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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.

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.

This article examines an often neglected topic in the history of science, namely clinical observation, specifically the objectivity and knowledge production associated with therapeutic trials. It will describe an eighteenth and nineteenth century pharmacological concept of objectivity and exemplify that concept using late nineteenth century European cocaine research. As conceived within clinical drug research, this concept of objectivity does not correspond with those described by Daston and Galison in their seminal book Objectivity (2007). I will explore the implications of this “new” concept of objectivity—as compared to the “old” ones postulated by Daston and Galison—for their core propositions.

PURPOSE OF REVIEW: The treatment landscape for older patients with acute myeloid leukemia (AML) is evolving. Many treatments have comparable efficacy making their impact on quality of life (QoL) an important differentiating factor. In this review, we discuss QoL in older adults with AML, focusing on therapeutic and observational trials that have incorporated QoL assessments. FINDINGS: Health-related quality of life (HRQoL) is a multi-dimensional concept incorporating physical, mental, emotional, and social functioning domains. HRQoL components overlap with components of geriatric assessment, a multidisciplinary diagnostic process that identifies underlying vulnerabilities of older adults and guides subsequent management strategies. HRQoL questionnaires may be general, cancer-specific, leukemia-specific, or symptom-focused. Therapeutic and observational cohort studies suggest HRQoL improves, or at least remains stable, during intensive and lower intensity therapies. Nonetheless, HRQoL is not routinely incorporated in AML therapeutic trials. SUMMARY: HRQoL assessments can inform both decision-making and management for older adults with AML.

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.

Fluctuating cognition is a complex and disabling symptom that is seen most frequently in the context of Lewy body dementias encompassing dementia with Lewy bodies and Parkinson’s disease dementia. In fact, since their description over three decades ago, cognitive fluctuations have remained a core diagnostic feature of dementia with Lewy bodies, the second most common dementia in the elderly. In the absence of reliable biomarkers for Lewy body pathology, the inclusion of such patients in therapeutic trials depends on the accurate identification of such core clinical features. Yet despite their diagnostic relevance, cognitive fluctuations remain poorly understood, in part due to the lack of a cohesive clinical and scientific explanation of the phenomenon itself. Motivated by this challenge, the present review examines the history, clinical phenomenology and assessment of cognitive fluctuations in the Lewy body dementias. Based on these data, the key neuropsychological, neurophysiological and neuroimaging correlates of cognitive fluctuations are described and integrated into a novel testable heuristic framework from which new insights may be gained.

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

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.

Transient neurological deficits can occur in the setting of subdural hemorrhages with subsequent unremarkable electrodiagnostic and radiological evaluation. This scenario is rare and can be difficult for physicians to interpret. These transient neurological deficits are thought to result from relative ischemia, secondary to a lesser-known concept known as cortical spreading depolarization. These transient neurological deficits are thought to result from relative ischemia, secondary to a lesser-known concept known as cortical spreading depolarization, which may present clinically as nonepileptic, stereotypical, and intermittent symptoms (NESIS). In these instances, patients are often misdiagnosed as epileptics and committed to long-term antiseizure drugs. We present a 51-year-old patient developing acute global aphasia following the evacuation of a subdural hematoma, with no significant findings on laboratory, microbiological, electrodiagnostic, or radiological evaluation. The patient experienced spontaneous improvement and returned to baseline in the subsequent weeks. Increased awareness of NESIS as a cortical spreading depolarization phenomenon can improve patient care and prevent both unnecessary, extended medical evaluations and therapeutic trials.

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.

This study was conducted to make a contribution in the treatment of dermatosis, particularly moths. Ointments of different concentrations made from the hydroethanolic extract of Terminalia ivorensis and shea butter were used. The best results were obtained with the following concentrations: C4: 0.01 g/mL; C5: 0.0125 g/mL; C6: 0.015 g/mL and C10: 0.025 g/mL for trichophytic clipping moth on eleven (11) selected persons with ringworm and C9: 0.0225 g/mL for microsporic clipping moth on one (1) person. The present study really provides the scientific basis for the use of this plant in the traditional treatment of diseases and may help to discover new chemical classes of antifungal substances that could serve as selective agents for infectious disease chemotherapy.

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.

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.

Chylomicron retention disease (CMRD) is a rare disorder of lipid absorption, and its prevalence is

INTRODUCTION: Diagnostic and therapeutic strategies in eosinophilic esophagitis (EoE) are evolving. New knowledge regarding the pathophysiology of EoE has been the foundation for updated diagnostic recommendations and new therapeutic trials. AREAS COVERED: We performed structured literature searches in Medline and PubMed, Cochrane meta-analyses, and abstracts of international congresses to review therapeutic approaches for EoE in July 2018. Additional articles were obtained by perusing the references of articles identified in the original PubMed search. Articles were excluded if they did not focus on the mechanism of disease, diagnosis, or treatment of humans with eosinophilic esophagitis. EXPERT COMMENTARY: Recent advances in the understanding of mechanisms underlying the pathology of eosinophilic esophagitis (EoE) have resulted in significant change in the diagnostic algorithm for EoE, and are identifying promising potential targets for personalized medicine. There is clinical need for improved targeted therapy for EoE, and better understanding the underlying pathophysiology of EoE will help to determine therapeutic targets. In this review, we highlight key mechanisms in the pathophysiology of EoE and how they are being utilized to change therapy in EoE.

