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Objectives There is a paucity of research on the impact of cancer treatment on the health-related quality of life (HRQOL) of adolescent and young adult (AYA) patients with cancer. Patient-reported outcomes (PROs) are self-report measures used to assess HRQOL and symptom burden. The extent to which PROs have been included in trials that include common AYA cancer types has not been previously assessed. Methods Therapeutic phase 3 trials among common AYA cancer types (Hodgkin lymphoma, non-Hodgkin lymphoma, acute lymphoblastic leukemia, sarcomas, and germ cell tumors) initiated between 2007 and 2020 were identified on ClinicalTrials.gov . The proportions and characteristics of trials including a PRO endpoint were assessed. For comparison with an older population, the proportion of breast and colorectal therapeutic phase 3 trials including PRO endpoints were assessed. Results Eighty-seven studies met the inclusion criteria. Overall, 20.7% of therapeutic phase 3 AYA trials included a PRO endpoint, and only one trial published PRO data. Germ cell tumors (42.9%) and non-Hodgkin lymphoma (40%) trials had the highest proportions of PRO inclusion. The European Organization for Research and Treatment of Cancer generic, cancer-specific quality of life questionnaire was the most commonly used PRO measure; nevertheless, the measures used varied within and between cancer types. The proportion of trials including a PRO endpoint did not change significantly between 2007 to 2013 and 2014 to 2020 (18.6% vs 22.7%, P=.79). Conclusions Few therapeutic phase 3 AYA cancer trials include PRO endpoints, fewer publish PRO data, and there is no homogeneity in the measures administered. Therapeutic trials represent an underused opportunity to capture PRO data in the AYA population with the goal of improving HRQOL outcomes.

Sepsis is a common cause of acute respiratory distress syndrome (ARDS) associated with a high mortality. A panel of biomarkers (BMs) to identify septic patients at risk for developing ARDS, or at high risk of death, would be of interest for selecting patients for therapeutic trials, which could improve ARDS diagnosis and treatment, and survival chances in sepsis and ARDS. We measured nine protein BMs by ELISA in serum from 232 adult septic patients at diagnosis (152 required invasive mechanical ventilation and 72 had ARDS). A panel including the BMs RAGE, CXCL16 and Ang-2, plus PaO2/FiO2, was good in predicting ARDS (area under the curve = 0.88 in total septic patients). Best performing panels for ICU death are related to the presence of ARDS, need for invasive mechanical ventilation, and pulmonary/extrapulmonary origin of sepsis. In all cases, the use of BMs improved the prediction by clinical markers. Our study confirms the relevance of RAGE, Ang-2, IL-1RA and SP-D, and is novel supporting the inclusion of CXCL16, in BMs panels for predicting ARDS diagnosis and ARDS and sepsis outcome.

Background Since pediatric cancer drug development is a global enterprise, we sought to provide an overview of the landscape of intercontinental clinical trials in pediatric oncology opened over the last decade. Methods ClinicalTrials.gov was systematically searched to identify all clinical therapeutic trials which opened between 2010 and 2020 and recruited pediatric patients (, Intercontinental collaboration is alarmingly rare in childhood cancer trials, despite the rare disease setting and despite pediatric clinical research being inevitably a global enterprise. Barriers to collaboration should be identified and met with specific solutions to accelerate urgently needed drug development for children and adolescents with cancer.

Background Cognitive diseases with Lewy bodies occur in two forms: dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), which follows the progression of Parkinson's disease. There is currently no curative treatment for these cognitive diseases with Lewy bodies. Therapeutic trials in DLB are rare, due to the recent description of the disease as well as its first international diagnostic criteria (1996). Method This article proposes a synthesis of the therapeutic trials carried out in DLB in the last 5 years, including PDD patients with DLB patients, using the Clinicaltrials.gov and Pubmed.gov databases. Results We identified 35 therapeutic trials on Clinical Trials and 14 on PubMed. According to our temporal criteria, 21 trials were analyzed. Among the 11 completed trials with reported results, two molecules showed positive results: two trials with zonisamide (phase 2 and 3) showed a gain on parkinsonism and one trial with neflamapimod (phase 2) a gain on cognition and walking. Conclusion In recent years, there has been an increase in the therapeutic research effort in DLB, which is consistent with the prevalence of this disease - approximately 200,000 patients in France. Compared to other cognitive neurodegenerative diseases, therapeutic research is largely insufficient, whereas the proportion of positive trials is important. An effective disease modifying would have strong consequences for the patient and the relatives.

Graphical Abstract In 2006, the induced pluripotent stem cell (iPSC) was presented to the world, paving the way for the development of a magnitude of novel therapeutic alternatives, addressing a diverse range of diseases. However, despite the immense cell therapy potential, relatively few clinical trials evaluating iPSC-technology have actually translated into interventional, clinically applied treatment regimens. Herein, our aim was to determine trends in globally conducted clinical trials involving iPSCs. Data were derived both from well-known registries recording clinical trials from across the globe, and databases from individual countries. Comparisons were firstly drawn between observational and interventional studies before the latter was further analyzed in terms of therapeutic and nontherapeutic trials. Our main observations included global distribution, purpose, target size, and types of disorder relevant to evaluated trials. In terms of nontherapeutic trials, the USA conducted the majority, a large average number of participants—187—was included in the trials, and studies on circulatory system disorders comprised a slightly higher proportion of total studies. Conversely, Japan was the frontrunner in terms of conducting therapeutic trials, and the average number of participants was much lower, at roughly 29. Disorders of the circulatory, as well as nervous and visual systems, were all studied in equal measure. This review highlights the impact that iPSC-based cell therapies can have, should development thereof gain more traction. We lastly considered a few companies that are actively utilizing iPSCs in the development of therapies for various diseases, for whom the global trends in clinical trials could become increasingly important. Supplementary Information The online version contains supplementary material available at 10.1007/s12015-021-10262-3.

The therapeutic trial was conducted from December 2018 to May 2019 to compare the therapeutic efficacy of different drug regimens in the treatment of impactive and spasmodic colic in donkeys in Gondar, Northwest Ethiopia. Twenty-five purposively selected donkeys were used in this study. Ten of them were showing suspected clinical signs of impactive colic and the remaining ten were with spasmodic colic. The rest five donkeys were kept as control group. For this trial, each disease category was again grouped into two subgroups. The first sub-group in group A with suspected spasmodic colic was treated with ivermectin and, the second sub-group was treated with fenbendazole. Similarly, the first subgroup in group B with suspected impactive colic was treated with meloxicam and the remaining sub-group was treated with hyoscine butyl bromide. Most vital parameters were recorded before and after treatment of colicky donkeys. Feces and blood samples were collected and examined pre and post-treatment from each donkey. Donkeys treated with ivermectin subcutaneously have 97.3% fecal egg count reduction percentage, whereas donkeys treated with fenbendazole orally have fecal egg count reduction percentage of 79.85%. Donkeys treated with meloxicam, most of the clinical signs disappear within 24 hours of time after treatment. Subcutaneous administration of ivermectin was effective for the treatment of spasmodic colic due to Strongyle infestation in donkeys. Therefore, field veterinarians should practice subcutaneous administration of ivermectin and intramuscular administration of meloxicam for effective treatment of spasmodic and impactive colic in donkeys, respectively.

