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Academics and multinational pharmaceutical companies from high-income countries (HIC) are major drivers of health research in many low- and low-middle-income countries (LMIC) but have neglected investing in and growing local research capacity. Community-focused health research in LMICs needs to be more locally driven and benefiting. The MicroResearch (MR) workshop program supports teams of local healthcare workers and community experts to identify local healthcare problems. Once a problem is clearly identified, the team then develops a research proposal and is empowered to conduct this research to find solutions to address the problem that fit the local context, culture and resources. Knowledge translation of the findings is a key element in MR. By placing the drivers of change in the hands of locals, the decolonization of the local health research has begun. MR also democratizes health research by extending community health research training beyond local academics and by fostering gender equity. More than half of the local MR research project team leaders, as selected by team members, are women. The success of MR in LMIC has led to its adaptation for use in HIC such as Canada. Decolonization and democratization of community-focused research is practical and achievable and should be seen as best practice in global health research capacity building., (© 2022. The Author(s) under exclusive license to The Canadian Public Health Association.)

Background: Emergency obstetric referrals develop adverse maternal-fetal outcomes partly due to delays in offering appropriate care at referral hospitals especially in resource limited settings. Referral hospitals do not get prior communication of incoming referrals leading to inadequate preparedness and delays of care. Phone based innovations may bridge such communication challenges. We investigated effect of a phone call communication prior to referral of mothers in labour as intervention to reduce preparation delays and improve maternal-fetal outcome at a referral hospital in a resource limited setting., Methods: This was a quasi-experimental study with non-equivalent control group conducted at Mbarara Regional Referral Hospital (MRRH) in South Western Uganda from September 2020 to March 2021. Adverse maternal-fetal outcomes included: early neonatal death, fresh still birth, obstructed labour, ruptured uterus, maternal sepsis, low Apgar score, admission to neonatal ICU and hysterectomy. Exposure variable for intervention group was a phone call prior maternal referral from a lower health facility. We compared distribution of clinical characteristics and adverse maternal-fetal outcomes between intervention and control groups using Chi square or Fisher's exact test. We performed logistic regression to assess association between independent variables and adverse maternal-fetal outcomes., Results: We enrolled 177 participants: 75 in intervention group and 102 in control group. Participants had similar demographic characteristics. Three quarters (75.0%) of participants in control group delayed on admission waiting bench of MRRH compared to (40.0%) in intervention group [p =  < 0.001]. There were significantly more adverse maternal-fetal outcomes in control group than intervention group (obstructed labour [p = 0.026], low Apgar score [p = 0.013] and admission to neonatal high dependency unit [p =  < 0.001]). The phone call intervention was protective against adverse maternal-fetal outcome [aOR = 0.22; 95%CI: 0.09-0.44, p = 0.001]., Conclusion: The phone call intervention resulted in reduced delay to patient admission at a tertiary referral hospital in a resource limited setting, and is protective against adverse maternal-fetal outcomes. Incorporating the phone call communication intervention in the routine practice of emergency obstetric referrals from lower health facilities to regional referral hospitals may reduce both maternal and fetal morbidities., Trial Registration: Pan African Clinical Trial Registry PACTR20200686885039., (© 2022. The Author(s).)

Objectives: International data on listeriosis during infancy from large populations are essential to guide evidence-based empiric antibiotic guidelines for sepsis in infancy. We aimed to determine the incidence, clinical manifestations, and outcome of listeriosis in infants <6 months of age in Canada and Switzerland., Methods: Prospective, active surveillance of listeriosis in infants <6 months of age was conducted through the Canadian Paediatric Surveillance Program (May 2015 to April 2017) and the Swiss Paediatric Surveillance Unit (April 2017 to March 2018). Confirmed and probable cases were included., Results: In Canada, eight sporadic listeriosis cases were reported (incidence, 1.1/100,000 live births/year). In Switzerland, four cases were reported (incidence, 4.5/100,000 live births/year) of which three were part of a confirmed outbreak with an unclear source. In the two countries, eight of the 12 cases (66.6%) presented as early-onset disease (within the first 7 days of life) and none presented after 28 days life., Conclusions: Neonatal listeriosis is rare. Infants presenting with sepsis, especially after 4 weeks of life, may not routinely require empiric antibiotic coverage for listeriosis. Outbreak-related cases still occur. Continued surveillance is important., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Canadian Paediatric Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

