RAS-activated PI3K/AKT signaling sustains cellular senescence via P53/P21 axis in experimental models of psoriasis.

BACKGROUND: Psoriasis is a chronic immune-mediated skin disease in which upper epidermal keratinocytes exhibit a senescent-like phenotype. In psoriatic skin, a variety of inflammatory cytokines can activate intracellular pathways including phosphatidylinositol 3-kinase (PI3K)/AKT signaling and RAS effectors. AKT and RAS participate to cellular senescence, but currently their role in senescence responses occurring in psoriasis have not yet been investigated. OBJECTIVE: The role of AKT molecular axis and RAS activation was evaluated in the context of cellular senescence in psoriasis disease. METHODS: RAS/AKT involvement in senescence was analyzed in psoriatic keratinocytes cultures subjected to multiple passages to promote senescence in vitro, as well as in skin lesions of patients affected by psoriasis. The impact of pharmacological inhibition of PI3K/AKT pathway on senescence and inflammation responses was tested in senescent psoriatic keratinocytes and in a psoriasiform dermatitis murine model induced by RAS overexpression in the upper epidermis of mice. RESULTS: We found AKT hyperactivation associated to the upregulation of senescence markers, in senescent psoriatic keratinocyte cultures, as well as in skin lesions of psoriatic patients. AKT-induced senescence was sustained by constitutive RAS activation, and down-stream responses were mediated by P53/P21 axis. PI3K/AKT inhibition contrasted senescence processes induced by cytokines in psoriatic keratinocytes. Additionally, RAS-induced psoriasis-like dermatitis in mice was accompanied by AKT upregulation, increase of senescence marker expression and by skin inflammation. In this model, both senescence and inflammation were significantly reduced by selective AKT inhibition. CONCLUSION: Therefore, targeting RAS-AKT pathway could be a promising novel strategy to counteract multiple psoriasis symptoms.

Differences in Protein Capture by SP3 and SP4 Demonstrate Mechanistic Insights of Proteomics Clean-up Techniques.

The goal of proteomics experiments is to identify proteins to observe changes in cellular processes and diseases. One challenge in proteomics is the removal of contaminants following protein extraction, which can limit protein identification. Single-pot, solid-phase-enhanced sample preparation (SP3) is a clean-up technique in which proteins are captured on carboxylate-modified particles through a proposed hydrophilic-interaction-liquid-chromatography (HILIC)-like mechanism. However, recent results have suggested that proteins are captured in SP3 due to a protein-aggregation mechanism. Thus, solvent precipitation, single-pot, solid-phase-enhanced sample preparation (SP4) is a newer clean-up technique that employs protein-aggregation to capture proteins without modified particles. SP4 has previously enriched low-solubility proteins, though differences in protein capture could affect which proteins are detected and identified. We hypothesize that the mechanisms of capture for SP3 and SP4 are distinct. Herein, we assess the proteins identified and enriched using SP3 versus SP4 for MCF7 subcellular fractions and correlate protein capture in each method to protein hydrophobicity. Our results indicate that SP3 captures more hydrophilic proteins through a combination of HILIC-like and protein-aggregation mechanisms, while SP4 captures more hydrophobic proteins through a protein-aggregation mechanism. From these results, we recommend clean-up techniques based on protein-sample hydrophobicity to yield high proteome coverage in biological samples.

CD4+ T cells reverse surface antigen persistence in a mouse model of HBV replication.

IMPORTANCE: Hepatitis B virus (HBV) is a leading causative agent of viral hepatitis. A preventative vaccine has existed for decades, but only limited treatment options are available for people living with chronic HBV. Animal models for studying HBV are constrained due to narrow viral tropism, impeding understanding of the natural immune response to the virus. Here, using a vector to overcome the narrow host range and establish HBV replication in mice, we identified the role of helper T cells in controlling HBV. We show that helper T cells promote the B cell's ability to generate antibodies that remove HBV and its associated surface antigen from the blood and that transfer of purified helper T cells from HBV-immunized mice can reverse the accumulation of virus and antigen, furthering our understanding of the immune response to HBV.

Implementing Holistic Review Practices in a Pulmonary and Critical Care Fellowship.