We presented the case of a 1-month-old girl with diffuse urticarial-like rash since birth. The initial evaluation showed elevated inflammatory markers. The response to treatment helped to narrow the diagnosis. In this case, we explored the differential diagnosis of rashes in this age group and the role of a therapeutic trial of medication as a diagnostic modality.

Background Comprehensive reporting of clinical trials is essential to allow the trial reader to evaluate the methodological rigor of the trial and interpret the results. Since publication of the updated Consolidated Standards of Reporting Trials (CONSORT) guidelines for reporting of parallel clinical trials in humans, extensions for reporting of abstracts and crossover trials have been published. Objectives To describe the types of trials using dogs and cats published from 2015 to 2020 and to evaluate the quality of reporting of a sample of recently published parallel and crossover trials. Animals None. Methods A comprehensive search was conducted to identify parallel or crossover design clinical trials using dogs and cats published from January 1, 2015 onwards. Quality of reporting was evaluated on a subset of trials published during 2019. The reporting of items recommended in the CONSORT reporting guidelines for abstracts, parallel trials, and crossover trials was evaluated independently by 2 reviewers using standardized forms created for this study. Disagreements among reviewers were resolved by consensus. Results were tabulated descriptively. Results The frequency of reporting of trial features varied from low to high. There remain deficiencies in the quality of reporting of key methodological features and information needed to evaluate and interpret trial results. Conclusions and Clinical Importance There is still a need for authors, peer‐reviewers, and editors to follow reporting guidelines such as CONSORT to maximize the value of clinical trials and to increase confidence in the validity of the trial results.

BACKGROUND Atopic dermatitis (AD) is a growing burden in all ages. The aim of this study was to compare trial characteristics between pediatric and adult AD trials. METHODS Data were collected from ClinicalTrials.gov on AD therapeutic trials completed between 2003 and 2019. The trials were classified as pediatrics (mean or median age

Purpose To compare the functional outcomes, knee stability, failure rate and complication rates of combined anterior cruciate ligament (ACL) and anterolateral ligament (ALL) reconstruction with hamstrings grafts between acute and chronic cases. Methods Consecutive patients who underwent combined ACL and ALL reconstruction with hamstrings grafts were evaluated. Patients operated on less than 8 weeks after injury were allocated to group 1, and the others were allocated to group 2. Demographic data, knee stability, and functional outcomes of the 2 groups were evaluated. Results Thirty-four patients in the acute group and 96 in the chronic group were evaluated. The follow-up time was similar between the groups (28.7 ± 5.2 [24-43] months vs 29.4 ± 7.2 [24-58] months; P = 0.696). No differences were found between the groups in age, sex, trauma mechanism, presence of knee hyperextension, graft diameter, and meniscal injuries. There was no difference between the groups in the postoperative KT-1000 and in the pre- or postoperative pivot shift. The preoperative KT-1000 was higher in group 2 (7.9 ± 1.1 vs 7.4 ± 1.2; P = 0.031). There were no differences in the International Knee Documentation Committee or Lysholm. Three (2.3%) patients developed failure, 1 (2.9%) in group 1 and 2 (2.1%) in group 2. The total complication rate was 10% and did not differ between the groups. Conclusions Combined ACL and ALL reconstruction has similar outcomes in patients undergoing surgery in the acute and chronic phases. Patients with chronic injury have similar knee stability, functional scores, and failure rates as acute-injury patients, and patients with acute injury have no more complications than chronic patients. Level of Evidence Level III, retrospective comparative therapeutic trial.

International audience; Background: The availability of effective treatments for psoriasis raises ethical questions about the use of a placebo group in therapeutic trials. We evaluated the use of the placebo over time in such trials.Methods: From trials in a living Cochrane review and network meta-analysis for psoriasis, we included trials comparing a biologic to a placebo or other systemic treatment. First, we tested the changes in placebo rate from 2001 to 2019 by linear regression, then constructed networks for 2004-2019 and evaluated the contribution of the placebo to the network meta-analysis estimates per trial and per comparison.Results: We included 81 trials (36,774 patients). The placebo rate did not decrease significantly over time. The proportion contribution of trials with a placebo decreased from 100% in 2004 to 86% in 2008 and 75% in 2019. However, the proportion contribution of trials without a placebo remained low (from 0% in 2004 to 25% in 2019).Conclusion: The design of future psoriasis trials should be reviewed to improve the number of patients to be included in a placebo group.

Highlights • Pulmonary exacerbation difference is an important clinical trial efficacy endpoint. • Regulators have stressed use of Fuchs criteria-based exacerbation definitions. • We compared criteria-based definitions to investigator assessments of 751 events. • Criteria-based definitions were insensitive, nonspecific, and prone to bias. • An alternative exacerbation definition is needed for future CF drug development., Background Cystic fibrosis (CF) pulmonary exacerbations can be serious respiratory events and reduction in exacerbation rate or risk are important efficacy endpoints for CF therapeutic trials. Variability in exacerbation diagnoses and treatment have led drug developers to employ “objective” exacerbation definitions combining antimicrobial treatment (AT) and the presence of ≥4 of 12 respiratory criteria (first published by Fuchs et al. [NEJM 1994;331(10):637–42]). Assumptions underlying this approach have yet to be formally evaluated. Methods Respiratory events (RE) observed during a 48-week trial of ataluren (NCT02139306), a read-through agent for premature nonsense codons, were compared across six exacerbation definitions: any AT, intravenous AT (IVAT), ≥4 Fuchs criteria present, AT plus ≥4 Fuchs criteria, IVAT plus ≥4 Fuchs criteria, and investigator assessment. Fuchs definitions were evaluated by assessing missingness of individual criteria and associations between criteria presence and clinician exacerbation assessment. Results Among 751 RE, more than one third had ≥4 Fuchs criteria present but were not assessed as exacerbations by investigators. Data for ≥1 and for 4 Fuchs criteria, respectively, were missing for ~ 90% and >30% of RE. Only 6/12 Fuchs criteria were present more often when investigators assessed RE as exacerbations than when they did not. Conclusions “Objective” definitions have shortcomings inconsistent with their purpose of optimizing exacerbation capture in clinical trials : 1) they capture events clinicians do not consider exacerbations, 2) are prone to data missingness which can bias the likelihood of meeting the definition, and 3) employ criteria that are not associated with investigator assessment of exacerbation.

