Design and rationale of a multi-center, pragmatic, open-label randomized trial of antimicrobial therapy - the study of clinical efficacy of antimicrobial therapy strategy using pragmatic design in Idiopathic Pulmonary Fibrosis (CleanUP-IPF) clinical trial

Compelling data have linked disease progression in patients with idiopathic pulmonary fibrosis (IPF) with lung dysbiosis and the resulting dysregulated local and systemic immune response. Moreover, prior therapeutic trials have suggested improved outcomes in these patients treated with either sulfamethoxazole/ trimethoprim or doxycycline. These trials have been limited by methodological concerns. This trial addresses the primary hypothesis that long-term treatment with antimicrobial therapy increases the time-to-event endpoint of respiratory hospitalization or all-cause mortality compared to usual care treatment in patients with IPF. We invoke numerous innovative features to achieve this goal, including: 1) utilizing a pragmatic randomized trial design; 2) collecting targeted biological samples to allow future exploration of 'personalized' therapy; and 3) developing a strong partnership between the NHLBI, a broad range of investigators, industry, and philanthropic organizations. The trial will randomize approximately 500 individuals in a 1:1 ratio to either antimicrobial therapy or usual care. The site principal investigator will declare their preferred initial antimicrobial treatment strategy (trimethoprim 160 mg/ sulfamethoxazole 800 mg twice a day plus folic acid 5 mg daily or doxycycline 100 mg once daily if body weight is < 50 kg or 100 mg twice daily if ≥50 kg) for the participant prior to randomization. Participants randomized to antimicrobial therapy will receive a voucher to help cover the additional prescription drug costs. Additionally, those participants will have 4-5 scheduled blood draws over the initial 24 months of therapy for safety monitoring. Blood sampling for DNA sequencing and genome wide transcriptomics will be collected before therapy. Blood sampling for transcriptomics and oral and fecal swabs for determination of the microbiome communities will be collected before and after study completion. As a pragmatic study, participants in both treatment arms will have limited in-person visits with the enrolling clinical center. Visits are limited to assessments of lung function and other clinical parameters at time points prior to randomization and at months 12, 24, and 36. All participants will be followed until the study completion for the assessment of clinical endpoints related to hospitalization and mortality events. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT02759120

Temperament Traits and Psychopathology in Young Clinically Referred Children Compared to a General Population Sample

Evidence from general population studies shows the contribution of various temperament traits to the development of child psychopathology. Little is known about which traits are associated with internalizing and externalizing problems in young clinically referred children. The current study assessed temperament and internalizing and externalizing problems in 216 referred children (M = 4.35 years, SD 0.89, 81% boys). A comparison was made with an age and gender matched general population sample. Referred children showed less effortful control than general population children. Less effortful control and more negative affectivity were associated with more internalizing and externalizing problems across groups. Surgency, and specifically temperamental impulsivity, was more strongly associated with externalizing problems in referred children compared to general population. Less soothability, less inhibitory control and more frustration predicted (sub)clinical levels of comborbid internalizing and externalizing problems in referred children. The results can be used in diagnostic and treatment procedures in early childhood

Prosthetic joint infections: new diagnostic and therapeutic strategies

A prosthetic joint infection (PJI) is a severe complication after arthroplasty. From the current thesis, three main conclusion can be drawn regarding diagnosis and treamtent of PJI. (a) Accurate self-monitoring of postoperative wounds after joint implantation helped elucidate the course of wound leakage and its association with acute prosthetic joint infections. (b) The collection of clinical data on different antimicrobial treatment strategies provided insight into the effectiveness of different treatment options for patients with a prosthetic joint infection. In this thesis, we report that personalized antimicrobial treatment for prosthetic joint infections is possible without compromising the effectiveness of treatment. (c) this thesis describes the role and importance of new anti-persister drugs against biofilm-associated infections. We developed a biofilm model that closely resembles the clinic of a prosthetic joint infection. Based on the results described in this thesis, future research will be aimed at better understanding the pathogenesis of biofilms. This should ultimately lead to better treatment options for patients with a prosthetic joint infection.Zorg en Zekerheid; Stichting de Merel; Innovatiefonds ZorgverzekeraarsLUMC / Geneeskund

Do health systems delay the treatment of poor children? A qualitative study of child deaths in rural Tanzania.

