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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.

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.

COVID‐19 continues to dominate the health‐care burden in the twenty‐first century. While health‐care professionals around the world try their best to minimize the mortality from this pandemic, we also continue to battle the high mortality from different types of cancer. For the hemostasis and thrombosis specialist, these two conditions present some unusual similarities including the high rate of thrombosis and marked elevation of D‐dimers. In this forum article, we discuss these similarities and provide some considerations for future research and therapeutic trials.

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.

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.

Brachiaria decumbens (signal grass) is a highly productive tropical grass that is widespread in some tropical countries due to its adaptation to a wide range of environments and soil types. However, a limiting factor for the use of this grass is its toxicity from steroidal saponins. Sporadic outbreaks of hepatogenous photosensitization in ruminants grazing on this grass have been reported. Sheep are more susceptible than other animal species and the young are more susceptible than adults. This review article will critically shed light on the B. decumbens profile, its toxic compounds, mechanisms, clinical responses, blood profile alterations, pathological changes, and acute phase responses related to signal grass intoxication. Further research is needed to integrate new findings on B. decumbens intoxication with previous preventive and therapeutic trials to minimize or remove its deleterious toxic effect.

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

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.

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.

Plasma amino-terminal pro-B-type natriuretic peptide (NT-proBNP) is a guideline-mandated biomarker in heart failure (HF). Used as an inclusion criterion for therapeutic trials, NT-proBNP enriches trial populations and is a valid surrogate endpoint. Its diagnostic performance is best validated in acute decompensated HF (ADHF). NT-proBNP offers prognostic information independent of standard clinical predictors and refines risk stratification. With the advent of combined angiotensin 2 type 1 receptor blockade and neprilysin inhibition (ARNI) NT-proBNP retains its relationship to cardiac status and is the marker of choice in assessment of possible ADHF and in serial monitoring of HF patients receiving ARNI treatment.

For children who stutter (CWS), there is good evidence of the benefits of treatment for pre-school age, but an evidence gap for elementary school age. Here we report on the effectiveness of a fluency shaping treatment for 6- to 9-year-old children. The main treatment component is the reinforcement of soft voice onsets. An intensive in-patient group treatment phase lasts 6 days, followed by a 6-month maintenance phase with 3 in-patient weekend group refresher courses. Child and a parent participate together in various treatment activities. In this controlled intervention study (waitlist control, intention-to-treat design) assessments were performed before treatment (T1), 4 weeks after the intensive phase (T2), at the end of the maintenance phase (T3), and 1 year later (T4). Participants were 119 children (108 boys, 11 girls, age 5.5‑10.4 years). Control conditions included a subgroup with delayed treatment (N=25) as well as the assessment of complexity of utterances, inter-rater reliability, and speech naturalness. From before treatment to 1-year follow-up, percent stuttered syllables and OASES-S (Overall Assessment of the Speaker's Experience with Stuttering - School-age) scores decreased with large effect size. Speech naturalness improved during this period but did not reach the level of non-stuttering children. Complexity of utterances increased during the intensive phase, but only temporarily. Twenty children (16.8 %, including dropouts) showed no demonstrable treatment benefit. Fluency shaping treatment can be effectively applied to young school children. It is assumed that parental support, group therapy, intensive treatment, and regular exercises at home are essential.

We present a rare case of Coombs-negative autoimmune haemolytic anaemia in a multiparous woman in secondary care. There were no known underlying medical or obstetric risk factors for haemolytic anaemia. Following extensive investigation and a therapeutic trial of oral corticosteroids, a diagnosis was made. Autoimmune haemolytic anaemia is potentially fatal, and prompt diagnosis with haematology input is essential to ensure maternal and fetal safety in pregnancy and the puerperium. With only a small number of cases of Coombs-negative autoimmune haemolytic anaemia reported in the literature, we present this rare case for discussion. We highlight the importance of thorough investigation of refractory anaemia in pregnancy and consider the associated challenges., Highlights • Anaemia is pregnancy is common. • Refractory anaemia should be thoroughly investigated, it can be associated with increased maternal morbidity and mortality. • Coombs negative anaemia in pregnancy is rare • We report a case report of Coombs negative anaemia in pregnancy, with no significant underlying medical or family history.