Introduction: Perniosis (chilblain) is a highly common, prolonged cold induced skin disorder, a very common nuisance in general skin OPD of northern parts of India where winters are long and prolonged and temperatures dip to almost zero. Various treatment modalities have been tried for its treatment, on time and again but none of the treatments have given optimum fast results. We conducted a study on perniosis in peak winters at one of the tertiary care center of the western India. Aim and Objectives: To study and compare, the efficacy of oral nifedipine v/s topical 5% minoxidil Gel in perniosis. Method: The patients clinically fitting in to the diagnosis of perniosis were divided randomly in to two groups. Necessary clinical examination and investigations were carried out to find out any other associated ailment including pregnancy. Group A was given oral nifedipine 10 mg three times daily and Group B was given topical minoxidil 5% Gel applied twice daily, topically. Irrespective of the group, all the patients were given oral antihistaminics. Both clinical and subjective responses were noted on day 3, 7 and 14, respectively. Results: Out of 84 patients, 30 were males and 54 were females with male to female ratio of 1:1.8. The House wives were affected more among all female patients (51%). In group A and B, 42 cases were included in the study and they completed the follow up till 14th day. In group A, after second week of follow up, 25 cases noted good response, 10 cases explained it as very good and in 6 cases, satisfying response was seen which was statistically significant (p

X-linked retinoschisis (XLRS) is an inherited retinal condition that leads to schisis of the retina. In the past, treatment trials for XLRS have generally used OCT monitoring of the schitic cavities as the primary structural outcome measure and best corrected visual acuity as the primary functional outcome. Here, we report two cases of genetically confirmed XLRS with marked fluctuations in OCT morphology in the absence of treatment. Given this demonstration of spontaneous fluctuation in retinal structure on OCT in XLRS we suggest that alternative measures of retinal function should be used in future therapeutic trials in XLRS.

Introduction: Patients with cholestatic diseases may develop fatigue and cognitive symptoms. The impact of symptom burden may be significant in some patients. To date, there are no effective pharmacological therapies to improve cognitive symptoms or fatigue in cholestasis and we are wholly reliant on supportive approaches. Area covered: This review provides an overview of cognitive symptoms and fatigue in the cholestatic liver disease primary biliary cholangitis (PBC), including pathophysiology and our approach to the management of these symptoms. Expert opinion: The impact of fatigue and cognitive symptoms on the perceived quality of life can be profound for patients with PBC. The pathophysiology of these symptoms is complex and poorly understood, making the development of therapeutic trials of symptom-directed therapies challenging. The current recommended management for fatigue and cognitive symptoms is mainly supportive.

PURPOSE: Despite considerable research on the barriers to enrollment in cancer therapeutic trials, few studies have elicited barriers from the perspective of community physicians, who provide the majority of cancer care. The purpose of this study was to characterize barriers to and facilitators of cancer therapeutic trials as perceived by oncologists in community practices. METHODS: Twenty semistructured interviews were conducted with oncologists at six community sites affiliated with City of Hope National Medical Center from March to June 2018. Responses were recorded digitally and transcribed. Data were analyzed using qualitative content analysis. RESULTS: Of the 20 participants, 4 (20%) were women, 13 (65%) had > 10 years of practice experience, and 16 (80%) reported that < 5% of their patients were enrolled in a therapeutic trial. Participants identified four system-level barriers: lack of appropriate trials for community-based settings, insufficient infrastructure support, restrictive eligibility criteria, and financial limitations; three physician-level barriers: lack of awareness of available trials, lack of knowledge of trial details, and lack of time; and two patient-level barriers: patient burden and negative beliefs/attitudes toward research. Efforts aimed to increase trial availability, clinical trial support personnel, and physician knowledge were identified as major facilitators. CONCLUSION: Community oncologists face numerous complex, multifaceted barriers to cancer therapeutic trial enrollment. Although expanding clinical research beyond the academic setting allows access to a larger and more diverse patient population, increasing generalizability and relevance of trial findings, there remains a substantial need for new strategies to improve cancer research delivery in the community.

Cough is among the most common complaints for which patients worldwide seek medical attention. In a majority of patients with chronic cough (defined as cough of greater than 8 weeks' duration), successful management results from a thorough evaluation and treatment of underlying causes. In a subgroup of patients, however, cough proves refractory to therapeutic trials aimed at known reversible causes of chronic cough. Such patients are appropriately termed as having refractory chronic cough. At present, safe and effective medications are lacking for this challenging patient population. Currently available therapeutic options are usually ineffective or achieve antitussive effect at the expense of intolerable side effects, typically sedation. Fortunately, the past decade has witnessed great progress in elucidating underlying mechanisms of cough. From that knowledge, aided by the development of validated instruments to measure objective and subjective cough-related end points, numerous antitussive drug development programs have emerged. The most active area of inquiry at present involves antagonists of the purinergic P2X receptors. Indeed, four clinical programs (one in Phase 3 and three in Phase 2) are currently underway investigating antagonists of receptors comprised entirely or partially of the P2X3 subunit as potential antitussive medications. Herein we review the foundation on which P2X receptor antagonists were developed as potential antitussive medications and provide an update on current clinical trials.

Alopecia areata (AA) is lost hair from a few or all regions of the body, for the most part from the scalp. Etiology and pathogenesis of alopecia areata being not totally comprehended, is accepted to be multifactorial in ancestry. Recently, studies suggested an association between alopecia and types of viruses, therefore we concerned to investigate the association between CMV infection and alopecia areata. This study included of 100 individuals (50 alopecia patients and 50 healthy). Mean age of study groups were 20.90 ± 11.07 and 22.64±12.29 years of cases and control group respectively. Mean of age onset of patients were 20.83 ± 10.0. Out of 50 patients 52{df6391716bcab23f197eab8ba5a452daee5812a1941604c42f67c7803ea6be47} were male, the rest were female. However, 1:1 of control group was male: female. 40{df6391716bcab23f197eab8ba5a452daee5812a1941604c42f67c7803ea6be47} of patients had a positive family history for this disease. Alopecia areata affected on scalp in 78{df6391716bcab23f197eab8ba5a452daee5812a1941604c42f67c7803ea6be47} of cases. All patients had a high concentration of CMV IgM. With treatment of oral ganciclovire drug, a decrease of anti-CMV IgM levels and an increase of CMV IgG levels were observed.

A 33-year-old with a history of endometriosis presented with pain post-orgasm, accompanied by breakthrough bleeding, nausea, sweatiness, and exhaustion. History and examination suggested a gynaecologic component, likely related to the uterus itself. After several therapeutic trials, a clinical response was obtained with the use of a gonadotropin-releasing hormone antagonist, elagolix. The case is discussed with respect to dysorgasmia and post-orgasm illness syndrome. Post-orgasm pain in women has not been well studied, and it is recommended that such periorgasm phenomena be the topic of future research.

