Looking beyond year 1 in the molecular era of pediatric brain tumor diagnosis: confirmatory testing of germline variants found on tumor sequencing.

Purpose: Somatic molecular profiling of pediatric brain tumors aids with the diagnosis and treatment of patients with a variety of high- and low-grade central nervous system neoplasms. Here, we report follow-up targeted germline evaluation for patients with possible germline variants following tumor only testing in the initial year in which somatic molecular testing was implemented at a single institution. Patients and Methods: Somatic testing was completed for all tumors of the central nervous system (CNS) undergoing diagnostic workup at Seattle Children's Hospital during the study period of November 2015 to November 2016. Sequencing was performed in a College of American Pathologists-accredited, Clinical Laboratory Improvements Amendments-certified laboratory using UW-OncoPlex™ assay (version 5), a DNA-based targeted next generation sequencing panel validated to detect genetic alterations in 262 cancer-related genes. We tracked subsequent clinical evaluation and testing on a subgroup of this cohort found to have potential germline variants of interest. Results: Molecular sequencing of 88 patients' tumors identified 31 patients with variants that warranted consideration of germline testing. To date, 19 (61%) patients have been tested. Testing confirmed germline variants for ten patients (31% of those identified for testing), one with two germline variants (NF1 and mosaic TP53). Eight (26%) patients died before germline testing was sent. One patient (13%) has not yet had testing. Conclusion: Clinically validated molecular profiling of pediatric brain tumors identifies patients who warrant further germline evaluation. Despite this, only a subset of these patients underwent the indicated confirmatory sequencing. Further work is needed to identify barriers and facilitators to this testing, including the role of genetic counseling and consideration of upfront paired somatic-germline testing.

A Communication and Decision-Making Framework for Pediatric Precision Medicine.

Advances in genomic testing have been pivotal in moving childhood cancer care forward, with genomic testing now a standard diagnostic tool for many children, adolescents, and young adults with cancer. Beyond oncology, the role of genomic testing in pediatric research and clinical care is growing, including for children with developmental differences, cardiac abnormalities, and epilepsy. Despite more standard use in their patients, pediatricians have limited guidance on how to communicate this complex information or how to engage parents in decisions related to precision medicine. Drawing from empirical work in pediatric informed consent and existing models of shared decision-making, we use pediatric precision cancer medicine as a case study to propose a conceptual framework to approach communication and decision-making about genomic testing in pediatrics. The framework relies on identifying the type of genomic testing, its intended role, and its anticipated implications to inform the scope of information delivered and the parents' role in decision-making (leading to shared decision-making along a continuum from clinician-guided to parent-guided). This type of framework rests on practices known to be standard in other complex decision-making but also integrates unique features of genomic testing and precision medicine. With the increasing prominence of genomics and precision medicine in pediatrics, with our communication and decision-making framework, we aim to guide clinicians to better support their pediatric patients and their parents in making informed, goal-concordant decisions throughout their care trajectory.

Transcranial doppler velocity in iron-deficient Nigerian children with sickle cell anemia.

Oral iron supplementation in iron deficient children with sickle cell anemia and normal transcranial Doppler ultrasound (TCD) velocities does not reduce arterial flow in the middle cerebral artery.

Laparoscopic subtotal cholecystectomy for the difficult gallbladder: Evolution of technique at a single teaching hospital.