Background: Molluscum contagiosum is a common self-limiting viral infection of the skin. Many therapeutic agents have been used with varying success rates. Objective: To evaluate and compare the effectiveness of topical 10% KOH solution and 25% podophyllin solution as home-based treatments of molluscum contagiosum. Patients and methods: This open randomized comparative therapeutic trial was conducted in the department of dermatology, Al-Yarmouk Teaching Hospital, Baghdad, Iraq between January and October 2015. The patients were divided randomly into two equal groups. Group A patients were treated with 10% KOH solution and those in group B with 25% podophyllin solution. All patients were assessed weekly for 4 weeks for therapeutic response. Results: Fifty-two patients (age: 2–34 years) with MC were enrolled in this study, 25 patients in group A and 20 patients in group B completed the study. Sixteen (64%) patients in group A showed complete clearance of lesions versus 14 (70%) patients in group B. No systemic side effects were reported in both groups and the local side effects were comparable between both groups. Conclusion: Both 10% KOH solution and 25% podophyllin solution are effective local therapies for the treatment of MC with comparable success rates (64% and 70% respectively).

Rationale and Objectives Accuracy of radiologic assessment may have a crucial impact on clinical studies and therapeutic decisions. We compared the variability of a central radiologic assessment (RECIST) and computer-aided volume-based assessment of lung lesions in patients with metastatic renal cell carcinoma (RCC). Materials and Methods The investigation was prospectively planned as a substudy of a clinical randomized phase IIB therapeutic trial in patients with RCC. Starting with the manual study diameter (SDM) of the central readers using RECIST in the clinical study, we performed computer-aided volume measurements. We compared SDM to an automated RECIST diameter (aRDM) and the diameter of a volume-equivalent sphere (effective diameter [EDM]), both for the individual size measurements and for the change rate (CR) between consecutive time points. One hundred thirty diameter pairs of 30 lung lesions from 14 patients were evaluable, forming 55 change pairs over two consecutive time points each. Results The SDMs of two different readers showed a correlation of 95.6%, whereas the EDMs exhibited an excellent correlation of 99.4%. Evaluation of CRs showed an SDM-CR correlation of 63.9%, which is substantially weaker than the EDM-CR correlation of 87.6%. The variability of SDM-CR is characterized by a median absolute difference of 11.4% points versus the significantly lower 1.8% points EDM-CRs variability (aRDM: 3.2% points). The limits of agreement between readers suggest that an EDM change of 10% or 1 mm can already be significant. Conclusions Computer-aided volume-based assessments result in markedly reduced variability of parameters describing size and change, which may offer an advantage of earlier response evaluations and treatment decisions for patients.

Objectives To review the controversial issues of the Testosterone Deficiency Syndrome (TDS) with an emphasis on the concerns about the diagnosis. Design and methods The relevant literature was reviewed with particular attention to matters related to the clinical manifestations of the syndrome, the need for biochemical assessment and questions of biological and analytical variation that have to be taken into account. Therapeutic options were also appraised. Results There are numerous difficulties with the clinical diagnosis of TDS due to the lack of specificity and subtlety of the manifestations when the degree of deficiency is not severe. Confirmation of the clinical impression requires laboratory evaluation but the choice of assays remains an unsettled issue although there is a general consensus that both free testosterone and bioavailable testosterone best reflect the degree of androgenicity. The laboratory diagnosis enjoys a great deal of credibility among clinicians but shortcomings in the interpretation of the assays need to be reiterated and the need for close collaboration between the clinician and the clinical biochemist is important for diagnostic accuracy. Even when the clinical picture is convincing, the laboratory may produce inconclusive results. The option of a therapeutic trial should be contemplated in this situation. Treatment options should be decided between the physician and the patient considering issues of availability, tolerance, efficacy and cost. Conclusions TDS is a prevalent condition but a matter of persistent controversy due to the vagaries of the clinical and laboratory diagnosis. Symptomatic men with documented T deficiency deserve treatment to improve their quality of life.