Skin conditions may have a major impact on the psychologic well-being of patients, ranging from depression to anxiety. The Dermatology Life Quality Index (DLQI) is the most commonly used quality of life tool in dermatology, though it has yet to be correlated with psychiatric measures used in clinical therapeutic trials. We conducted a systematic review to determine whether there is any correlation between the DLQI and psychiatric measure scores, potentially allowing the DLQI to be used as a surrogate measure for depression or psychiatric screening. Six databases were searched using the following keywords: “DLQI,” “Dermatology Life Quality Index,” “Psych*,” “depression,” “anxiety,” “stress,” and “trial*.” All randomized trials where full DLQI and psychiatric scores were provided were included. PRISMA guidelines were followed. In all, 462 records were screened, but only seven met inclusion criteria. Hospital Anxiety and Depression Scale (HADS) was the most commonly used psychiatric measure; the “depression” component score changes correlated strongly with the DLQI (r = 0.715). There needs to be guidance on psychiatric measurement and reporting in clinical trials. Although the DLQI correlated well with the “depression” domain of the HADS scale, interviews and screening for depression are still vital for full assessment of patient psychologic well-being.

Glioblastoma is the most frequent primary brain tumor, with more than half of all patients being at least 65 years old. The treatment of the elderly in this pathology represents therefore a considerable challenge for oncologists and radiation therapists. However, in most clinical trials, age is a non-eligible criterial. In the last ten years, geriatric therapeutic trials have been multiplied. The treatment of glioblastoma consists of adjuvant chemoradiotherapy. In elderly patients, the evaluation of performans status and the molecular characteristics of the tumor are important factors in order to propose the appropriate treatment in terms of efficacy and toxicity.

Community-acquired pneumonia (CAP) is a common infectious disease and one of the main causes of mortality worldwide. Despite an improvement in management globally, mortality remains high especially in severe forms of CAP. Adequate early antibiotics remain the cornerstone of the treatment but adjuvant corticosteroid administration is being considered to counterbalance the systemic inflammatory reaction and modulate the immune response. In the last ten years, several clinical trials and meta-analyses have been conducted in severe and non-severe CAP to assess the efficacy of corticosteroids. The benefits on the duration of hospitalization and the time to clinical stability are quite small and early mortality does not seem to be improved. Corticosteroids should not, therefore, be used routinely in patients with CAP, even in severe cases. However, new therapeutic trials are currently underway.

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.

Chronic cough is a common clinical issue, but has been a neglected area in many ways regarding research and basic guidelines for the health-care system. Patients with chronic cough, often by chance, meet physicians more or less acquainted with the problem. Initial diagnostic approach includes history taking, physical examination, and routine diagnostic tests, which may help to identify clinical traits associated with chronic cough. However, the clinical picture is frequently complex or unclear, and it is challenging to decide whether, or when, to go further with advanced clinical setups and examinations. This is more problematic in cases where no treatable traits are found in routine basic evaluations. Meanwhile, various medications are available aiming to improve coughing by targeting different organ systems associated with cough, such as the upper or lower airways, the gastrointestinal tract, and the central nervous system. The choice of medication should be ideally based on clinical findings. However, in patients without apparent treatable traits, sequential empirical trials are considered, but physicians should evaluate positive and negative effects of such treatments and decide when to stop them and consider alternative therapy. The aim of this book chapter is to provide an overview of diagnostic and therapeutic trials for adult patients with chronic cough. The recommendations are mostly based on the recently published European Respiratory Society cough guidelines.

The randomized controlled trial is a relatively new method for assessing the efficacy of an intervention in the field of urology. Randomized controlled trials address inherent biases through allocation of concealment but are still subject to important biases and limitations. Non-muscle-invasive bladder cancer trials include both adjuvant and non-adjuvant therapeutic trials which have unique outcomes and methodology. Here, we review important biases, endpoints, and aspects of clinical trial design in non-muscle-invasive bladder cancer as well as explore the underpinnings of pivotal trials that changed management for this disease.

Our understanding of fatty liver syndromes and their relationship with the metabolic syndrome has improved over recent decades and, paralleling this, we are now at the dawn of the NAFLD (nonalcoholic fatty liver disease) to MAFLD (metabolic-associated fatty liver disease) transition. The pitfalls of NAFLD diagnosis, together with disappointing results in therapeutic trials, and the inconsistencies and risks inherent in a “negative” definition (such as “nonalcoholic”) as opposed to a “positive” one (i.e., “metabolic”) are predicted to facilitate the proposed renaming of NAFLD to MAFLD. However, a premature change of terminology would not necessarily address major unmet needs in this area, and may even become counterproductive. As an aid to selecting more homogeneous cohorts of patients, I propose the LDE (Liver, Determinants, Extra-hepatic) classification system which, in principle, may help to assess the natural course of disease as well as the efficacy of novel drugs in patients with NAFLD/MAFLD.