This commentary draws on sub-Saharan African health researchers' accounts of their countries' responses to control the spread of COVID-19, including social and health impacts, home-grown solutions, and gaps in knowledge. Limited human and material resources for infection control and lack of understanding or appreciation by the government of the realities of vulnerable populations have contributed to failed interventions to curb transmission, and further deepened inequalities. Some governments have adapted or limited lockdowns due to the negative impacts on livelihoods and taken specific measures to minimize the impact on the most vulnerable citizens. However, these measures may not reach the majority of the poor. Yet, African countries' responses to COVID-19 have also included a range of innovations, including diversification of local businesses to produce personal protective equipment, disinfectants, test kits, etc., which may expand domestic manufacturing capabilities and deepen self-reliance. African and high-income governments, donors, non-governmental organizations, and businesses should work to strengthen existing health system capacity and back African-led business. Social scientific understandings of public perceptions, their interactions with COVID-19 control measures, and studies on promising clinical interventions are needed. However, a decolonizing response to COVID-19 must include explicit and meaningful commitments to sharing the power-the authority and resources-to study and endorse solutions.

In this series of interviews, the Clinical and Investigative Medicine editorial team gathered expert opinions on the future of physician-scientist training and career prospects in Canada. This was inspired by recent publications that voiced concerns over the diminishing support for the physician-scientist in Canada and the United States. For this editorial, the term physician-scientist was intentionally broad and inclusive; referring to individuals who identify both clinical work and biomedical or healthcare research as major components of their career. The following leaders in medical research or research funding shared their perspectives: Roderick R. McInnes; Michel G. Bergeron; Thomas J. Marrie; and Bev J. Holmes.

Background: Exclusive breastfeeding (EBF) is one of the key strategies to ensure infants and young children survive and grow. However, a 2010 study showed that it was only practiced by 50% of Tanzanian women. That study also found that men were rarely supportive; either at home or in the health facilities, due to their personal beliefs or to traditional beliefs and culture of the community. In a report six years later the rate of EBF has decreased to 30%, in one region., Methods: In this qualitative study, we used focus groups to assess the knowledge and attitudes of 35 men from three villages on the benefits of EBF, the disadvantages of not breastfeeding , and how they can support their partners' breastfeeding. In addition, we assessed how they felt about spending time at home, if they considered handling the infant to be rewarding and whether they helped the mother with home chores. Differences in village infrastructure and characteristics were noted., Results: Five themes were identified, including traditional roles, and feelings of exclusion/inclusion and resistance. Men felt they needed better information on EBF. They wished that their partners could breastfeed for a longer time, since they realized it improved infant growth and prevented disease; however, they did not have time to remain with the infant at home. Poverty required the men to work for long periods outside the home. As well, the men were not involved with the Reproductive Child Health Clinic (RCHC) except at the time of delivery or for mandatory HIV testing, however, they wanted to be educated together with their partners at the RCHC., Conclusion: Most men in this study understood that the EBF period was important, and that it broadened their relationship with their partner. EBF, however, could be a challenge for couples because of poverty. Nevertheless, many men wanted to help and to become more involved., Competing Interests: Competing interestsNone., (© The Author(s). 2019.)

Bob is a pediatric infectious disease specialist at Dalhousie University, where he did research on the ontogeny of the immune system in neonates. He was VP Research at the IWK Health Centre (1992-2007). He developed the curriculum for a CIHR train-ing program and edited "Handbook for Clinician Scientists". In 2008, he cofounded MicroResearch, which helps clinicians in Africa do research that will improve health programs there. He is also a Professor Emeritus at Dalhousie University and current Editor-in-Chief of CIM.

Think back; think wayyy back: before laptops, internet and smartphones. Bank machines didn't exist, tele-phones were permanently plugged into the wall, airport security meant only checking that you paid for your ticket and medical journals came in the mail (as did the bills for the journals). As it turned out, the 1970s was not a kind decade for medical journals, and several were struggling financially. Even the New England Journal of Medicine (NEJM), desperate for cash, was forced to offer a lifetime subscription to anyone who could pay the princely sum of $350! (A colleague of ours, now retired, still receives the weekly NEJM by mail, 45 years later!).