Alzheimer's disease (AD) is a slowly progressing disorder in which pathophysiological abnormalities, detectable in vivo by biomarkers, precede overt clinical symptoms by many years to decades. Five AD biomarkers are sufficiently validated to have been incorporated into clinical diagnostic criteria and commonly used in therapeutic trials. Current AD biomarkers fall into two categories: biomarkers of amyloid-β plaques and of tau-related neurodegeneration. Three of the five are imaging measures and two are cerebrospinal fluid analytes. AD biomarkers do not evolve in an identical manner but rather in a sequential but temporally overlapping manner. Models of the temporal evolution of AD biomarkers can take the form of plots of biomarker severity (degree of abnormality) versus time. In this Review, we discuss several time-dependent models of AD that take into consideration varying age of onset (early versus late) and the influence of aging and co-occurring brain pathologies that commonly arise in the elderly.

BIBLIOGRAPHY Ando K, Hattori H, Yamauchi Y. Histopathological differences between early and old lesions of hyperkeratosis Lenticularis Perstans (Flegel’s disease). Am J Dermatopathol 2006;28:122-6. Bean SF. The genetics of hyperkeratosis lenticularis perstans. Arch Dermatol 1972;106:72. Flegel H. Hyperkeratosis lenticularis perstans. Hautarzt 1958;9: 363-4. Jang KA, Choi JH, Sung KJ, Moon KC, Koh JK. Hyperkeratosis lenticularis perstans (Flegel’s disease): histologic, immunohistochemical, and ultrastructural features in a case. Am J Dermatopathol 1999;21:395-8. Langer K, Zonzits E, Konrad K. Hyperkeratosis lenticularis perstans (Flegel’s disease). Ultrastructural study of lesional and perilesional skin and therapeutic trial of topical tretinoin versus 5-fluorouracil. J Am Acad Dermatol 1992;27(5 pt 2):812-6. Pearson LH, Smith JG Jr, Chalker DK. Hyperkeratosis lenticularis perstans (Flegel’s disease). Case report and literature review. J Am Acad Dermatol 1987;16(1 pt 2):190-5. Price ML, Wilson JE, MacDonald DM. A clinicopathological study of Flegel’s disease (hyperkeratosis lenticularis perstans). Br J Dermatol 1987;116:681-91. Cunha Filh o R, Almeida HL Jr. Hyperkeratosis lenticularis perstans. An Bras Dermatol 2011;86(4 suppl 1):S76-7. Sterneberg-Vos H, van Marion AM, Frank J, Poblete-Gutierrez P. Hyperkeratosis lenticularis perstans (Flegel’s disease) successful treatment with topical corticosteroids. Int J Dermatol 2008;47(suppl 1):38-41.

Background Clinical trials of seasonal allergic rhinoconjunctivitis use the mountain cedar ( Juniperus ashei ) season as the predominate model. Objective To evaluate clinical trials of rhinoconjunctivitis using mountain cedar, to present analysis of pollen counts during 18 seasons, and to discuss the model. Methods The medical literature was searched for clinical trials performed using mountain cedar either in or out of season. Pollen counts were recorded and analyzed for the duration of 18 seasons. Results Thirty-eight trials were identified. Of these, 1 evaluated onset of allergy, 8 were immunotherapy trials, 28 were pharmaceutical clinical trials, and 1 studied symptoms elicited in a pollen challenge chamber trial. Many generic equivalency trials are unreported. In the 18 years of counts in the Texas Hill Country, a dependable and intense pollen density was present in every season. The combination of dependable seasons without confounding pollens, the large number of allergic patients, and the ability to concentrate resources in one geographic area has made mountain cedar allergy a mainstay for therapeutic trials for allergic rhinoconjunctivitis. Conclusion Mountain cedar allergy presents a dependable and durable model of allergic rhinoconjunctivitis.

In vivo imaging of amyloid-β (Aβ) with positron emission tomography has moved from the research arena into clinical practice. Clinicians working with cognitive decline and dementia must become familiar with its benefits and limitations. Amyloid imaging allows earlier diagnosis of Alzheimer disease and better differential diagnosis of dementia and provides prognostic information for mild cognitive impairment. It also has an increasingly important role in therapeutic trial recruitment and for evaluation of anti-Aβ treatments. Longitudinal observations are required to elucidate the role of Aβ deposition in the course of Alzheimer disease and provide information needed to fully use the prognostic power of this investigation.