BACKGROUND: We have developed an algorithmic approach to laparoscopic cholecystectomy, including subtotal cholecystectomy, as a bailout strategy when the Critical View of Safety cannot be safely achieved due to significant inflammation and fibrosis of the hepatocystic triangle. METHODS: This is a retrospective cohort study comparing postoperative outcomes in patients with severe cholecystitis who underwent laparoscopic cholecystectomy or laparoscopic subtotal cholecystectomy at St. Joseph's Health Centre from May 2016 to July 2021, as well as against a historical cohort. We further stratified laparoscopic subtotal cholecystectomy cases based on fenestrating or reconstituting subtype. RESULTS: The cohort included a total of 105 patients who underwent laparoscopic cholecystectomy and 31 patients who underwent laparoscopic subtotal cholecystectomy. Bile leaks (25.8% vs 1.0%, relative risk 3.5, 95% confidence interval 3.5-208.4) were more common in the laparoscopic subtotal cholecystectomy group. Postoperative endoscopic retrograde cholangiopancreatography (22.6% vs 3.8%, relative risk 5.9, 95% confidence interval 1.9-18.9) and biliary stent insertion (19.4% vs 1.0%, relative risk 20.3, 95% confidence interval 2.5-162.5) were also more common in the laparoscopic subtotal cholecystectomy group. Bile leaks in laparoscopic subtotal cholecystectomy were only documented in the fenestration subtype, most of which were successfully managed with endoscopic retrograde cholangiopancreatography and biliary stenting. Compared to our previous study of laparoscopic cholecystectomy and subtotal cholecystectomy for severe cholecystitis between 2010 and 2016, there has been a decrease in postoperative laparoscopic cholecystectomy complications, subtotal cholecystectomy cases, and no bile duct injuries. CONCLUSION: Following our algorithmic approach to safe laparoscopic cholecystectomy has helped to prevent bile duct injury. Laparoscopic cholecystectomy remains the gold standard for the management of severe cholecystitis; however, in extreme cases, laparoscopic subtotal cholecystectomy is a safe bailout strategy with manageable morbidity.

Closed incision negative pressure wound therapy following pancreaticoduodenectomy for prevention of surgical site infections in high-risk patients.

BACKGROUND: Surgical site infection (SSI) is one of the most common sources of morbidity after pancreaticoduodenectomy. Surgical site infections are associated with readmissions, prolonged length of stay, delayed initiation of adjuvant chemotherapy and negative effects on quality of life. Incisional vacuum-assisted closure (iVAC) devices applied on closed incisions may reduce SSI rates. The objective of this retrospective review is to evaluate the impact of iVAC on SSI rate after pancreaticoduodenectomy. METHODS: A cohort of patients undergoing pancreaticoduodenectomy at a single institution who had at least 1 risk factor for SSI and who received an iVAC were compared with a historical cohort of high-risk patients who received conventional dressings after pancreaticoduodenectomy. The primary outcome was incidence of SSI within 30 days, abstracted from chart review. Secondary outcomes were 30-day readmission, 90-day mortality, rate of postoperative pancreatic fistula and rate of delayed gastric emptying. RESULTS: In total, 175 patients were included, of whom 61 received an iVAC. The incidence of SSI was 13% (8 of 61 patients) and 16% (18 of 114 patients) in the iVAC and conventional dressing groups, respectively (odds ratio 0.81, 95% confidence interval 0.33-1.98). Preoperative biliary drainage was the most frequent SSI risk factor. Binary logistic regression using SSI as the outcome demonstrated no significant association with iVAC use when adjusted for SSI risk factors. There were no differences in rates of postoperative pancreatic fistula, delayed gastric emptying or 90-day mortality. CONCLUSION: This report describes the outcomes of the integration of iVAC devices into routine clinical practice at a high-volume institution. Application of this device after pancreaticoduodenectomy for patients at elevated risk of SSI was not associated with a reduction in the rate of SSIs.

Comparing the Warshaw technique with vessel-preservation in laparoscopic spleen preserving distal pancreatectomy: is there a better approach?

