35, 21%), spinal stenosis (n = 31, 18%) or osteoporosis (n = 27, 16%). CONCLUSION: RCTs of interventions for non-specific low back pain have incorporated diverse inclusion and exclusion criteria. Guidance on standardisation of inclusion and exclusion criteria for nsLBP trials will increase clinical homogeneity, facilitating greater interpretation of between-trial comparisons and meta-analyses. We propose a template for reporting inclusion and exclusion criteria.