Necrotizing enterocolitis (NEC) is a leading cause of neonatal morbidity and mortality, and preventive therapies that are both effective and safe are urgently needed. Current evidence from therapeutic trials suggests that probiotics are effective in decreasing NEC in preterm infants, and probiotics are currently the most promising therapy for this devastating disease. However, concerns regarding safety and optimal dosing have limited the widespread adoption of routine clinical use of probiotics in preterm infants. This article summarizes the current evidence regarding the use of probiotics, prebiotics, and postbiotics in the preterm infant, including their therapeutic role in preventing NEC.

BACKGROUND: The recent development of automated cough monitors has enabled objective assessment of cough frequency. A study was undertaken to determine whether short-duration recordings( < 6 h) accurately reflect 24-h cough frequency and to investigate their responsiveness. METHODS: One hundred adults with chronic cough underwent 24-h cough frequency monitoring with the Leicester Cough Monitor and completed cough visual analog scales (VASs) and the Leicester Cough Questionnaire (LCQ). Cough recordings were analyzed using customized software to derive cough frequencies from 1 to 6 h and 24-h recordings. Responsiveness was assessed with repeat assessments following therapeutic trials. RESULTS: The median (interquartile range) 24-h cough frequency was 11.5 (5.8-26.6) coughs/h. Four hours was considered the shortest recording duration that represented 24-h cough frequency( ρ= 0.9, P ≤ .001). Median 4-h cough frequency was 16.6 (7.3-36.8) coughs/h. Both 4-h and 24-h cough frequency correlated moderately with cough VAS ( ρ= 0.49, P ≤ .01 and ρ= 0.44, P ≤ .01)and LCQ ( ρ = - 0.48, P ≤ .01; ρ = - 0.50, P ≤ .01). Four-hour cough frequency was responsive to improvements in cough severity following trials of therapy. CONCLUSIONS: Four-hour cough frequency correlates highly with 24-h cough frequency recordings and relates equally well with subjective measures in chronic cough. Short-duration cough monitoring could be a practical tool to validate the presence of cough and assess response to trials of therapy in the clinic setting.

BACKGROUND: The current study was undertaken to explore whether older age predicts adverse event rates in metastatic melanoma patients participating in cancer clinical trials. METHODS: Six phase II studies conducted at our institution for patients with metastatic disease were used in these pooled analyses: 1) ABT-510; 2) bortezomib, paclitaxel, and carboplatin; 3) everolimus; 4) bevacizumab, paclitaxel, carboplatin; 5) carboplatin and abraxane; and 6) temozolomide and everolimus. In total, 233 patients, 64 elderly (≥ 70 years) and 169 younger, were analyzed for age-based differences in grade 2 or worse adverse events and other clinical outcomes. RESULTS: Despite the fact that older patients had slightly worse performance scores, based on age, no differences in rates of adverse events were observed. Only worse baseline performance score predicted a higher rate of adverse events: patients with performance scores of one or worse were almost 4 times more likely to experience adverse events. Median cancer progression free survival and overall survival were comparable between older and younger patients. CONCLUSION: These findings suggest that concern for adverse event rates should not preclude the enrollment of elderly melanoma patients to cancer clinical trials. Such patients should continue to be monitored carefully for tumor response and toxicity.

The Golden Retriever Muscular Dystrophy (GRMD) dog is the closest animal counterpart of Duchenne muscular dystrophy in humans and has, for this reason, increasingly been used in preclinical therapeutic trials for this disease. The aim of this study was to describe the abnormalities in canine dystrophic muscle non-invasively, quantitatively, thoroughly and serially by means of NMR imaging. Thoracic and pelvic limbs of five healthy and five GRMD dogs were imaged in a 3T NMR scanner at 2, 4, 6 and 9months of age. Standard and fat-saturated T 1 -, T 2 - and proton-density-weighted images were acquired. A measurement of T 1 and a two-hour kinetic study of muscle enhancement after gadolinium-chelate injection were also performed. Ten out of the 15 indices evaluated differed between healthy and GRMD dogs. The maximal relative enhancement after gadolinium injection and the proton-density-weighted/ T 2 -weighted signal ratio were the most discriminating indices. Inter-muscle heterogeneity was found to vary significantly for most of the indices. The body of data that has been acquired here will help in designing and interpreting preclinical trials using dystrophin-deficient dogs.