BACKGROUND: Laparoscopic spleen-preserving distal pancreatectomy (LSPDP) can be accomplished with either resection of the splenic vessels via the Warshaw Technique (WT) or via preservation of the splenic vessels (SVP). Our study aims to compare outcomes for the two methods of LSPDP. METHODS: We performed a retrospective chart review with intent-to-treat analysis of adults undergoing LSPDP at a single institution from 2009 to 2021. We compared demographic characteristics, operative parameters, oncologic pathology review, and postoperative outcomes. RESULTS: There were 102 consecutive cases of LSPDP (59 WT, 43 SVP) over 12 years. The rate of successful spleen preservation was not significantly different between the two groups (76.3%WT, 65.1%VSP,p = 0.27). Rates of conversion to laparotomy, postoperative complications including pancreatic fistulas and splenic infarcts and amount of intraoperative blood loss were similar between the groups. Median operative time was significantly shorter with the WT (141 vs. 177 min, p < 0.05). The median length of stay in hospital was not significantly different among the groups. CONCLUSION: Both techniques are safe and effective in preserving the spleen in laparoscopic distal pancreatectomy. Our experience suggests that the Warshaw Technique may be more efficient with respect to the use of limited operative resources.

Profiles of Burnout and Response to the COVID-19 Pandemic Among General Surgery Residents at a Large Academic Training Program.

BACKGROUND: COVID-19 has placed demands on General Surgery residents, who are already at high risk of burnout. This study examined the pandemic's impact on burnout and wellness among General Surgery residents at a large training program. METHODS: General Surgery residents at our institution completed a survey focused on self-reported burnout, mental health, perceptions of wellness resources, and changes in activities during the pandemic. Burnout was measured using the Maslach Burnout Inventory (MBI). Unsupervised machine learning (k-means clustering) was used to identify profiles of burnout and comparisons between profiles were made. RESULTS: Of 82 eligible residents, 51 completed the survey (62% response rate). During COVID-19, 63% of residents had self-described burnout, 43% had depression, 18% acknowledged binge drinking/drug use, and 8% had anxiety. There were no significant differences from pre-pandemic levels (p all >.05). Few residents perceived available wellness resources as effective (6%). Based on MBI scores, the clustering analysis identified three clusters, characterized as "overextended", "engaged", and "ineffective". Engaged residents had the least concerning MBI scores and were significantly more likely to exercise, retain social contact during the pandemic, and had less self-reported anxiety or depression. Research residents were overrepresented in the ineffective cluster (46%), which had high rates of self-reported burnout (77%) and was characterized by the lowest personal accomplishment scores. Rates of self-reported burnout for overextended and engaged residents were 73% and 48%, respectively. CONCLUSION: Surgical residents have high rates of self-reported burnout and depression during the COVID-19 pandemic. Clusters of burnout may offer targets for individualized intervention.

Hydroxyurea for secondary stroke prevention in children with sickle cell anemia in Nigeria: a randomized controlled trial.

We tested the hypothesis that fixed oral moderate-dose hydroxyurea (20 mg/kg per day) for initial treatment of secondary stroke prevention results in an 80% relative risk reduction of stroke or death when compared with fixed oral low-dose hydroxyurea (10 mg/kg per day) in a phase 3 double-blind, parallel-group, randomized controlled trial in children with sickle cell anemia (SCA) living in Nigeria. A total of 101 participants were randomly allocated to low-dose (n = 49) and moderate-dose (n = 52) hydroxyurea treatment groups. The median participant follow-up was 1.6 years (interquartile range, 1.0-2.3), with a planned minimum follow-up of 3.0 years. A total of 6 recurrent strokes and 2 deaths vs 5 recurrent strokes and 3 deaths occurred in the low- and moderate-dose groups, respectively. The incidence rate ratio (IRR) of the primary outcome measure of stroke or death in the low- and moderate-dose hydroxyurea treatment groups was 0.98 (95% confidence interval [CI], 0.32-3.00; P = .97). The trial was stopped early owing to no clinical difference in the incidence rates of the primary outcome measure. The incidence rates of recurrent strokes were 7.1 and 6.0 per 100 person-years in the low- and moderate-dose groups, respectively, (IRR, 1.18; 95% CI, 0.30-4.88; P = .74). As a measure of adherence to the oral hydroxyurea therapy, the median percent of returned pills was 3.0% and 2.6% in the low- and moderate-dose groups, respectively. No participant had hydroxyurea therapy stopped for myelosuppression. For children with SCA in low-income settings without access to regular blood transfusion therapy, initial low-dose hydroxyurea is a minimum known efficacious dose for secondary stroke prevention.