Introduction the aim of this study was to evaluate the correlation among dysphonic and vocal tract discomfort symptoms in patients who underwent empiric therapeutic trial with proton pump inhibitor (PPI) for a suspected laryngopharyngeal reflux (LPR). Materials and methods A total of 34 patients with suspected LPR were enrolled in this study. All of them were evaluated using the reflux finding score, the reflux symptom Index (RSI), the vocal tract discomfort scale (VTDS), and the voice symptom scale (VoiSS) before and after the PPI treatment. Results A significant difference was found between pretreatment and posttreatment reflux finding score, RSI, VTDS, and VoiSS scores. Significant correlations among RSI, VTDS, and VoiSS before the PPI treatment were found. Conclusion PPI treatment determined a significant improvement of symptoms related to dysphonia and vocal tract discomfort in patients with suspected LPR, in addition, significant correlations among the RSI, VTDS, and VoiSS scores were demonstrated thus suggesting that LPR might influence the response of questionnaires not specifically developed in order to assess the complains in LPR patient.

Qualitative and quantitative surveys show that many German general practitioners (GPs) use complementary and alternative medicine (CAM) in their daily work. However, participants in such studies were mostly experienced GPs.The aim of this study was to investigate systematically how young GPs view CAM and to what extent and how they use CAM treatments.Thirteen young physicians in specialist training for general practice as well as GPs who had completed their specialist training within the last 2 years participated in problem-oriented interviews. Interviews were evaluated by qualitative content analysis.The attitudes of participants towards CAM in general and towards specific CAM modalities varied strongly, but doubts regarding a firm evidence base and specific effects over placebo were expressed frequently. Nevertheless, participants were generally open to herbal medicines and all seemed to use them more or less regularly in clinical practice. Other CAM treatments seemed to be used infrequently. Participants used CAM often for minor illnesses; largely as a first low-intensity therapeutic trial to avoid potentially harmful conventional treatments; and to comply with patient preferences.Compared to more experienced GPs, the participants in our study tended to be more critical towards CAM. Apart from herbal medicines, CAM treatments were used rarely.Hintergrund: Quantitative und qualitative Studien haben gezeigt, dass viele deutsche Allgemeinmediziner*innen komplementär- und alternativmedizinischen Verfahren (KAV) in ihrer täglichen Arbeit verwenden. Diese Studien wurden jedoch primär mit erfahrenen Ärzt*innen durchgeführt. Ziel: Ziel der Studie war es zu untersuchen, wie junge Allgemeinmediziner*innen KAV einschätzen und in welchem Umfang und wie sie solche Verfahren einsetzen. Methoden: Dreizehn Ärzt*innen, die sich in Weiterbildung zum Facharzt für Allgemeinmedizin befanden oder diese maximal vor zwei Jahren abgeschlossen hatten, wurden in problemorientierten Interviews befragt. Die Interviews wurden inhaltsanalytisch qualitativ ausgewertet. Ergebnisse: Die Haltung der Teilnehmer*innen gegenüber KAV im Allgemeinen und gegenüber einzelnen Verfahren variierte stark, aber Zweifel an der Evidenzbasierung und an spezifischen Effekten über Placebo hinaus wurden häufig geäußert. Dennoch waren die Teilnehmer*innen durchgehend offen gegenüber pflanz­lichen Arzneimitteln und verwendeten diese mehr oder weniger regelmäßig in der ärztlichen Routine. Andere KAV schienen aktuell selten verwendet zu werden. Die Teilnehmer*innen setzen KAV häufig bei leichteren Erkrankungen ein, im Sinne eines ersten therapeutischen Versuchs, um nebenwirkungsreichere konventionelle Behandlungen zu vermeiden, und um den Wünschen ihrer Patienten entgegenzukommen. Schlussfolgerung: Im Vergleich zu erfahreneren Allgemeinmediziner*innen waren die Teilnehmer*innen in unserer Studie gegenüber KAV kritischer eingestellt. Abgesehen von pflanzlichen Arzneimitteln wurden KAV nur selten eingesetzt.

The Movement Disorder Society criteria for progressive supranuclear palsy introduced the category 'probable 4-repeat (4R)-tauopathy' for joint clinical diagnosis of progressive supranuclear palsy and corticobasal degeneration.To validate the accuracy of these clinical criteria for 'probable 4R-tauopathy' to predict underlying 4R-tauopathy pathology.Diagnostic accuracy for 4R-tauopathies according to the established criteria was estimated retrospectively in autopsy-confirmed patients with progressive supranuclear palsy and corticobasal degeneration (grouped as 4R-tauopathies), and Parkinson's disease, multiple system atrophy, and frontotemporal lobar degeneration (grouped as non-4R-tauopathies).We identified 250 cases with progressive supranuclear palsy (N = 195) and corticobasal degeneration (N = 55) and with and non-4R-tauopathies (N = 161). Sensitivity and specificity of 'probable 4R-tauopathy' was 10% and 99% in the first year and 59% and 88% at final record.The new diagnostic category 'probable 4R-tauopathy' showed high specificity and may be suitable for the recruitment of patients with progressive supranuclear palsy and corticobasal degeneration into therapeutic trials targeting 4R-tauopathy. The low sensitivity underpins the need for diagnostic biomarkers. © 2019 International Parkinson and Movement Disorder Society.

Children, although at lower risk of poor outcomes from COVID-19 relative to adults, still stand to benefit from therapeutic interventions. Understanding of COVID-19 clinical presentation and prognosis in children is essential to optimize therapeutic trials design. This perspective illustrates how to collectively accelerate pediatric COVID-19 therapeutic research and development, based on the experience of the Global Accelerator for Paediatric Formulations.

We sought to identify the total number of therapeutic trials targeting FLT3-mutant acute myeloid leukemia (AML) to estimate the number of patients needed to satisfy recruitment when compared with the incidence of this mutation in the US AML population. A systematic review of all therapeutic clinical trials focusing on adult FLT3-mutated AML was conducted from 2000 to 2017. An updated search was performed using ClinicalTrials.gov for trials added between October 2017 and December 2018. Analysis was performed for ClinicalTrials.gov search results from 2000 to 2017 to provide descriptive estimates of discrepancies between anticipated clinical trial enrollment using consistently cited rates of adult participation of 1%, 3%, and 5%, as well as 10% participation identified by the American Society of Clinical Oncology in 2008. Twenty-five pharmaceutical or biological agents aimed at treating FLT3-mutant AML were identified. Pharmaceutical vs cooperative group/nonprofit support was 2.3:1, with 30 different pharmaceutical collaborators and 13 cooperative group/nonprofit collaborators. The number of patients needed to satisfy study enrollment begins to surpass the upper bound of estimated participation in 2010, noticeably surpassing projected participation rates between 2015 and 2016. The number of patients needed to satisfy study enrollment surpasses 3% and 5% rates of historical participation for US-only trials in 2017. We estimate that 15% of all US patients with FLT3-mutant AML would have to enroll in US and internationally accruing trials to satisfy requirements in 2017, or approximately 3 times the upper level of historical participation rates in the United States. The current clinical trial agenda in this space requires high percentage enrollment for sustainability.