For several years, veterinary oncologists have been struggling with the prognosis of mammary tumours in dogs and cats. Translation of tumour characteristics into prognostic information is an invaluable tool for the use of the most appropriate therapies, as well as for planning innovative therapeutic trials. Moreover, canine and feline spontaneous mammary gland tumours are good models for the study of human breast cancer. Collecting and interpreting information regarding the prognosis of canine and feline mammary tumours is difficult due to the fact that different methods have been applied to study various components and characteristics. This review identifies some of the challenges of prognostic studies of spontaneous canine and feline mammary tumours and suggests standardized procedures to overcome these challenges and facilitate reproducibility and assessment of results.

A large number of new studies on all the concepts of inflammatory bowel disease were presented at Digestive Disease Week 2011, showing a rapidly changing scenario. Although therapeutic trials usually receive the lion's share of attention, the changes in definitions and diagnostic processes were, if anything, more striking. Genetic studies are starting to define new subgroups of patients. More and more data show that traditional clinical evaluation is insufficient to assess patients' real status. Both objective indexes of disease activity (biomarkers, imaging techniques, quantification and validation of indexes) and new perspectives are required. These new perspectives include gaining greater insight into the economic, personal and social consequences of the disease, as well as assessing other issues such as the risks of other diseases, which are sometimes the direct consequence of treatments.

In the last years, much progress has been achieved in the treatment of lysosomal storage disorders. Until recently only symptomatic treatment was available for the affected patients. Progressively enzyme replacement treatments have been developed for several diseases, namely Gaucher disease, Fabry disease, mucopolysaccharidoses type I, II and VI and Pompe disease. In this review we will summarize the efficacy and safety of these treatments and describe new therapeutic trials for other lysosomal storage disorders or perspectives in the use of currently available treatments.

BackgroundAlthough cough is a commonly reported symptom, objective quantitation of cough during normal activity has not been performed in patients with CF.MethodsAn ambulatory device was used to characterize cough over 24hours. Pulmonary function and subject-reported coughing were also assessed.ResultsPatients included 19 clinically stable adults with CF (males:females=10:9; median age [range]=26 [19-57] years; median %-predicted FEV1 [range]=65 [44-106]%). Median [range] cough rate was 27 [13-66] coughs/hour, with values while awake of 41 [20-102] and while asleep of 2 [0.1-7] (p

Objectives The objectives of this study were to estimate the levels of eotaxin, RANTES and tumor necrosing factor-∞ in allergic rhinitis and their relation to disease severity. Study design Prospective study. Setting Mansoura University Hospital. Patients and methods Twenty nine patients suffering from allergic rhinitis were included in this study (19 patients with allergic rhinitis and 10 patients control group). The patients underwent estimation of eotaxin, RANTES, TNF-∞ in the nasal wash using Elisa technique. The patients were divided according to the disease severity into mild allergic rhinitis, severe allergic rhinitis and control groups. Results The mean values of eotaxin, RANTES, TNF-∞ in severe allergic rhinitis (33.6 ± 11.07 pg/ml, 72.17 ± 87.61 pg/ml, 25.47 ± 4.04 pg/ml) were statistically higher than in mild allergic rhinitis (9.80 ± 6.79 pg/ml, 10.50 ± 6.90 pg/ml, 12.99 ± 3.27 pg/ml) and the mean values of all these parameters were higher in both groups compared to control group (0.6 ± 0.69 pg/ml, 0.65 ± 0.74 pg/ml, 0.63 ± 0.54 pg/ml). Conclusion This study suggests the role of local chemokines in the pathogenesis of allergic rhinitis as well as their possible relation to the severity of the disease which may direct the attention to therapeutic trials against these locally produced chemokines.