A decade of CITAC Annual General Meetings: 2007-2017 In 2007, the Clinician Investigator Trainee Association of Canada (CITAC) launched its inaugural Annual General Meeting (AGM). The AGM has since become a major annual event, jointly organized by CITAC and leaders from the Canadian Society for Clinical Investigation (CSCI), and continues to provide a forum for clinician investigator (CI) trainees to exchange ideas, advance career prospects and engage with the broader community. Indeed, since its inception, all Canadian institutions with medical doctor and clinician investigator (MD+CI) training programs have participated in the AGM, while more than 1,000 trainees have registered as CITAC members. The 10th CITAC-CSCI AGM was recently held in Toronto (November 20-22, 2017). There were nearly 200 attendees, including CI trainees, faculty member and physician leaders from across Canada (Figure 1A, 1B). Trainees spanning diverse career stages had opportunities to participate in interactive poster sessions, workshops and lectures by leading physician-scientists. These exercises were designed to encourage and enhance networking, career development and mentorship for prospective physician-scientists.

It is hard to believe but Clinical and Investigative Medicine (CIM), the official journal of Canadian Society for Clinical Investigation (CSCI), will soon celebrate its 40th birthday!  Over these past four decades, CIM has been the premier journal for Canadian clinician scientists; publishing over 1,000 articles on breakthroughs and major advances from Canada and around the world.  We are listed on Medline, PubMed and the Library of Science. We have been, and will continue to be, an independent journal. To celebrate this auspicious occasion, we have plans to become an even bigger showpiece for national and international clinical advances. We want to connect more closely with Canadian clinician scientists and trainees and we particularly want to encourage more Canadian publications. Changes will soon be coming to CIM with several new features: Newsletter with announcements and news on activities of interest to clinician scientists and trainees; Focused Reviews on specific areas of research; Reflections on work and life experiences of trainees and senior clinician scientists; Methods Papers describing novel methods anticipated to be useful for others; and  Guidelines or Recommendations on clinical care that are endorsed by a Canadian Medical or Surgical Society. Starting in 2018, we will be publishing on a quarterly basis. This will help to ensure we will focus on important breakthroughs and commentaries. However, we are also planning a special edition in the autumn to commemorate the 40th birthday. Stay tuned! Of course CIM will continue to publish original papers on discoveries in pathophysiology, prevention, management, treatment and outcome of clinical problems confronting clinicians in Canada and around the world.  Please join us as we embark on these changes and a new era for CIM, Robert Bortolussi Clinical and Investigative Medicine (CIM) Editor in Chief.

The urgent need in Africa for research capacity building has been recognized by African leaders and governments for many years. However, lack of large research funding opportunities has been seen as a major obstacle to improving research capacity in precisely those countries that need it the most. Microfinance has shown that a small infusion of capital can "prime the pump" to creative local economic productivity. In a similar way, MicroResearch has proven effective in promoting a similar bottom-up strategy to find sustainable solutions to local health challenges through local community focused research. Specifically, MicroResearch through hands-on didactic courses, mentoring and small-scale research funding promotes small research projects that improve research skills across the entire health-care provider spectrum to unleash a culture of inquiry. This in turn stimulates health care providers to identify the locally most relevant obstacles that need to be overcome and implement locally feasible and sustainable solutions. MicroResearch is a bottom-up strategy proven effective at finding sustainable solutions to local health challenges., (Copyright © 2015 The British Infection Association. Published by Elsevier Ltd. All rights reserved.)

Prophylactic antibiotics for urinary tract infections are no longer routinely recommended. A large number of children must be given prophylaxis to prevent one infection and antibiotic resistance is a major concern when treating community-acquired urinary tract infections. The results of three recent significant studies are examined, with focus on the efficacy of prophylaxis, and recommendations are made.