Thinking Your Way Through a Difficult Laparoscopic Cholecystectomy: Technique for High-Quality Subtotal Cholecystectomy.

Laparoscopic subtotal cholecystectomy (LSC) is a bailout strategy to prevent bile duct injury in difficult gallbladder cases. It is associated with acceptable morbidity that is readily managed with postoperative interventions. Here we share our techniques for LSC. We begin with landmarking, which includes the line of safety, a theoretical line the sulcus of Rouvière and the junction of the cystic and hilar plates. If the fundus can be grasped, then the gallbladder is dissected off the cystic plate using the top-around approach. The gallbladder is then amputated, creating a short cuff of proximal gallbladder. This cuff can be left patent (2A) or cinched close with an ENDOLOOP (Ethicon) if it is small, ideally less than 1 cm (1A). If the fundus cannot be grasped, then an inverted T incision is made on the anterior gallbladder wall. The longitudinal incision is extended toward the fundus, and the transverse incision is extended superiorly along the cystic plate edge. Two "bunny ears" are developed and ultimately resected to excise the anterior gallbladder wall at an oblique angle while leaving the posterior wall intact (2B). If the remaining cuff is small, then it can be sutured closed against the gallbladder back wall (1B). In the setting of extensive bowel adhesion to the anterior gallbladder, we perform a fundectomy, from which we extend two incisions along the cystic plate to open the gallbladder like a clamshell. Our paper describes and illustrates our St Joseph's Health Centre institutional LSC approach and subtype classification (1A, 1B, 2A, and 2B).

Variations of intestinal malrotation in adults: A case report of midgut volvulus and literature review for the surgeon.

INTRODUCTION: Intestinal malrotation is a rare congenital abnormality occurring in 0.2-1% of the population. Adult presentations comprise only 0.2-0.5% of all cases leading to diagnostic challenges and worse outcomes in adults. We present a rare case of chronic/intermittent midgut volvulus with unique anatomic findings in an adult with intestinal malrotation. PRESENTATION OF CASE: An 18-year-old Caucasian male presented to a community hospital with abdominal pain, nausea, and vomiting. He underwent a CT scan demonstrating concern for small bowel volvulus and subsequently underwent a negative exploratory laparotomy. He was discharged post-operatively with no identified etiology for his presentation. He subsequently had multiple presentations to the ED with recurrent symptoms, review of imaging led to concern for duodenal volvulus resulting in transfer to a tertiary hepatobiliary centre. Repeat CT scan two weeks following initial presentation was consistent with intestinal malrotation with midgut volvulus. Bloodwork was unremarkable and physical exam demonstrated normal vital signs with a tender epigastrium. He underwent an exploratory laparotomy with Ladd's procedure. Intra-operative findings included a midgut volvulus and uniquely positioned Ladd's bands to the transverse colon. Post-operatively he tolerated oral intake and was discharged with three-month follow-up. DISCUSSION: Adults with intestinal malrotation suffer from delays in diagnosis and management. In contrast to the neonatal population, adults often present with vague, or chronic symptoms, which obscures the diagnosis. CONCLUSION: The increased morbidity and mortality observed in adults with intestinal malrotation highlights the need for surgeons to appreciate the challenges associated with this diagnosis in the adult population to ensure early recognition and management.

Hydroxyurea for primary stroke prevention in children with sickle cell anaemia in Nigeria (SPRING): a double-blind, multicentre, randomised, phase 3 trial.