Background: Over the last 20 years, diverse outcome measures have been used to evaluate the effectiveness of therapies for eosinophilic esophagitis (EoE). This systematic review aims to identify the readouts used in observational studies of topical corticosteroids, diet, and dilation in adult EoE patients. Methods: We searched MEDLINE and Embase for prospective and retrospective studies (cohorts/case series, randomized open-label, and case-control) evaluating the use of diets, dilation, and topical corticosteroids in adults with EoE. Two authors independently assessed the articles and extracted information about histologic, endoscopic, and patient-reported outcomes and tools used to assess treatment effects. Results: We included 69 studies that met inclusion criteria. EoE-associated endoscopic findings (assessed either as absence/presence or using Endoscopic Reference Score) were evaluated in 24/35, 11/17, and 9/17 studies of topical corticosteroids, diet, and dilation, respectively. Esophageal eosinophil density was recorded in 32/35, 17/17, and 11/17 studies of topical corticosteroids, diet, and dilation, respectively. Patient-reported outcomes were not uniformly used (only in 14, 8, and 3 studies of topical corticosteroids, diet, and dilation, respectively), and most tools were not validated for use in adults with EoE. Conclusions: Despite the lack of an agreed set of core outcomes that should be recorded and reported in studies in adult EoE patients, endoscopic EoE-associated findings and esophageal eosinophil density are commonly used to assess disease activity in observational studies. Standardization of outcomes and data supporting the use of outcomes are needed to facilitate interpretation of evidence, its synthesis, and comparisons of interventions in meta-analyses of therapeutic trials in adults with EoE.

Memantine’s benefits in Alzheimer’s disease (AD) are modest and heterogeneous. We tested the feasibility of using sensitivity to acute memantine challenge to predict an individual’s clinical response. Eight participants completed a double-blind challenge study of memantine (placebo versus 20 mg) effects on autonomic, subjective, cognitive, and neurophysiological measures, followed by a 24-week unblinded active-dose therapeutic trial (10 mg bid). Study participation was well tolerated. Subgroups based on memantine sensitivity on specific laboratory measures differed in their clinical response to memantine, some by large effect sizes. It appears feasible to use biomarkers to predict clinical sensitivity to memantine.

Objective To explore willingness/hesitancy to vaccinate self and children against severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) among caregivers of childhood cancer survivors (CCS). Methods A 19‐question survey was sent to caregivers of CCS and completed between February 25 and April 13, 2021. Logistic regression was used to investigate relationships between willingness/hesitancy to vaccinate (a) self and (b) CCS, and demographic variables, confidence in the government and medical community's responses to coronavirus disease 2019 (COVID‐19), and factors specific to the CCS community (e.g., previous participation in an investigational therapeutic trial). Results Caregivers (6% male) from 130 unique families completed the survey. Mean CCS age at survey was 15 years (SD 6.4). Mean CCS age at diagnosis was 4.3 years (SD 4.3). Mean time from CCS diagnosis to survey completion was 10 years (SD 6.2). Twenty‐one percent of caregivers expressed hesitancy to vaccinate themselves and 29% expressed hesitancy to vaccinate their CCS. Caregivers expressing confidence in the federal government's response to COVID‐19 were six‐fold likelier to express willingness to self‐vaccinate (p

Background The Global Initiative for Asthma has only recently added tiotropium bromide as adjunct controller therapy in severe asthma (Step 4 or 5) in adults (2015) and children (2019). Although not yet approved for pediatric use by Health Canada, it has been occasionally offered by asthma specialists as a therapeutic trial in children with troublesome asthma or treatment for adverse effects. The objective of this study was to describe the indications and real-life clinical experience in initiating tiotropium in children with asthma. Methods We designed a retrospective mixed-method case series study of children aged 1–17 years who initiated tiotropium in our tertiary-care centre between 2013 and 2020. Clinical information was extracted from electronic medical records and tiotropium dispensing, from drug claims. Parents/children and physicians independently completed a questionnaire about treatment goals, perceived efficacy, safety, satisfaction, and lessons learned. Results The 34 (11 females; 23 males) children had a median (range) age of 9.1 (1.4–17.8) years. Children were primarily on Step 4 (85%) or 5 (6%) prior to tiotropium initiation, yet most (84%) did not increase their treatment step after tiotropium initiation. The physicians’ treatment goals were to improve asthma control, alleviate adverse effects of current therapy, and/or improve lung function. The most improved symptoms were coughing/moist cough, difficulty breathing, whistling breath, and bronchial secretions/mucus. Although most parents and physicians reported a significant benefit with tiotropium bromide, physicians particularly remarked, as their “lesson learned’, on the improvement in chronic symptoms in asthmatic children, particularly those with prominent moist cough and in lung function, in those with seemingly none (or incompletely) reversible obstruction as well as the ability to decrease the ICS and/or LABA dose to lessen adverse effects. A few physicians raised caution on the risk of lower adherence with an additional inhaler. Conclusion In children with severe asthma on Step 4 or 5, tiotropium bromide was primarily used as substitute, rather than additional, adjunct therapy to improve asthma control, alleviate adverse effects, and/or to improve lung function. The latter two indications, combined with its perceived effectiveness in children with prominent moist cough, also suggest additional indications of tiotropium to be formally explored.

Objectives The aim of this study was to assess and compare the diagnostic utility of a new diagnostic criteria for amyotrophic lateral sclerosis (ALS), abbreviated as the ‘Gold Coast Criteria’, with the revised El Escorial (rEEC) and Awaji criteria. Methods Clinical and electrophysiological data of 1185 patients from January 2014 to December 2019 in the Peking Union Medical College Hospital ALS database were reviewed. The sensitivity of the Gold Coast criteria was compared to that of the possible rEEC and Awaji criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS). Results A final diagnosis of ALS was recorded in 1162 patients. The sensitivity of the Gold Coast criteria (96.6%, 95% confidence interval [CI] = 95.3%–97.5%) was greater than that of the rEEC (85.1%, 95%CI = 82.9%–87.1%) and Awaji (85.3%, 95%CI = 83.2%–87.3%). In addition, the sensitivity of the novel criteria maintained robust across subgroups, and the advantage was more prominent in limb-onset ALS patients and those who completed electromyographic tests. In those who did not achieve any of the rEEC diagnostic categories, the sensitivity of Gold Coast criteria was 84.4%. Conclusions The current study demonstrated that the Gold Coast criteria exhibited greater diagnostic sensitivity than the rEEC and Awaji criteria in a Chinese ALS population. The application of the Gold Coast criteria should be considered in clinical practice and future therapeutic trials.