Recent studies have resulted in major changes in the management of urinary tract infections (UTIs) in children. The present statement focuses on the diagnosis and management of infants and children >2 months of age with an acute UTI and no known underlying urinary tract pathology or risk factors for a neurogenic bladder. UTI should be ruled out in preverbal children with unexplained fever and in older children with symptoms suggestive of UTI (dysuria, urinary frequency, hematuria, abdominal pain, back pain or new daytime incontinence). A midstream urine sample should be collected for urinalysis and culture in toilet-trained children; others should have urine collected by catheter or by suprapubic aspirate. UTI is unlikely if the urinalysis is completely normal. A bagged urine sample may be used for urinalysis but should not be used for urine culture. Antibiotic treatment for seven to 10 days is recommended for febrile UTI. Oral antibiotics may be offered as initial treatment when the child is not seriously ill and is likely to receive and tolerate every dose. Children <2 years of age should be investigated after their first febrile UTI with a renal/bladder ultrasound to identify any significant renal abnormalities. A voiding cystourethrogram is not required for children with a first UTI unless the renal/bladder ultrasound reveals findings suggestive of vesicoureteral reflux, selected renal anomalies or obstructive uropathy.

We evaluated the efficacy of oral glutamine supplementation in children 2 to 60 months of age with persistent diarrhea by 1:1 randomization to standard treatment alone or together with twice daily glutamine. The failure rate was similar in both arms (relative risk: 1.8 [95% confidence interval: 0.8-3.7], P = 0.12). Glutamine supplementation showed no benefit on the outcome of persistent diarrhea.

The uniform use in Canada of a single Haemophilus influenzae type b conjugate vaccine in combination with diphtheria, tetanus, acellular pertussis, and inactivated poliovirus vaccines (DTaP.IPV/Hib) facilitates ongoing assessment of vaccine effectiveness, including any effects of recently added concurrent vaccinations and increasing time since vaccination. Surveillance at 12 pediatric centers in 2004-2007 indicates that vaccine failures remain rare and case totals approach an irreducible minimum, with no age shift.

Purpose: Human newborn infants have increased susceptibility to gram-negative bacterial infection. Since lipopolysaccharide (LPS) primes polymorphonuclear neutrophils (PMN) to enhance host defense functions, we investigated its effect on adult and newborn PMN in vitro., Methods: PMN were isolated from blood of healthy adults and umbilical cords of full term newborns using dextran and Ficoll-Paque gradient sedimentation. Gel electrophoresis and Western blotting of membranes were used to probe for Mitogen-Activated Protein (MAP) kinase p38 phosphorylation, Toll-like Receptor-4 (TLR-4) and Myeloid Differentiation Factor 88 (MyD88) on isolated PMN membranes using specific antibodies. LPS induced degranulation was assessed using CD66 expression on PMN measured by flow cytometry., Results: We show that p38 phosphorylation in newborn PMN is attenuated in response to LPS stimulation even though adult and newborn PMN have similar amounts of p38 protein. The degree of attenuation in newborn PMN is dependent on the osmolarity of the medium. In addition, LPS-induced degranulation, a process that is p38 dependent, was also absent in newborn PMN. Although the LPS receptor TLR-4 is present at similar levels on newborn and adult PMN, its downstream adaptor protein MyD88 was significantly diminished in newborn PMN compared to adult cells., Conclusions: Although the mechanism of PMN priming by LPS is not fully understood, our results suggest that MyD88 and p38 phosphorylation are important pathways in the process and contribute to attenuated response of newborn PMN to LPS in vitro.

A boy with lifelong recurrent bacterial infection at cutaneous and mucosal sites was investigated. PMN oxidative burst to phorbol myristate acetate (PMA) and zymosan was normal but was increased 20- to 50-fold upon C5a or formyl-met-leu-phe (fMLP) chemoattractant stimulation, accompanied by accelerated PMN apoptosis. His PMNs showed increased constitutive tyrosine phosphorylation of 21-, 25-, and 44-kDa proteins, and of src-family kinases (p59(hck), p58(fgr), and p53/56(lyn)). Phosphorylation was abnormally enhanced following fMLP stimulation. Expression and activity of the major PMN tyrosine phosphatases, i.e., CD45, CD148, and SHP-1 and -2, was normal. However, dephosphorylation of phospho-p58(fgr) and phospho-p53/56(lyn) by lysates of patient's PMNs was enhanced. Thus, another phosphatase may be overactive, perhaps dephosphorylating a regulatory (inhibitory) site on a protein tyrosine kinase, accounting for the abnormal PMN tyrosine phosphorylation and function. With age (now 13 years), T-cell lymphopenia and loss of T-cell responses developed. This appears to be a unique primary immunodeficiency with abnormal PMN oxidative and apoptotic responses to chemoattractants, dysregulated protein tyrosine phosphorylation, serious bacterial infection, and T-lymphocyte attrition.