To assess safety and effects of five C-tDCS (charge density 342,857 C/m 2 ) delivered at increasing time intervals in 25 h. Safety was defined as absence of serious adverse events and by magnetic resonance imaging and spectroscopy. Effects on motor cortex excitability were evaluated by motor evoked potential (MEP) amplitudes. Inter-individual MEP variability was calculated by the SEM at baseline and subjects were classified on the basis of the ratio between normalized MEPs after the first stimulation compared to baseline. Thirty-two healthy subjects were enrolled. No serious adverse events occurred. Magnetic resonance imaging and spectroscopy did not show structural and biochemical alterations. Only 56% of subjects responded to cathodal-tDCS with the expected reduction of MEP amplitude, 25% were non-responders and 19% opposite responders. In responders, MEP suppression was 32% one hour after the first cathodal-tDC, 21% three hours after the second, no longer present four hours after the third and 12 h after the fourth cathodal-tDCS. Loss of effect was due to the increasing interval between C-tDCS and not to intervening homeostatic plasticity. Five C-tDCS in 25 h are safe. Interindividual variability on motor cortex excitability and effect duration limited to three hours should be considered in planning therapeutic trials utilizing repeated C-tDCS.

Painful chronic pancreatitis is a challenging problem for clinicians and patients. Many patients receive a therapeutic trial of pancreatic enzyme supplementation at some point in the course of their disease, but it is unclear what the expected outcome of such a trial should be and whether or not all patients should receive a trial of pancreatic enzymes. We searched PubMed for all studies of pancreatic enzyme supplementation for painful chronic pancreatitis from 1980 to the present. We also searched the references of identified manuscripts and requested additional information from study authors when necessary. Manuscripts were assessed for study design, bias, pain assessment, and pain management protocol. The results are described in full.

Early diagnosis of primary systemic vasculitis is important to allow the early commencement of therapy in order to avoid damage and poor outcomes. The heterogeneous nature of vasculitis presents a diagnostic challenge which may hinder early diagnosis. Anti-neutrophilic cytoplasmic antibody testing has been of particular benefit in defining a subgroup of small-vessel vasculitides and facilitating their earlier diagnosis. Suspicion of vasculitis is an important first step to begin a process of investigation to make or refute the diagnosis. No useful diagnostic criteria exist, but classification criteria have been developed to permit a vasculitis patient to be placed in a diagnostic subgroup. The exclusion of vasculitis 'mimics' and secondary causes of vasculitis are components of diagnosis, which otherwise relies on the recognition of a compatible clinical presentation supported by specific laboratory or imaging tests and confirmatory histology. When the diagnosis remains uncertain, observation over time, repeat investigation and a therapeutic trial may improve the probability of the diagnosis or identify an alternative disease.

Since its inception, the amyloid cascade hypothesis has dominated the field of Alzheimer's disease (AD) research and has provided the intellectual framework for therapeutic intervention. Although the details of the hypothesis continue to evolve, its core principle has remained essentially unaltered. It posits that the amyloid-beta peptides, derived from amyloid precursor protein (APP), are the root cause of AD. Substantial genetic and biochemical data support this view, and yet a number of findings also run contrary to its tenets. The presence of familial AD mutations in APP and presenilins, demonstration of Abeta toxicity, and studies in mouse models of AD all support the hypothesis, whereas the presence of Abeta plaques in normal individuals, the uncertain nature of the pathogenic Abeta species, and repeated disappointments with Abeta-centered therapeutic trials are inconsistent with the hypothesis. The current state of knowledge does not prove nor disprove the amyloid hypothesis, but rather points to the need for its reassessment. A view that Abeta is one of the factors, as opposed to the factor, that causes AD is more consistent with the present knowledge, and is more likely to promote comprehensive and effective therapeutic strategies.

Prompt diagnosis, intervention, and risk assessment are critical in caring for septic patient but remain difficult with currently available methods. Biomarkers may become useful adjuncts to clinicians and ultimately serve as targets for future therapeutic trials in sepsis. The most relevant markers are reviewed in this article, including interleukin-6, C-reactive protein, procalcitonin, triggering receptor expressed on myeloid cells-1, and biomarker panels.

The authors report a pilot open-label two-center therapeutic trial of oxatomide in 14 steroid-naive DMD boys aged 5–10 years. Comparison of linear evolutions between 3 months medication-free lead-in periods and 6 months treatment periods showed no significant differences in quantitative (QMT) and manual (MMT) measurements of muscle strength and timed functional tests. A modest mitigation of strength deterioration over time cannot be excluded.