Background: Medical schools have used holistic review in admissions to increase mission-aligned enrollment of students from backgrounds underrepresented in medicine. Graduate medical education programs have increasingly followed suit. However, there is a paucity of literature regarding holistic review at the fellowship level. Objective: Here, we share our experience implementing the Association of American Medical Colleges core principles of holistic review during the 2021 recruitment cycle. Methods: We used a partially asynchronous and online learning strategy to train division members on the principles of holistic review. Following the match, we conducted a survey of faculty members and fellows to understand their opinions on our holistic review training and implementation. Results: Although few of our colleagues clearly understood holistic review before the training, they were able to identify broad-based criteria that aligned with our division's mission and balanced applicants' experiences, attributes, competencies, and metrics. These were viewed as better selection criteria than traditional measures and were incorporated into the individualized consideration of applicants. Our survey had a 41.5% response rate, with 10 of 22 fellows and 24 of 60 faculty members responding. Most faculty members and fellows agreed that holistic review decreases socioeconomic disparities in fellowship recruitment (79.2% and 80.0%, respectively) and promotes inclusion and diversity (83.3% and 90.0%, respectively). Faculty members appeared more confident than fellows that our training efforts had influenced recruitment. All respondents agreed that it would be critical for such training to be repeated yearly. Conclusion: Although this was a single-institution experience, implementing holistic review was feasible and well received by faculty and fellows.

Virtual interviewing for graduate medical education recruitment and selection: A BEME systematic review: BEME Guide No. 80.

BACKGROUND: The COVID-19 pandemic caused graduate medical education (GME) programs to pivot to virtual interviews (VIs) for recruitment and selection. This systematic review synthesizes the rapidly expanding evidence base on VIs, providing insights into preferred formats, strengths, and weaknesses. METHODS: PubMed/MEDLINE, Scopus, ERIC, PsycINFO, MedEdPublish, and Google Scholar were searched from 1 January 2012 to 21 February 2022. Two authors independently screened titles, abstracts, full texts, performed data extraction, and assessed risk of bias using the Medical Education Research Quality Instrument. Findings were reported according to Best Evidence in Medical Education guidance. RESULTS: One hundred ten studies were included. The majority (97%) were from North America. Fourteen were conducted before COVID-19 and 96 during the pandemic. Studies involved both medical students applying to residencies (61%) and residents applying to fellowships (39%). Surgical specialties were more represented than other specialties. Applicants preferred VI days that lasted 4-6 h, with three to five individual interviews (15-20 min each), with virtual tours and opportunities to connect with current faculty and trainees. Satisfaction with VIs was high, though both applicants and programs found VIs inferior to in-person interviews for assessing 'fit.' Confidence in ranking applicants and programs was decreased. Stakeholders universally noted significant cost and time savings with VIs, as well as equity gains and reduced carbon footprint due to eliminating travel. CONCLUSIONS: The use of VIs for GME recruitment and selection has accelerated rapidly. The findings of this review offer early insights that can guide future practice, policy, and research.

Mucosal-associated invariant T cells restrict reactive oxidative damage and preserve meningeal barrier integrity and cognitive function.

Increasing evidence indicates close interaction between immune cells and the brain, revising the traditional view of the immune privilege of the brain. However, the specific mechanisms by which immune cells promote normal neural function are not entirely understood. Mucosal-associated invariant T cells (MAIT cells) are a unique type of innate-like T cell with molecular and functional properties that remain to be better characterized. In the present study, we report that MAIT cells are present in the meninges and express high levels of antioxidant molecules. MAIT cell deficiency in mice results in the accumulation of reactive oxidative species in the meninges, leading to reduced expression of junctional protein and meningeal barrier leakage. The presence of MAIT cells restricts neuroinflammation in the brain and preserves learning and memory. Together, our work reveals a new functional role for MAIT cells in the meninges and suggests that meningeal immune cells can help maintain normal neural function by preserving meningeal barrier homeostasis and integrity.

Methylone pre-exposure differentially impacts the aversive effects of MDPV and MDMA in male and female Sprague-Dawley rats: Implications for abuse vulnerability.