Human newborns are more susceptible than adults to bacterial infection. With gram-negative bacteria, this may be due to a diminished response of newborn leukocytes to lipopolysaccharide (LPS). Since protein tyrosine kinase inhibition abolishes LPS priming in adult cells, we hypothesized that protein tyrosine kinases may have a critical role in LPS priming of polymorphonuclear neutrophils (PMNs) and that newborn PMNs may have altered protein tyrosine kinase activities. In the present study, we investigated the role of src family protein tyrosine kinases in the LPS response of newborn PMNs compared to adult cells. In a respiratory assay, the LPS-primed increase in formylmethionylleucylphenylalanine (fMLP)-triggered O2- release by adult PMNs was greatly decreased by PP1 [4-amino-5-(4-methyphenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine], a src kinase inhibitor, to the level of untreated newborn PMNs, in which LPS failed to prime. LPS activated the src-like kinases p59hck (HCK) and p58fgr (FGR) in both adult and newborn PMNs but increased the activation of p53/56lyn (LYN) only in adult cells. In newborn PMNs, LYN was highly phosphorylated independent of LPS. We evaluated subcellular fractions of PMNs and found that the phosphorylated form of LYN was mainly in the Triton-extractable, cytosolic fraction in adult PMNs, while in newborn cells it was located mainly in Triton-insoluble, granule- and membrane-associated fractions. In contrast, the phosphorylated mitogen-activated protein kinases ERK1/2 and p38 were mainly detected in the cytosol in both adult and newborn PMNs. These data indicate a role for LYN in the regulation of LPS priming. The trapping of phosphorylated LYN in the membrane-granule fraction in newborn PMNs may contribute to the deficiency of newborn cells in responding to LPS stimulation.

Human newborns are more susceptible than adults to infection by gram-negative bacteria. We hypothesized that this susceptibility may be associated with a decreased response by leukocytes to lipopolysaccharide (LPS). In this study, we compared LPS-induced secretion of tumor necrosis factor alpha (TNF-alpha) by mononuclear cells (MNC) from adult peripheral blood and newborn umbilical cord blood in vitro and attempted to determine the mechanisms involved in its regulation. At a high concentration of LPS (10 ng/ml) and in the presence of autologous plasma, MNC from adults and newborns secreted similar amounts of TNF-alpha. However, in the absence of plasma, MNC from newborns secreted significantly less TNF-alpha compared to MNC from adults. Moreover, at a low concentration of LPS (0.1 ng/ml) and in the presence of plasma, TNF-alpha secretion was significantly lower for newborn MNC compared to adult MNC. Adults and newborns had similar numbers of CD14 and Toll-like receptor 4 (TLR-4)-positive cells as measured by flow cytometry. However, the intensity of the CD14 marker was greater for adult than for newborn cells. Incubation of cells with LPS led to an increase in CD14 and TLR-4 intensity for adult cells but not for newborn cells. The effect of LPS stimulation of adult or newborn cells was similar for ERK, p38, and IkappaBalpha phosphorylation, as well as IkappaBalpha degradation. Finally, we assessed levels of the TLR-4 adapter protein, the myeloid differentiation antigen 88 (MyD88). We found a direct relation between adult and newborn TNF-alpha secretion and MyD88, which was significantly decreased in newborn monocytes. Since TLR-4 signals intracellularly through the adapter protein, MyD88, we hypothesize that MyD88-dependent factors are responsible for delayed and decreased TNF-alpha secretion in newborn monocytes.