BACKGROUND: In high-income countries, standard care for primary stroke prevention in children with sickle cell anaemia and abnormal transcranial Doppler velocities results in a 92% relative risk reduction of strokes but mandates initial monthly blood transfusion. In Africa, where regular blood transfusion is not feasible for most children, we tested the hypothesis that initial moderate-dose compared with low-dose hydroxyurea decreases the incidence of strokes for children with abnormal transcranial Doppler velocities. METHODS: SPRING is a double-blind, parallel-group, randomised, controlled, phase 3 trial of children aged 5-12 years with sickle cell anaemia with abnormal transcranial Doppler velocities conducted at three teaching hospitals in Nigeria. For randomisation, we used a permuted block allocation scheme with block sizes of four, stratified by sex and site. Allocation was concealed from all but the pharmacists and statisticians. Participants were assigned in a 1:1 ratio to low-dose (10 mg/kg per day) or moderate-dose (20 mg/kg per day) oral hydroxyurea taken once daily with monthly clinical evaluation and laboratory monitoring. The primary outcome was initial stroke or transient ischaemic attack, centrally adjudicated. The secondary outcome was all-cause hospitalisation. We used the intention-to-treat population for data analysis. The trial was stopped early for futility after a planned minimum follow-up of 3·0 years to follow-up for participants. This trial was registered with ClinicalTrials.gov, number NCT02560935. FINDINGS: Between Aug 2, 2016, and June 14, 2018, 220 participants (median age 7·2 years [IQR 5·5-8·9]; 114 [52%] female) were randomly allocated and followed for a median of 2·4 years (IQR 2·0-2·8). All participants were Nigerian and were from the following ethnic groups: 179 (82%) people were Hausa, 25 (11%) were Fulani, and 16 (7%) identified as another ethnicity. In the low-dose hydroxyurea group, three (3%) of 109 participants had strokes, with an incidence rate of 1·19 per 100 person-years and in the moderate-dose hydroxyurea group five (5%) of 111 had strokes with an incidence rate of 1·92 per 100 person-years (incidence rate ratio 0·62 [95% CI 0·10-3·20], p=0·77). The incidence rate ratio of hospitalisation for any reason was 1·71 (95% CI 1·15-2·57, p=0·0071), with higher incidence rates per 100 person-years in the low-dose group versus the moderate-dose group (27·43 vs 16·08). No participant had hydroxyurea treatment stopped for myelosuppression. INTERPRETATION: Compared with low-dose hydroxyurea therapy, participants treated with moderate-dose hydroxyurea had no difference in the stroke incidence rate. However, secondary analyses suggest that the moderate-dose group could lower incidence rates for all-cause hospitalisations. These findings provide an evidence-based guideline for the use of low-dose hydroxyurea therapy for children with sickle cell anaemia at risk of stroke. FUNDING: National Institute of Neurological Disorders and Stroke.

Establishing Sickle Cell Disease Stroke Prevention Teams in Africa is Feasible: Program Evaluation Using the RE-AIM Framework.

We used the Reach, Effectiveness, Adoption, Implementation, and Maintenance (RE-AIM) framework to evaluate a Stroke Prevention Team's readiness to prevent strokes in children with sickle cell anemia living in northern Nigeria. The NIH sponsored Stroke Prevention Trial in Nigeria included a goal of a sustainable stroke prevention program. The program's 1-year reach for transcranial Doppler screening was 14.7% (4710/32,000) of which 6.0% (281/4710) had abnormal velocities (≥200 cm/s). All participants with abnormal transcranial Doppler velocities were started on hydroxyurea (effectiveness). The leaders of all 5 hospitals agreed to adopt the program. After 1 year, program-implementation and maintenance rates were 100%, demonstrating the program's feasibility and short-term sustainability.

Capacity Building for Primary Stroke Prevention Teams in Children Living With Sickle Cell Anemia in Africa.