BACKGROUND: Polydrug use is well documented in synthetic cathinone users, although the consequences of such use are not well characterized. In pre-clinical research, a pre-exposure to a drug has been reported to attenuate the aversive effects of other drugs which has implications for their abuse potential. The goal of the present study was to investigate the impact of pre-exposure to the synthetic cathinone methylone on the aversive effects of MDPV and MDMA. METHOD: Male and female Sprague-Dawley rats were exposed to 10 mg/kg of methylone every 4th day (for a total of five injections) prior to taste avoidance training with 1.8 mg/kg of MDPV or 1 mg/kg of MDMA. RESULTS: MDPV and MDMA induced taste avoidance in males and females (all p's < 0.05). In males, methylone pre-exposure attenuated the avoidance induced by MDPV and MDMA (all p's < 0.05) with the attenuation greater with MDPV. In females, methylone pre-exposure attenuated avoidance induced by MDPV (all p's < 0.05), but it had no effect on those induced by MDMA (all p's > 0.05). CONCLUSIONS: The effects of exposure to methylone on taste avoidance induced by MDPV and MDMA were drug- (MDPV > MDMA) and sex- (MDMA only in males) dependent. The attenuating effects of methylone pre-exposure on MDPV and MDMA were discussed in terms of their shared neurochemical action. These findings suggest that a history of methylone use may reduce the aversive effects of MDPV and MDMA which may have implications for polydrug use involving the synthetic cathinones.

Learning Outcomes in a Live Virtual versus In-Person Curriculum for Medical and Pharmacy Students.

Background: The coronavirus disease (COVID-19) pandemic has been a source of disruption, changing the face of medical education. In response to infection control measures at the University of California, San Diego, the hybrid in-person and recorded preclerkship curriculum was converted to a completely virtual format. The impact of this exclusive virtual teaching platform on the quality of trainee education is unknown. Objective: To determine the efficacy of a virtual course, relative to traditional hybrid in-person and recorded teaching, and to assess the impact of supplementary educational material on knowledge acquisition. Methods: A retrospective observational cohort study was performed to assess an introductory course, held mostly in person in 2019 versus completely virtual in 2020, for first-year medical students and second-year pharmacy students at the University of California, San Diego, School of Medicine and Skaggs School of Pharmacy and Pharmaceutical Sciences. Results: The midterm and final examination scores were similar for the hybrid and virtual courses. There was no association between the hours of recorded lectures watched and final examination scores for either course. In the 2019 in-person and recorded course, students who demonstrated consistent on-time use of practice quizzes scored statistically higher on the final examination (P = 0.0066). In the 2020 virtual course, students who downloaded quizzes regularly had statistically higher scores on the midterm examination (P < 0.0001). Conclusion: The similar examination scores for the hybrid in-person and recorded and exclusively virtual courses suggest that the short-term knowledge acquired was equivalent, independent of the modality with which the content was delivered. Consistent on-time use of practice quizzes was associated with higher examination scores. Future studies are needed to assess the difference between a completely in-person versus virtual curriculum.

Political orientation, moral foundations, and COVID-19 social distancing.

During the COVID-19 pandemic, governments have advocated numerous social distancing measures, and compliance with these has likely saved millions of lives globally. In an online sample drawn from the U.S. and Canada (N = 209), participants completed measures of political orientation, moral foundations, and COVID-19 social distancing attitudes and behaviours. A more left-wing political orientation, and greater endorsement of the individualizing moral foundations were significantly related to more positive social distancing attitudes, and greater self-reported compliance with relevant restrictions. A more right-wing political orientation, and greater endorsement of the binding and economic liberty foundations were associated with less positive attitudes and reduced compliance. In a series of mediation analyses, the relationships between political orientation and various social distancing measures were significantly mediated by variations in participants' moral foundations, particularly their endorsement of economic liberty and the individualizing foundations. Further data indicated that the perceived persuasiveness of messages based on each moral foundation advocating for continued social distancing was significantly related to both participants' moral values and their political orientation. Findings are discussed in terms of understanding politicized differences around social distancing as partly reflecting differential valuation of the moral foundations, and in creating effective public health messaging regarding compliance.