Child mortality remains one of the major public-health problems in Tanzania. Delays in receiving and accessing adequate care contribute to these high rates. The literature on public health often focuses on the role of mothers in delaying treatment, suggesting that they contact the health system too late and that they prefer to treat their children at home, a perspective often echoed by health workers. Using the three-delay methodology, this study focus on the third phase of the model, exploring the delays experienced in receiving adequate care when mothers with a sick child contact a health-care facility. The overall objective is to analyse specific structural factors embedded in everyday practices at health facilities in a district in Tanzania which cause delays in the treatment of poor children and to discuss possible changes to institutions and social technologies. The study is based on qualitative fieldwork, including in-depth interviews with sixteen mothers who have lost a child, case studies in which patients were followed through the health system, and observations of more than a hundred consultations at all three levels of the health-care system. Data analysis took the form of thematic analysis. Focusing on the third phase of the three-delay model, four main obstacles have been identified: confusions over payment, inadequate referral systems, the inefficient organization of health services and the culture of communication. These impediments strike the poorest segment of the mothers particularly hard. It is argued that these delaying factors function as 'technologies of social exclusion', as they are embedded in the everyday practices of the health facilities in systematic ways. The interviews, case studies and observations show that it is especially families with low social and cultural capital that experience delays after having contacted the health-care system. Reductions of the various types of uncertainty concerning payment, improved referral practices and improved communication between health staff and patients would reduce some of the delays within health facilities, which might feedback positively into the other two phases of delay

Outcomes of amputation due to long-standing therapy-resistant complex regional pain syndrome type I

Objective: To assess long-term outcomes of amputation in patients with long-standing therapy-resistant complex regional pain syndrome type I (CRPS-I). Design: Partly cross-sectional, partly longitudinal study. Subjects: Patients who had amputation of a limb due to long-standing, therapy-resistant CRPS-I, at the University Medical Centre Groningen, The Netherlands, between May 2000 and September 2015 (n=53) were invited to participate. Methods: Participants were interviewed in a semi-structured way regarding mobility, pain, recurrence of CRPS-I, quality of life, and prosthesis use. Those who reported recurrence of CRPS-I underwent physical examination. Results: A total of 47 patients (median age at time of amputation, 41.0 years; 40 women) participated. Longitudinal evaluation was possible in 17 participants. Thirty-seven participants (77%) reported an important improvement in mobility (95% confidence interval (95% CI) 63; 87%). An important reduction in pain was reported by 35 participants (73%; 95% CI 59; 83%). CRPS-I recurred in 4 of 47 participants (9%; 95% CI 3; 20%), once in the residual limb and 3 times in another limb. At the end of the study of the 35 participants fitted with a lower limb prosthesis, 24 were still using the prosthesis. Longitudinal evaluation showed no significant deteriorations. Conclusion: Amputation can be considered as a treatment for patients with long-standing, therapy-resistant CRPS-I. Amputation can increase mobility and reduce pain, thereby improving the quality of patients' lives. However, approximately one-quarter of participants reported deteriorations in intimacy and self-confidence after the amputation

Bisphosphonate-Associated Osteonecrosis of the Jaw: Are We Dealing with a Localized Non-Traditional Calciphylaxis?

The bisphosphonate (BP) family of drugs has been used as a vital component in cancer therapy and many other diseases. One of the main adverse effects related to (BP) is BP-associated osteonecrosis of the jaw (ONJ). Although this condition was first recognized in 2003, the pathophysiologic mechanism remains undefined. Our hypothesis is that ONJs clinical course and delayed wound healing is in part correlated to a localized non-traditional calciphylaxis. This effect is identified by the evidence of calcium deposition in the connective tissue and around small blood vessels in the soft tissues immediately adjacent to ONJ lesions. This phenomenon helps to fill gaps in the cascade of events which leads to soft tissue ischemia, necrosis, and non-healing ONJ lesions. Our finding adds to the current knowledge of the potential pathophysiologic mechanisms related to ONJ