This case report details the efficacy of in-clinic customized scleral lens trial with self-preserved antibiotic eye drop in the liquid reservoir, in promoting fast healing of persistent corneal epithelial defect (PED). A 57-year-old man with a PED following injury, not responding to conventional treatment, underwent an in-clinic therapeutic trial of prosthetic replacement of ocular surface ecosystem device, to promote epithelial healing. After device wear with antibiotic eye drop in the liquid reservoir for 8 hrs during the day on five consecutive days and pressure patching at night with antibiotic eye ointment, there was complete resolution of the PED. Prosthetic replacement of ocular surface ecosystem scleral lenses are an effective treatment modality for PED. In-clinic daytime lens wear with night time pressure patching is a cost-effective option. Expert supervision avoids patient learning curve issues. Corneal re-epithelization happens because of the moisture and protection of the fragile healing epithelium afforded by these high DK lenses.

Treatment options for multidrug-resistant (MDR) gram-negative infection are growing. However, postregistration, pragmatic, and clinician-led clinical trials in this field are few, recruit small sample sizes, and experience deficiencies in design and operations. MDR gram-negative therapeutic trials are often inefficient, only evaluating a single antibiotic or strategy at a time. Novel clinical trial designs offer potential solutions by attempting to obtain clinically meaningful conclusions at the end or during a trial, for many treatment strategies, simultaneously. An integrated, consensus approach to MDR gram-negative infection trial design is crucial.

In therapeutic trials, the incidence of adverse muscle effects under statin is low, exceptional for some authors

International audience; Our objective was to identify a sensitive marker of disease progression in Friedreich’s ataxia. We prospectively evaluated speech, voice, and oromotor function in 40 patients at two timepoints. The mean disease duration was 20.8 ± 9.8 years and mean SARA score 23.7 ± 8.6 at baseline. Oral motor mobility, assessed by a combination of movements of the face, eyes, cheeks, lips, and tongue, decreased significantly after 1 year (P < 0.0001). The standardized response mean over 12 months was considered as large for oral mobility (1.26) but small for SARA (0.12). Oral mobility could therefore be a sensitive marker in therapeutic trials.

Sjogren's syndrome (SS) is a systemic orphan disease. It is characterized by the involvement of epithelial tissues leading to the term of autoimmune epithelitis. New classification criteria have been developed in 2016. New scores have also been developed: a patient-reported outcome called ESSPRI and a score assessing systemic activity of the disease called ESSDAI. These new tools are very helpful to better stratify patients and to customize the management of this very heterogeneous disease. Among the autoimmune diseases, SS is associated with the highest risk of lymphoma. Five to ten percent of the patients will have a B cell lymphoma mostly a low-grade lymphoma developing from mucosa-associated lymphoid tissue (MALT). Major advances have been made in this field: pathogeny is better understood, new predictors are available and progresses have been made in the management of this severe complication. Research in the field of SS is very dynamic as illustrated by the high number of therapeutic trials. There is hope that these innovations, reviewed in the present article, will have potential significant repercussions for the patients in the next few years.

Terminology used to define clinical cough is based on features such as duration, underlying causes and associated characteristics such as whether the cough is 'dry' or 'productive'. Terms such as 'Refractory Chronic Cough', 'Unexplained Chronic Cough' and 'Idiopathic Cough' are commonly used to describe a cough that persists despite extensive investigation and therapeutic trials. The use of these terms, sometimes interchangeably, has led to a degree of confusion and with the emergence of the new clinical and mechanisitic concept associated with cough, 'cough hypersensitivity syndrome', there is a need for some clarity in the nomenclature used to describe this condition.

ZusammenfassungDie primäre chologene Diarrhö (PCD) wurde bei ihrer Erstbeschreibung 1976 als sehr seltene Erkrankung angesehen, heute wird die Inzidenz auf > 1 % geschätzt. Das diagnostische Instrumentarium ist unterschiedlich verfügbar und es gibt in Deutschland keine einheitliche Empfehlung zur Diagnostik. Die PCD wird immer noch zu selten diagnostiziert.Seit Anfang der 90er Jahre haben wir die Probebehandlung mit Colestyramin und anschließende Bestätigung durch den Gallensäureresorptionstest (SeHCAT-Test) mit einer 7-Tage-Retention von 20 % als Schwellenwert zum Nachweis der chologenen Diarrhö (CD) in unser diagnostisches Vorgehen aufgenommen.Ausgewertet werden konnten 70 Patienten mit positiver Probebehandlung zwischen April 1991 und März 2017, von denen 60 mit SeHCAT-Test untersucht wurden. Nicht aufgenommen wurden Patienten mit CD Typ 1 oder Typ 3, ausgenommen Z. n. Cholezystektomie.85 % (35/41) der Patienten mit PCD blieben bei einer Nachbeobachtungszeit von median 8,3 (1 – 23,6) Jahren behandlungsbedürftig, davon nahmen 68,6 % (24/35) Colestyramin, 31,4 % (11/35) andere Antidiarrhoika. 14,6 % (6/41) berichteten eine Spontanremission nach median 2,9 (0,7 – 5,7) Jahren.In der Gruppe von Patienten mit CD nach Cholezystektomie waren 82 % (8/11) nach median 7,7 (1 – 24,5) Jahren weiter behandlungsbedürftig, 8 nahmen Colestyramin, ein Patient keine Medikamente, zwei Spontanremissionen.Alle acht Patienten mit normalem SeHCAT-Test (7-Tage-Retention > 20 %) wurden nach median 3,6 (1,2 – 6,3) Monaten wieder beschwerdefrei.Auch 70 % (7/10) der Patienten ohne Bestätigung durch den SeHCAT-Test waren nach median 4,3 (3,7 – 18,3) Jahren weiter behandlungsbedürftig.Mit der Probebehandlung allein steht die Diagnose einer CD auf schwachen Füßen. Sie ist aber ubiquitär verfügbar und sollte im diagnostischen Algorithmus der chronischen Diarrhö einen festen Platz haben, wenn andere Verfahren nicht zur Verfügung stehen. Durch den primären Einsatz des SeHCAT-Tests ist nach aktueller Literatur eine deutlich höhere diagnostische Ausbeute zu erwarten und eine Einsparung unnötiger Folgeuntersuchungen möglich. Die therapeutischen Konsequenzen sind wegen der bekannten Limitationen des Colestyramin jedoch begrenzt. Eine besser verträgliche und zugelassene Alternative für Colestyramin wird dringend benötigt.