Initial Experience with Apixaban for Extended Venous Thromboembolism Prophylaxis After Radical Cystectomy.

Patients who undergo radical cystectomy (RC) are at elevated risk of venous thromboembolism and associated morbidity and mortality. Guidelines recommend extended thromboprophylaxis (ETP), typically with heparins, but adherence is low. Outside urology, low-dose apixaban has been used for postoperative ETP with success. We describe our first experiences with low-dose apixaban for ETP after RC for bladder cancer. In our sample of 72 patients who underwent RC for cancer and subsequently received apixaban 2.5 mg twice daily for ETP, there were no symptomatic thromboembolic events and no major bleeding events. Other complication rates were in line with historical reports. Our experience with apixaban 2.5 mg twice daily for ETP after RC demonstrates safety and potential efficacy. A transition from injectable to oral thromboprophylaxis has the potential to improve adherence and patient satisfaction, while allowing the possibility of further extending prophylaxis beyond 28 d, which may be beneficial in selected patients. Further evaluation of apixaban for thromboprophylaxis in urologic cancer surgery is warranted. PATIENT SUMMARY: Home injectable heparin is used for 4 weeks after bladder removal surgery to prevent blood clots. We evaluated our use of the oral medication apixaban for prevention of blood clots after bladder removal surgery and found that none of our patients had major bleeding events or symptomatic blood clots. We conclude that there should be further evaluation of the use of oral instead of injectable medication to prevent blood clots after urology surgery.

Hazardous alcohol use and alcohol-related harm in rural and remote communities: a scoping review.

Alcohol use is a major risk factor for death and disease worldwide and alcohol-related harms appear to be more prevalent in rural and remote, relative to urban, communities. This Review synthesised international research on rural-urban disparities in hazardous and harmful alcohol use and risk factors for these outcomes within rural and remote communities. 280 studies from 49 countries were included in the Scoping Review. Most studies (60%) found rural, relative to urban, residence to be associated with an increased likelihood of hazardous alcohol use or alcohol-related harm. This proportion increased between 1990 and 2019 and varied by country, age group, and outcome type, being highest in Australia, among young adults, and for more severe alcohol-related harms, such as drink driving and alcohol-related suicide. Improved public health strategies to reduce the burden of alcohol use in rural communities are required but their efficacy will depend on how well they are tailored to the unique needs of the region they are implemented in.

Ethanol pre-exposure differentially impacts the rewarding and aversive effects of α-pyrrolidinopentiophenone (α-PVP): Implications for drug use and abuse.

RATIONALE: Exposure to a drug can subsequently impact its own reactivity as well as that of other drugs. Given that users of synthetic cathinones, i.e., "bath salts", typically have extensive and varied drug histories, an understanding of the effects of drug history on the behavioral and physiological consequences of synthetic cathiones may be important to their abuse liability. OBJECTIVES: The goal of the current work was to assess the effects of an ethanol pre-exposure on the rewarding and aversive effects of α-PVP. METHODS: Adult male Sprague Dawley rats were exposed to ethanol prior to combined conditioned taste avoidance/conditioned place preference training in which rats were injected with 1.5, 3 or 5 mg/kg of racemic α-PVP or vehicle. Following a 7-day washout period, rats were then tested for thermoregulatory effects of α-PVP using subcutaneous probes to measure body temperature changes over the course of 8 h. This was followed 10 days later by assessments for α-PVP-induced locomotor activity and stereotypies over a 1-h session. RESULTS: α-PVP induced significant dose- and trial-dependent taste avoidance that was significantly attenuated by ethanol history and dose- and time-dependent increases in locomotor activity that were significantly increased by ethanol. α-PVP also induced place preferences and dose- and time-dependent increases in body temperature, but these measures were unaffected by ethanol history. CONCLUSIONS: α-PVP's aversive effects (as measured by taste avoidance) were attenuated, while its rewarding effects (as indexed by place preference conditioning) were unaffected, by ethanol pre-exposure. Such a pattern may indicate increased α-PVP abuse liability, as changes in the balance of aversion and reward may impact overall drug effects and likelihood of drug intake. Future self-administration studies will be necessary to explore this possibility.