BACKGROUND: Nigeria has the highest proportion of children with sickle cell anemia (SCA) globally; an estimated 150,000 infants with SCA are born annually. Primary stroke prevention in children with SCA must include Nigeria. We describe capacity-building strategies in conjunction with two National Institutes of Health-funded primary stroke prevention trials (a feasibility trial and phase III randomized controlled trial) with initial hydroxyurea treatment for children with SCA and abnormal transcranial Doppler (TCD) velocities in Nigeria. We anticipated challenges to conducting clinical trials in a low-resource setting with a local team that had not previously been involved in clinical research and sought a sustainable strategy for primary stroke prevention. METHODS: This is a descriptive, prospective study of challenges, solutions, and research teams in two trials that enrolled a total of 679 children with SCA. RESULTS: As part of the capacity-building component of the trials, over eight years, 23 research personnel (physicians, nurses, research coordinators, a statistician, and a pharmacist) completed a one-month research governance and ethics training program at Vanderbilt University Medical Center, USA. A lead research coordinator for each site completed the Society of Clinical Research Professionals certification. TCD machines were donated; radiologists and nonradiologists were trained and certified to perform TCD. A scalable E-prescription was implemented to track hydroxyurea treatment. We worked with regional government officials to support ongoing TCD-based screening and funding for hydroxyurea for children with SCA at a high risk of stroke. CONCLUSIONS: Our trials and capacity building demonstrate a sustainable strategy to initiate and maintain pediatric SCA primary stroke prevention programs in Africa.

Relationship Between Breast and Axillary Pathologic Complete Response in Women Receiving Neoadjuvant Chemotherapy for Breast Cancer.

OBJECTIVE: We aim to delineate the relationship between breast and axillary pathologic complete response (pCR) in patients receiving neoadjuvant chemotherapy for breast cancer. METHODS: We performed a retrospective cohort study of patients with clinical T1-4N0-3M0 breast cancer receiving neoadjuvant chemotherapy followed by surgical therapy at Sunnybrook Health Sciences Centre in Toronto, Canada between 2014 and 2019. Clinicopathologic data were abstracted from the electronic medical record. Women were stratified into receptor subtypes as follows: hormone receptor positive (HR+)/human epidermal growth factor receptor 2 negative (HER2-), HR+/HER2+, HR-/HER2+ and HR-/HER2- (triple negative) and compared with Fisher's exact test. Our primary outcome was to assess the positive predictive value of breast pCR for determining axillary pCR, and vice versa. RESULTS: There were 374 breast cancers, with 109 (29.1%) achieving breast pCR (ypT0/Tis). Amongst node-positive tumours achieving breast pCR, rates of associated axillary pCR (ypN0/0i+) were as follows: HR+/HER2- (2/6, 33.3%), HR+/HER2+ (12/13, 92.3%), HR-/HER2+ (15/17, 88.2%) and triple negative (15/17, 88.2%) (P = 0.02). Conversely, amongst node-positive tumours achieving axillary pCR, rates of associated breast pCR were: HR+/HER2- (2/10, 20.0%), HR+/HER2+ (12/23, 52.2%), HR-/HER2+ (15/24, 62.5%) and triple negative (15/26, 57.7%) (P = 0.1). CONCLUSIONS: Breast pCR is a strong predictor of axillary pCR in women with HER2-positive and triple-negative breast cancers. Conversely, axillary pCR is a modest predictor of breast pCR for these subtypes. There is a poor relationship between breast and axillary pCR in women with hormone receptor-positive disease. These data may inform future de-escalation of surgery in women with HER2-positive and triple-negative disease.

Helping the Surgeon Recover: Peer-to-Peer Coaching after Bile Duct Injury.