Digital vascular complications are a major cause of disease-related morbidity in systemic sclerosis (SSc). Demonstrating treatment efficacy in the management of cutaneous vascular manifestations of SSc has been challenging. The contrasting findings of clinical trials of Raynaud’s phenomenon (RP) and digital ulcers (DU) for within-class medications have led to doubt on likely efficacy; with geographic variation in reimbursement policies and variation in clinical practice. In this paper, we compare the contrasting trials of phosphodiesterase inhibitors in the management of SSc-RP and endothelin receptor antagonists in the management of SSc-DU to help identify potential barriers for future successful clinical trials in these fields. Scrutiny of the contrasting clinical trials in these fields has identified a number of important differences in trial design and patient characteristics that may account for differences in clinical trial outcomes. These factors include differences in patient selection, impact of seasonal variation in weather, and the definitions applied to SSc manifestations. The contrasting findings of clinical trials of within-class medications for the management of digital vascular manifestations of SSc have been disappointing but can provide investigators with valuable insight into treatment response in SSc and the pre-requisites for future effective clinical trial design.

Diagnostic investigation and management of chronic diarrhoea in dogs can be cost‐prohibitive to many owners. The objectives of this study were to evaluate evidence‐based, individualised diagnostic and therapeutic protocols for management of dogs with chronic diarrhoea, where financial constraints dictate a budget‐limited approach and where more expensive approaches are deferred until simple affordable protocols are unsuccessful. Twenty‐two client‐owned dogs with chronic (minimum 2 weeks duration) untreated small, large or mixed small/large bowel diarrhoea were enrolled in a budget‐limited step‐wise management protocol (maximum expenditure $300 over 6 weeks), with diagnostic testing and therapeutic trials managed in an individualised and evidence‐based fashion. Success was defined as complete resolution of diarrhoea for a minimum of 1 month. Dogs that failed to respond to a budget‐limited protocol were then enrolled for complete, referral‐level management. Four dogs exited the project early (one death due to caval syndrome, three lost to follow‐up). Thirteen out of the remaining 18 dogs had complete resolution of diarrhoea utilising a budget‐limited approach (success rate 72.2%, confidence intervals 46.5–90.3%) and five dogs were moved on to a referral‐level investigation, with complete resolution of diarrhoea in four out of five. Seventeen out of the 18 dogs therefore responded to a protocol based on a budget‐limited approach followed by extensive investigation only if needed, for an overall success rate of 94.4% (CI 72.7–99.9%). Comprehensive investigation of chronic diarrhoea can be deferred while simple affordable diagnostics and therapeutic trials are conducted in stable canine patients and, often, an extensive management approach will be unnecessary.

The accumulation of pathological misfolded tau is a feature common to a collective of neurodegenerative disorders known as tauopathies, of which Alzheimer’s disease (AD) is the most common. Related tauopathies include progressive supranuclear palsy (PSP), corticobasal syndrome (CBS), Down’s syndrome (DS), Parkinson’s disease (PD), and dementia with Lewy bodies (DLB). Investigation of the role of tau pathology in the onset and progression of these disorders is now possible due the recent advent of tau-specific ligands for use with positron emission tomography (PET), including first- (e.g., [18F]THK5317, [18F]THK5351, [18F]AV1451, and [11C]PBB3) and second-generation compounds [namely [18F]MK-6240, [18F]RO-948 (previously referred to as [18F]RO69558948), [18F]PI-2620, [18F]GTP1, [18F]PM-PBB3, and [18F]JNJ64349311 ([18F]JNJ311) and its derivative [18F]JNJ-067)]. In this review we describe and discuss findings from in vitro and in vivo studies using both initial and new tau ligands, including their relation to biomarkers for amyloid-β and neurodegeneration, and cognitive findings. Lastly, methodological considerations for the quantification of in vivo ligand binding are addressed, along with potential future applications of tau PET, including therapeutic trials.

Most people who see, treat or experience migraine will be aware that its clinical manifestations exceed the symptom of head pain. However, available acute treatments so far have targeted migraine symptoms only in the context of the pain phase of an attack. The associated disability clearly involves more than just these symptoms, and the phenotype can include additional painless features, including alterations in mood, cognition and homeostasis and sensory sensitivities. Recognising these symptoms, understanding their neurobiological basis and systematically recording them prospectively in clinical therapeutic trials are likely to offer valuable pathophysiological and therapeutic insights into this complex brain disorder, ultimately helping to improve the quality of lives of sufferers. We aim to explore the multifaceted disorder that is migraine, with a particular focus on the non-painful non-aura symptoms.

International audience; ObjectivesIn March 2020, the World Health Organization declared the coronavirus disease 2019 (COVID-19) a pandemic. In absence of official recommendations, implementing daily multidisciplinary team (MDT) COVID-19 meetings was urgently needed. Our aim was to describe our initial institutional standard operating procedures for implementing these meetings, and their impact on daily practice.MethodsAll consecutive patients who were hospitalized in our institution due to COVID 19, from March 31 to April 15, 2020, were included. Criteria to be presented at MDT meetings were defined as a proven COVID-19 by PCR or strongly suspected on CT scan, requiring hospitalization and treatment not included in the standard of care. Three investigators identified the patients who met the predefined criteria and compared the treatment and outcomes of patients with predefined criteria that were presented during MDT meeting with those not presented during MDT meeting. COVID-19 MDT meeting implementation and adhesion were also assessed by a hospital medical staff survey.ResultsIn all, 318 patients with confirmed or suspected COVID-19 were examined in our hospital. Of these, 230 (87%) were hospitalized in a COVID-19 unit, 91 (40%) of whom met predefined MDT meeting criteria. Fifty (55%) patients were presented at a MDT meeting versus 41 (45%) were not. Complementary exploration and inclusion in the CorImmuno cohort were higher in MDT meeting group (respectively 35 vs. 15%, P = 0.03 and 80 versus 49%, P = 0.0007). Prescription of hydrocortisone hemisuccinate was higher in group of patients not presented during MDT meeting (24 vs. 51%, P = 0.007). Almost half of the patients fulfilling the inclusion criteria were not presented at MDT meeting, which can be partly explained by technical software issues.ConclusionsMultidisciplinary COVID-19 meetings helped implementing a single standard of care, avoided using treatments that were untested or currently being tested, and facilitated the inclusion of patients in prospective cohorts and therapeutic trials.