Type I Interferon signaling controls the accumulation and transcriptomes of monocytes in the aged lung.

Aging is paradoxically associated with a deteriorated immune defense (immunosenescence) and increased basal levels of tissue inflammation (inflammaging). The lung is particularly sensitive to the effects of aging. The immune cell mechanisms underlying physiological lung aging remain poorly understood. Here we reveal that aging leads to increased interferon signaling and elevated concentrations of chemokines in the lung, which is associated with infiltration of monocytes into the lung parenchyma. scRNA-seq identified a novel Type-1 interferon signaling dependent monocyte subset (MO-ifn) that upregulated IFNAR1 expression and exhibited greater transcriptomal changes with aging than the other monocytes. Blockade of type-1 interferon signaling by treatment with anti-IFNAR1 neutralizing antibodies rapidly ablated MO-ifn cells. Treatment with anti-IFNAR1 antibodies also reduced airway chemokine concentrations and repressed the accumulation of the overall monocyte population in the parenchyma of the aged lung. Together, our work suggests that physiological aging is associated with increased basal level of airway monocyte infiltration and inflammation in part due to elevated type-1 interferon signaling.

Straight-Up Approach to Bedside Ureteral Stents.

OBJECTIVE: To demonstrate placement of bedside double-j ureteral stents in an Emergency Department or hospital floor setting. BACKGROUND: Ureteral stent placement is a potentially lifesaving intervention and is one of the most common procedures performed by urologists. Although this procedure is typically performed in the operating room, studies have shown placing ureteral stents at the bedside could potentially decrease delay in stent placement, alleviate financial burdens of operating room use, decrease radiation exposure, and avoid general anesthesia risks1-5. We demonstrate a safe and efficacious method for bedside ureteral stent placement without fluoroscopic guidance. MATERIALS AND METHODS: In the setting of the Emergency Department we use ketamine for conscious sedation and local anesthesia while on the wards, we utilize just local anesthesia. After the patient has been sterilely prepped and draped, the operator passes the flexible cystoscope into the bladder in the standard fashion. The obstructed ureteral orifice is identified, and an extra-long guidewire is used to place a 4.8-French ureteral stent through the scope and beyond the obstruction. A post-operative plain film x-ray of the abdomen confirms proper placement. If significant issues are encountered, the procedure is abandoned, and standard operating room stent placement is undertaken. RESULTS: The technique is simple and reproducible for placing double-j ureteral stents outside of the operating room environment without general anesthesia. CONCLUSION: In select patients, bedside double-j ureteral stent placement using our method is a safe and reproducible way to avoid the costs and risks associated with general anesthesia and to optimize utilization of scarce operating room resources.

Assessment of aversive effects of methylone in male and female Sprague-Dawley rats: Conditioned taste avoidance, body temperature and activity/stereotypies.

Methylone's rewarding effects have been well characterized; however, little is known about its aversive effects and how such effects may be impacted by sex. In this context, the present study investigated the aversive effects of methylone (vehicle, 5.6, 10 or 18 mg/kg, IP) in 35 male and 31 female Sprague-Dawley rats assessed by conditioned taste avoidance and changes in body temperature and activity/stereotypies. Methylone induced significant taste avoidance, changes in temperature and increased activity and stereotypies in both males and females. Similar to work with other synthetic cathinones, methylone has aversive effects as indexed by significant taste avoidance and changes in temperature and activity (two characteristics of methylone overdose in humans). The only endpoint for which there were significant sex differences was in general activity with males displaying a faster onset and females displaying a longer duration. Although sex was not a factor with taste avoidance and temperature, separate analyses for males and females revealed different patterns, e.g., males displayed a more rapid acquisition of taste avoidance and females displayed changes in temperature at lower doses. Males displayed a faster onset and females displayed a longer duration of activity (consistent with the analyses considering sex as a factor), while time- and dose-dependent stereotypies did not show consistent pattern differences. Although sex differences were relatively limited when sex was specifically assessed as a factor (or only evident when sex comparisons were made in the patterns of effects), sex as a biological variable in the study of drugs should be made to determine if differences exist and, if evident, the basis for these differences.