BACKGROUND: Bile duct injury sustained during laparoscopic cholecystectomy is associated with high morbidity and mortality, and can be a devastating complication for a general surgeon. We introduce a novel, individualized surgical coaching program for surgeons who recently injured a bile duct in laparoscopic cholecystectomy. We aim to explore the perception of coaching among these surgeons and to assess surgeons' experiences in the coaching program. STUDY DESIGN: Six general surgeons who injured a bile duct at an emergency laparoscopic cholecystectomy participated in a 1-on-1 coaching session with a hepatopancreatobiliary surgeon. The session focused on debriefing the index case with video feedback, and discussion of strategies for safe laparoscopic cholecystectomy. The pilot program ran from March to November 2020. Exit interviews were then conducted. Themes covering perception of surgical training, perception of complications, and experience in the coaching program were explored. RESULTS: Surgeons were generally accepting of the coaching program, especially when the goals aligned with their self-identified areas of development. One-on-1 sessions with a local expert in the area, and the use of video feedback created a unique and interactive coaching opportunity. Peer coaching was identified as a valuable resource in helping surgeons regain confidence and maintain well-being after a bile duct injury. Maintaining a collegial, nonjudgmental relationship is critical in establishing positive coaching experiences. CONCLUSIONS: An individualized surgical coaching program creates a unique opportunity for professional development and may help promote safe laparoscopic cholecystectomy.

The inferior boundary of dissection as a novel landmark for safe laparoscopic cholecystectomy.

BACKGROUND: Since the introduction of laparoscopic cholecystectomy over 30 years ago, rates of bile duct injury have remained elevated compared to the era of open cholecystectomy. We propose an anatomical landmark, the Inferior Boundary of Dissection, to help prevent dangerous dissection in the porta hepatis and provide clues as to when a critical view of safety may not be immediately achieved. METHODS: This landmarking approach is based on fundamentals of biliary anatomy and surface landmarks of the liver. RESULTS: The 'Boundary' extends from Rouviere's sulcus to the junction of the peritoneum and fat overlying the cystic and hilar plates, near the base of segment 4. This anatomic landmark represents the lower boundary for safe dissection, by outlining the location of the biliary pedicles. CONCLUSION: The two points of reference are reliable surface landmarks with predictable and consistent relationships to the biliary pedicles. It also serves as a line above which the gallbladder can be opened or mobilized in a 'top-around' approach, facilitating subtotal cholecystectomy when the hepatocystic triangle appears hostile due to inflammation. The landmark has been well-received in our region as a facile instrument for safe cholecystectomy and we advocate for its broader use.

Primary prevention of stroke in children with sickle cell anemia in sub-Saharan Africa: rationale and design of phase III randomized clinical trial.

Strokes in children with sickle cell anemia (SCA) are associated with significant morbidity and premature death. Primary stroke prevention in children with SCA involves screening for abnormal transcranial Doppler (TCD) velocity coupled with regular blood transfusion therapy for children with abnormal velocities, for at least one year. However, in Africa, where the majority of children with SCA live, regular blood transfusions are not feasible due to inadequate supply of safe blood, cost, and the reluctance of caregivers to accept transfusion therapy for their children. We describe the Primary Prevention of Stroke in Children with Sickle Cell Disease in Nigeria Trial [StrokePreventioninNigeria (SPRING) trial, NCT02560935], a three-center double-blinded randomized controlled Phase III clinical trial to 1) determine the efficacy of moderate fixed-dose (20 mg/kg/day) versus low fixed-dose (10 mg/kg/day) hydroxyurea therapy for primary stroke prevention; 2) determine the efficacy of moderate fixed-dose hydroxyurea for decreasing the incidence of all cause-hospitalization (pain, acute chest syndrome, infection, other) compared to low fixed-dose hydroxyurea. We will test the primary hypothesis that there will be a 66% relative risk reduction of strokes in children with SCA and abnormal TCD measurements, randomly allocated, for a minimum of three years to receive moderate fixed-dose versus low fixed-dose hydroxyurea (total n = 220). The results of this trial will advance the care of children with SCA in sub-Saharan Africa, while improving research capacity for future studies to prevent strokes in children with SCA.