Background. Safe, more efficacious treatments are needed to address the considerable morbidity and mortality associated with tuberculosis (TB). However, the current practice in TB therapeutics trials is to use composite binary outcomes, which in the absence of standardization may inflate false positive and negative errors in evaluating regimens. The lack of standardization of outcomes is a barrier to the identification of highly efficacious regimens and the introduction of innovative methodologiesMethods. We conducted a systematic review of trials designed to advance new TB drugs or regimens for regulatory approval and inform practice guidelines. Trials were primarily identified from the WHO International Clinical Trial Registry Platform (ICTRP). Only trials that collected post-treatment follow-up data and enrolled at least 100 patients were included. Protocols and Statistical Analysis Plans (SAP) for eligible trials from 1995 to the present were obtained from trial investigators. Details of outcome data, both explicit and implied, were abstracted and organized into three broad categories: Favorable, Unfavorable, and Not Assessable. Within these categories, individual trial definitions were recorded and collated, and areas of broad consensus and disagreement were identified and described. Results. From 2205 TB-related trials, 51 were selected for protocol and SAP review, from which 31 were both eligible and had accessible documentation. Within the three designated categories, we found broad consensus in the definitions of Favorable and Unfavorable outcomes, although specific details were not always provided, and when explicitly addressed, were heterogeneous. Favorable outcomes were handled the most consistently but were widely variable with respect to specification. In some cases, the same events were defined differently by different protocols, particularly in distinguishing Unfavorable from Not Assessable events. Death was often interpreted conditional on cause. Patients who did not complete the study because of withdrawal or loss to follow-up presented a particular challenge to consistent interpretation and analytic treatment of outcomes.Conclusions. In a review of 31 clinical trials, we found that outcome definitions were heterogeneous, highlighting the need to establish clearer specification and a move towards universal standardization of outcomes across TB trials. The ICH E9 (R1) addendum provides guidelines for undertaking and achieving this goal.Registration PROSPERO 2020 CRD42020197993

Purpose of review To review current understanding of the prevalence, clinical features, outcome measures and recent therapeutic trials in axial psoriatic arthritis (axPsA). Recent findings The prevalence of axPsA is estimated at 40-50%. However, the definition of axPsA remains unclear, therefore these estimates may be inaccurate. Ax PsA appears to be distinct from ankylosing spondylitis in demographic, clinical, genetic and therapeutic features. Because of the lack of widely accepted definition of axPsA it has been difficult to design therapeutic trials for this domain of PsA. Several studies have demonstrated the uniquness of axPsA. Few recent trials suggest that therapies that work for peripheral arthritis also work for axPsA.

Objective The diagnosis of amyotrophic lateral sclerosis (ALS) remains problematic, with current diagnostic criteria (revised El Escorial [rEEC] and Awaji) being complex and prone to error. Consequently, the diagnostic utility of the recently proposed Gold Coast criteria was determined in ALS. Methods We retrospectively reviewed 506 patients (302 males, 204 females) to compare the diagnostic accuracy of the Gold Coast criteria to that of the Awaji and rEEC criteria (defined by the proportion of patients categorized as definite, probable, or possible ALS) in accordance with standards of reporting of diagnostic accuracy criteria. Results The sensitivity of Gold Coast criteria (92%, 95% confidence interval [CI] = 88.7-94.6%) was comparable to that of Awaji (90.3%, 95% CI = 86.69-93.2%) and rEEC (88.6, 95% CI = 84.8-91.7%) criteria. Additionally, the Gold Coast criteria sensitivity was maintained across different subgroups, defined by site of onset, disease duration, and functional disability. In atypical ALS phenotypes, the Gold Coast criteria exhibited greater sensitivity and specificity. Interpretation The present study established the diagnostic utility of the Gold Coast criteria in ALS, with benefits evident in bulbar and limb onset disease patients, as well as atypical phenotypes. The Gold Coast criteria should be considered in clinical practice and therapeutic trials. ANN NEUROL 2021;89:979-986.

Background: Primary progressive aphasias (PPA) have been investigated by clinical, therapeutic, and fundamental research but examiner-consistent language tests for reliable reproducible diagnosis and follow-up are lacking.Methods: We developed and evaluated a rapid language test for PPA (“PARIS”) assessing its inter-examiner consistency, its power to detect and classify PPA, and its capacity to identify language decline after a follow-up of 9 months. To explore the reliability and specificity/sensitivity of the test it was applied to PPA patients (N = 36), typical amnesic Alzheimer's disease (AD) patients (N = 24) and healthy controls (N = 35), while comparing it to two rapid examiner-consistent language tests used in stroke-induced aphasia (“LAST”, “ART”).Results: The application duration of the “PARIS” was ~10 min and its inter-rater consistency was of 88%. The three tests distinguished healthy controls from AD and PPA patients but only the “PARIS” reliably separated PPA from AD and allowed for classifying the two most frequent PPA variants: semantic and logopenic PPA. Compared to the “LAST” and “ART,” the “PARIS” also had the highest sensitivity for detecting language decline.Conclusions: The “PARIS” is an efficient, rapid, and highly examiner-consistent language test for the diagnosis, classification, and follow-up of frequent PPA variants. It might also be a valuable tool for providing end-points in future therapeutic trials on PPA and other neurodegenerative diseases affecting language processing.

Primary Sjögren’s syndrome (pSS) is a systemic autoimmune disorder characterized by very heterogeneous features. The spectrum of this disorder may vary from benign but disabling symptoms such as dryness, due to lachrymal and salivary involvement, pain and fatigue, to systemic, potentially severe, manifestations that may involve any organ. In recent decades, the arrival of biotechnological therapy has offered new opportunities for the treatment of this—until now—orphan disease. Currently, the possible use of these new drugs in therapeutic trials has made it necessary to have reliable outcome measures to evaluate their efficacy in this disease. A great effort has been made in multicenter, often multinational, studies to develop and validate instruments capable of assessing the different disease-related features. The adoption in therapeutic trials of the newly developed outcome measures aimed at assessing systemic features and patient reported symptoms has often yielded disappointing results. These negative data have been ascribed, on the one hand, to the trial design not being completely appropriate, and, on the other hand, to the fact that a single instrument may be not sufficient to cover the great clinical heterogeneity of the disease features. There is now growing belief that composite end points that include instruments that are able to assess the various aspects of the disease may be more properly and successfully used in future therapeutic trials.

Mild traumatic brain injury (mTBI) constitutes the majority of brain trauma cases. Despite its prevalence, detection in clinical imaging remains a challenge, as does the ability to predict duration and extent of disability. Advanced magnetic resonance imaging (MRI) methods combined with improved data analytic techniques have already demonstrated the potential to meet this challenge. This chapter reviews the recent progress in detection and outcome prediction in mTBI using the latest MRI techniques, including diffusion tensor imaging (DTI) and susceptibility-weighted imaging (SWI and SWIM), among others. Several recent published reports have found that DTI is sensitive to alterations in white matter ultrastructure not revealed by conventional MRI. More specifically, DTI reveals alterations in the ultrastructure of white matter axons caused by traumatic shear and stretch, which have been shown to correlate with clinical severity indicators and neuropsychological deficits. By virtue of its excellent sensitivity to iron and deoxygenated hemoglobin, SWI/SWIM has demonstrated exquisite detection of micro-hemorrhages and further quantification of hemorrhage and blood oxygenation. Used together, these advanced imaging techniques have the potential to serve as a set of surrogate biomarkers which can be used in determining prognosis and will likely have a major role in animal and human therapeutic trials, both to improve selection criteria of experimental subjects and to provide a number of new biomarkers for use in addition to conventional clinical and behavioral measures.