A Qualitative Assessment of Patient Satisfaction with Radical Cystectomy for Bladder Cancer at a Single Institution: How Can We Improve?

PURPOSE: To evaluate patient satisfaction (with emphasis on preoperative education) with radical cystectomy for bladder cancer at our institution, the University of Missouri Hospital, qualitatively in order to identify specific areas where improvements can be made. MATERIALS AND METHODS: We developed a patient survey that used open-ended questions to identify positive and negative experiences that contributed to patient satisfaction. We administered the survey to radical cystectomy patients who met inclusion criteria and agreed to participate. We recorded, transcribed and qualitatively coded the responses. We identified four themes under which both positive and negative responses were placed, and constructed two diagrams to better illustrate contributors to patient experience and satisfaction. RESULTS: We identified 25 patients who met inclusion criteria. Of those, 13 participated in the survey. Regarding overall experience, 92.3% of patients rated their care as excellent or good. Regarding preoperative education, 76.9% of patients reported they definitely or somewhat received enough information on what to expect after surgery, and 76.9% definitely received enough guidance on how to care for themselves after surgery. From qualitative coding of patient responses to open-ended questions, we identified preoperative preparation, delivery of care, caregiver availability, and patient-centered care as themes that contributed positively and negatively to patient experience. CONCLUSION: Although the overall patient satisfaction could be perceived as high (92.3%), qualitative analysis revealed several areas where improvements can be made to improve patient experience with radical cystectomy at our institution. As previously expected, preoperative preparation was a contributor.

Effects of Massage on Postoperative Pain in Infants With Complex Congenital Heart Disease.

BACKGROUND: Pain management is an essential component of care for pediatric patients following surgery. Massage reduces self-reported postoperative pain in adults with heart disease but has received little attention in postoperative pediatric patients with complex congenital heart disease (CCHD). OBJECTIVES: The aim of the study was to evaluate the effectiveness of massage compared to a rest period on postoperative pain scores and physiological responses in infants with CCHD. METHODS: We used a two-group randomized clinical trial design with a sample of 60 infants with CCHD between 1 day and 12 months of age following their first cardiothoracic surgery. Both groups received standard postoperative care. Group 1 received a daily 30-minute restriction of nonessential caregiving (quiet time), and Group 2 received a daily 30-minute massage. Interventions continued for seven consecutive days. Pain was measured six times daily using the Face, Legs, Activity, Cry, Consolability Pain Assessment Tool (FLACC). Average daily doses of analgesics were recorded. Heart rates (HRs), respiratory rates (RRs), and oxygen saturations (SpO2) were recorded continuously. Daily averages, pre- and postintervention FLACC scores, and physiological responses were analyzed using descriptive statistics, generalized linear mixed models repeated measures, latent growth models, and/or regression discontinuity analysis. Fentanyl-equivalent narcotic values were used as a time-varying covariate. RESULTS: Adjusted pain scores were lower for the massage group on all days except Day 7. Overall, there were no group effects on level of pain or differential rate of change in pain. However, the massage group had lower daily pain scores with small to medium effect size differences, largest at Days 4, 5, and 6, and lower average daily HR and RR. There was little difference between groups in SpO2. Infants demonstrated immediate effects of massage, with HR and RR decreasing and oxygen saturations increasing. DISCUSSION: This study provides beginning evidence that postoperative massage may reduce pain and improve physiological parameters in infants with congenital heart disease. This nonpharmacological adjunct to pain management may provide a particular benefit for this population by reducing demand on the cardiorespiratory system.

Photocontrolled miR-148b nanoparticles cause apoptosis, inflammation and regression of Ras induced epidermal squamous cell carcinomas in mice.