Les nouveaux traitements des maladies orphelines se doivent d’etre evalues en respectant les principes de base de la methodologie des essais therapeutiques : essais controles et randomises, permettant, sur un critere d’evaluation unique, de mettre en evidence une difference statistiquement significative et cliniquement signifiante. Les contraintes liees aux maladies orphelines peuvent entrainer des entorses aux regles habituelles de la methodologie mais ne doivent pas remettre en question le niveau de preuve de l’efficacite therapeutique.

Summary With 21% of parents taking their excessively crying infant to a healthcare professional, chiropractors are often selected to treat these infants. The personal, family and social costs of this crying syndrome are high, yet there is no agreed treatment protocol. A large number of studies have been aimed at providing useful interventions, but no “cure” has been demonstrated. With some evidential backing, chiropractors are well-placed to provide therapy for this syndrome. A seven-step process of thorough history (including ante-natal and natal factors), administration of depression index to the mother, examination of the infant to rule out illness, differential diagnosis, specific treatment plan for specific disorders, therapeutic trial and reassurance to the parents provides a rational framework for appropriate chiropractic care of this enigmatic and problematic condition.

Purpose To examine reported clinical trials on herpes simplex virus epithelial keratitis as a case study for the configuration and possible motives of overlapping publications in the ophthalmic literature. Design Cross-sectional bibliometric survey. Methods One hundred and forty-four reports of 98 randomized clinical trials that formed the framework for a systematic review on dendritic and geographic keratitis were assembled by electronic and manual searching of biomedical journals and transactions, excluding meeting abstracts. Overlapping reports were identified by comparing methods and results. Main articles giving the most detailed results among overlapping reports were contrasted with trial reports without duplication. Annual citation rates since publication were estimated from the number of times each report was cited by subsequent scientific articles indexed in an online citation database. Results Sixty-one articles were published once, while 83 articles overlapped in 23 clusters, of which 14 (50%) lacked bibliographic cross-reference. Of 55 secondary reports, 34 (62%) had a smaller sample size than their corresponding main report. Secondary articles were less likely to appear in an ophthalmological publication than main reports ( P P = .01). Compared to trial reports published once, main articles with an overlapping report had a significantly higher citation rate ( P = .04). Conclusion Overlapping publications of therapeutic trials on herpetic keratitis often had undisclosed or fragmentary interconnections. Subsequent authors cited articles having an overlapping report more often than trials published once.

Computer-aided diagnosis (CAD) technology is becoming an important tool to assess treatment response in clinical trials. However, CAD software alone is not sufficient to conduct an imaging-based clinical trial. There are a number of architectural requirements such as image receive (from multiple field sites), a database for storing quantitative measures, and data mining and reporting capabilities. In this paper we describe the architectural requirements to incorporate CAD into clinical trials and illustrate their functionality in therapeutic trials for emphysema.

The objective of a phase I trials in paediatrics is to determine the recommended dose of a new treatment in children while evaluating its toxicity. These trials are proposed when no effective curative treatment is available. The probability of a benefit in terms of disease control is certainly very low, but greater than zero. On the basis of the work conducted by an Assistance publique-Hopitaux de Paris Espace ethique group in collaboration with parents, healthcare personnels and a philosopher, phase I therapeutic trials can be considered to be an ethically acceptable proposal provided the criteria and risks of inclusion in such a trial are clearly defined. This article discusses the main elements of this process and is designed to provide guidelines for healthcare personnel and parents. The need for an information provided gently but honestly, the importance of a sufficient time to think about the proposed trial, a two-sided dialogue and partnership between the various actors, and the priority given to the child's best interest, as should always be the case, constitute the decisive elements to guide the proposed inclusion in a phase I trial. These conditions help to ensure that a decision is reached which appears to be morally founded for all parties, while allowing the child to remain alive up until the end, i.e. a human being capable of relating. This decision allows parents and healthcare personnel to retain a good self-image; if the child dies, it is by keeping their self-esteem that parents can live with their bereavement and healthcare personnel can reinvest in other patients.