Introduction: Penicillin allergy, commonly reported in children, leads to use of more expensive, broad-spectrum drugs. The results and effectiveness of a skin testing program for immediate hypersensitivity to penicillin in children were studied., Methods: Children seen at the IWK Health Centre in Halifax between 1986 and 2000 with a history of suspected penicillin allergy were referred by their family physician or pediatrician. Two-stage skin testing (scratch, intradermal) of benzylpenicilloyl-polylysin and penicillin G sodium, with histamine and saline as positive and negative controls, was carried out. If the test results were negative, an oral challenge was conducted and the child observed for 60 minutes. If no adverse reaction was noted, a letter was sent to the referring physician and to Health Records at the IWK Health Centre, indicating that warning labels should be removed from the chart., Results: Of 72 children tested, 32% described their past cutaneous eruption as hives and 68% had other rashes; 96% of rashes were generalized. The mean age at the time of the suspected penicillin allergy was 4.4 years; it was 7.4 years at the time of testing. There was no positive response to the scratch testing, but 4% of children had a positive response to intradermal testing. No adverse responses to oral challenge were observed. Letters confirming negative status were not received in 4% (3 of 69) cases, resulting in ongoing avoidance of penicillins and falsely labelling of the child as penicillin allergic., Conclusions: In this referral setting, true penicillin allergy was uncommon, suggesting that many children are incorrectly labelled as penicillin-allergic. Communication of test results to family and care providers and health records administration must be effective if testing is to affect prescribing behaviour.

Neutrophil (PMN) functions can be primed for greatly increased oxidative radical release by exposure to certain agents such as lipopolysaccharide (LPS). Although a variety of signaling pathways involving both tyrosine kinases and mitogen-activated protein (MAP) kinases may be operative, the mechanisms of PMN priming are still not understood. We found that PMN priming was not achieved by treatment of cells with a very low concentration (5 ng/ml) of LPS unless additional "helper" factors were present in plasma (5%). Under these conditions, LPS induced tyrosine phosphorylation of a 38-kDa protein, which was coincident with the MAP kinase p38 action in this situation. LPS-mediated activation of p38 in human PMNs was dependent on the presence of LPS binding protein from plasma and CD14 on the surfaces of the cells. Phosphorylation of p38 was highly correlated with LPS priming of a formyl-methionyl-leucyl-phenylalanine (fMLP)-stimulated PMN respiratory burst. Treatment of PMN with the p38-specific inhibitor SB203580 significantly attenuated the respiratory burst in cells primed by LPS and stimulated by fMLP. These results suggest that the LPS signaling pathway leading to p38 activation may be an important mechanism in regulation of PMN priming. The mediator(s) linking CD14 to p38 involves proteins that are functionally sensitive to genistein but insensitive to tyrphostin AG126 and to Src- and Syk-family kinase, protein kinase C, and phosphatidylinositol 3-kinase inhibitors. Elucidating this pathway will provide insight into possible regulation of PMN priming by LPS.

Objective: Canadian and international guidelines for research ethics practices have advocated that research ethics boards (REBs) should implement mechanisms to review and monitor human research. Despite this, few Canadian REBs fulfil this expectation. The objective of this report is to summarize the results of 6 audits of clinical research ethics conducted between 1992 and 2000 in a children's and women's academic hospital in Canada in an effort to guide other academic centres planning a similar process., Design: Research audits were conducted by members of a research audit review committee made up of REB volunteers. With use of random and selective processes, approximately 10% of research protocols were audited through interviews with research investigators and research coordinators and by sampling research records. Predetermined criteria were used to assess evidence of good record keeping, data monitoring, adherence to protocol, consents and the recording of adverse events during the research study. An estimate of time required to undertake an audit was made by recall of participants and records., Results: Thirty-five research studies were reviewed including 16 multicentre clinical trials and 19 single-site clinical studies. Review of record keeping and research practice revealed some deficiencies: researchers failed to maintain original authorization (7%) or renewal documentation (9%); there was 1 instance of improper storage of medication; in 5% of 174 participants for whom consent was reviewed, an outdated consent form had been used, and in 4% the signature of the enrolee was not properly shown. Other deficiencies in consent documentation occurred in less than 2% of cases. Nineteen recommendations were made with respect to deficiencies and process issues. A total of 9 to 20 person-hours are required to review each protocol in a typical audit of this type., Conclusions: Information from research audits has been useful to develop educational programs to correct deficiencies identified through the audits. The research audit is a valuable tool in improving research ethics performance but requires considerable resources.