Despite evidence that microRNAs (miRNAs) are essential in modulating tumorigenesis, a major challenge in cancer treatment is to achieve tumor-specific selectivity and efficient yet safe delivery of miRNAs in vivo. In this study, we have developed a light-inducible silver nanoparticle nucleic acid delivery system that demonstrates precise spatiotemporal control, high cellular uptake, low cytotoxicity, escape from endosomes and release of functional miRNA into the cytosol. Using this approach, we delivered exogenous miR-148b to induce apoptosis in Ras-expressing keratinocytes and murine squamous cell carcinoma cells while avoiding cytotoxicity in untransformed keratinocytes. When administered to transgenic mice with HRasG12V-driven skin tumors, a single dose of silver nanoparticle conjugates followed by 415 nm LED irradiation at the tumor site caused a rapid and sustained reduction in tumor volume by 92.8%, recruited T cells to the tumor site, and acted as a potent immunomodulator by polarizing the cytokine balance toward Th1 both locally and systemically. In summary, our results demonstrate that spatiotemporal controlled miR-148b mimic delivery can promote tumor regression efficiently and safely.

Patient navigators for people with chronic disease: A systematic review.

BACKGROUND: People with chronic diseases experience barriers to managing their diseases and accessing available health services. Patient navigator programs are increasingly being used to help people with chronic diseases navigate and access health services. OBJECTIVE: The objective of this review was to summarize the evidence for patient navigator programs in people with a broad range of chronic diseases, compared to usual care. METHODS: We searched MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, and Social Work Abstracts from inception to August 23, 2017. We also searched the reference lists of included articles. We included original reports of randomized controlled trials of patient navigator programs compared to usual care for adult and pediatric patients with any one of a defined set of chronic diseases. RESULTS: From a total of 14,672 abstracts, 67 unique studies fit our inclusion criteria. Of these, 44 were in cancer, 8 in diabetes, 7 in HIV/AIDS, 4 in cardiovascular disease, 2 in chronic kidney disease, 1 in dementia and 1 in patients with more than one condition. Program characteristics varied considerably. Primary outcomes were most commonly process measures, and 45 of 67 studies reported a statistically significant improvement in the primary outcome. CONCLUSION: Our findings indicate that patient navigator programs improve processes of care, although few studies assessed patient experience, clinical outcomes or costs. The inability to definitively outline successful components remains a key uncertainty in the use of patient navigator programs across chronic diseases. Given the increasing popularity of patient navigators, future studies should use a consistent definition for patient navigation and determine which elements of this intervention are most likely to lead to improved outcomes. TRIAL REGISTRATION: PROSPERO #CRD42013005857.

Short-course antimicrobial therapy for paediatric respiratory infections (SAFER): study protocol for a randomized controlled trial.

BACKGROUND: Community-acquired pneumonia (CAP) is commonly diagnosed in children. The Infectious Disease Society of America guidelines recommend 10 days of high-dose amoxicillin for the treatment of non-severe CAP but 5-day "short course" therapy may be just as effective. Randomized trials in adults have already demonstrated non-inferiority of 5-day short-course treatment for adults hospitalized with severe CAP and for adults with mild CAP treated as outpatients. Minimizing exposure to antimicrobials is desirable to avoid harms including diarrhoea, rashes, severe allergic reactions, increased circulating antimicrobial resistance, and microbiome disruption. METHODS: The objective of this multicentre, randomized, non-inferiority, controlled trial is to investigate whether 5 days of high-dose amoxicillin is associated with lower rates of clinical cure 14-21 days later as compared to 10 days of high-dose amoxicillin, the reference standard. Recruitment and enrolment will occur in the emergency departments of McMaster Children's Hospital and the Children's Hospital of Eastern Ontario. All children in the study will receive 5 days of amoxicillin after which point they will receive either 5 days of a different formulation of amoxicillin or a placebo. Assuming a clinical failure rate of 5% in the reference arm, a non-inferiority margin of 7.5%, one-sided alpha set at 0.025 and power of 0.80, 270 participants will be required. Participants from a previous feasibility study (n = 60) will be rolled over into the current study. We will be performing multiplex respiratory virus molecular testing, quantification of nasopharyngeal pneumococcal genomic loads, salivary inflammatory marker testing, and faecal microbiome profiling on participants. DISCUSSION: This is a pragmatic study seeking to provide high-quality evidence for front-line physicians evaluating children presenting with mild CAP in North American emergency departments in the post-13-valent pneumococcal, conjugate vaccine era. High-quality evidence supporting the non-inferiority of short-course therapy for non-severe paediatric CAP should be generated prior to making changes to established guidelines. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02380352 . Registered on 2 March 2015.