The pediatric surgeon-scientist: An evolving Breed or endangered phenotype?

INTRODUCTION: National Institute of Health (NIH) funding is a "gold-standard" of achievement; we examined trends in NIH-funded pediatric surgeons. METHODS: NIH Research Portfolio Online Reporting Tools (RePORT) was queried for American Pediatric Surgical Association (APSA) members (2012 vs 2022). Demographics and time-to-award (TTA) from fellowship were compared. Number of grants, funding allotment, award classification, administering institutes/centers, research type were studied. RESULTS: Thirty-eight (4.6%) APSA members were NIH-funded in 2012 compared to 37 (2.9%) in 2022. Of funded surgeons in 2022, 27% were repeat awardees from 2012. TTA was similar (12 vs 14years, p=0.109). At each point, awards were commonly R01 grants (40 vs 52%, p â€‹= â€‹0.087) and basic science-related (76 vs 63%, p = â€‹0.179). Awardees were predominantly men (82% in 2012 vs 78% in 2022, p=0.779) and White (82% in 2012 vs 76% in 2022, p=0.586). Median amount per grant increased: $254,980 (2012) to $364,025 (2022); by $96,711 for men and $390,911 for women. Median awards for White surgeons increased by $215,699 (p=0.035), and decreased by $30,074 for non-White surgeons, though not significantly (p=0.368). CONCLUSION: The landscape of NIH-funded pediatric surgeons has remained unchanged between time points. With a substantial number of repeat awardees, predominance of R01 grants, and a median TTA over a decade after fellowship graduation, the phenotypes of early career pediatric surgeon-scientists are facing academic endangerment.

Bingo as a Novel Approach to Skill Building in the Initial Months of Surgical Internship: A Pilot Implementation.

Introduction: We have observed inconsistencies in residents' experiences regarding important procedures and tasks necessary for patient care. We aimed to improve individual motivation to learn and become facile with specific practices earlier in the timeline of the internship years. Methods: Intern Bingo was implemented in a single general surgery residency. Two sites, both tertiary care centers with institutional practices, were utilized. Twenty-four procedures/tasks important to clinical practice were identified, including but not limited to Nasogastric Tube placement, IV insertion, incision and drainage, laceration repair, vascular doppler exam, and clinical documentation. Bingo cards were randomly generated. To assess comprehension, interns taught back necessary components to a senior resident or attending to complete each bingo square; including indications, supplies, steps, troubleshooting techniques, and complications. First, the residents were awarded prizes to complete a row and a full card (a cloth scrub cap and portable pulse-oximeter, respectively). A Likert-scale survey assessing satisfaction was administered following the completion of the internship period. Results: The first row was completed in two weeks and the first full card at four weeks. All participants finished the cards within 8 weeks. 54% of the participants returned the survey and 100% reported positive experiences. 50% felt that bingo created a healthy learning environment with improved teaching, and the remaining 50% were neutral. 75% reported that Bingo positively influenced decisions to seek out opportunities. 100% conveyed a desire to repeat Bingo as mentors. Feedback from the attendings was gathered, with positive assessments of the interns' skills and confidence. Conclusion: Bingo is a simple and easily implemented educational tool that works to alleviate variations in experience early in the internship period. It represents a novel and effective way to motivate the interns to learn important procedures and tasks within the first two months of residency. Cards may be effortlessly tailored to a variety of residency programs and rotations.

Outcomes of Prolonged Open Abdomen in Children.

INTRODUCTION: We sought to better characterize outcomes in pediatric patients requiring open abdomen for instability with ongoing resuscitation, second look surgery, or left in discontinuity or congenital or acquired loss of domain that may lead to prolonged open abdomen (POA) or difficulties in successful abdominal wall closure. METHODS: We performed a single-institution retrospective review of patients aged less or equal to 18 years who presented to our institution from 2015 to 2022. We defined POA as requiring three or more surgeries prior to abdominal wall closure. Descriptive statistics were performed using median and interquartile range. RESULTS: Median age was 15 years (interquartile range 0-6 years), 46% female, and 69% White. Survival rate was 93% for the entire cohort. The most common indication for open abdomen was second look/discontinuity 22/41 (54%). The most common temporary abdominal wall closure was wound vac (43%). Fifty eight percent patients achieved primary tissue closure, the remaining required mesh. Of the 42 patients, 25 required POA. They had increasing rate of secondary infections at 56% compared to 44% (P = 0.17). The groups were further divided into indications for open abdomen including ongoing resuscitation, second look/discontinuity, and loss of domain with similar outcomes. CONCLUSIONS: In the largest series of long-term outcomes in pediatric patients with an open abdomen, we found that a majority of children were able to be primarily closed without mesh despite the number of surgeries required. Further studies require a protocolized approach to improve the long-term outcomes of these patients.

Clinical relevance of inflammation on rectal biopsy for Hirschsprung disease: An outcomes analysis.

OBJECTIVES: Inflammation on diagnostic rectal biopsy for children with suspected Hirschsprung disease (HSCR) is reported on pathology, and its significance is unknown. We describe the management and outcomes of a cohort with inflammation on rectal biopsy compared to those without. Specifically, to address the hypothesis that inflammation on diagnostic biopsy is associated with increased complication rates irrespective of intervention type and timing. METHODS: A single institution retrospective review of children with HSCR who underwent biopsy and endorectal pull-through (ERPT) from 2010 to 2020 was performed. The primary outcome was overall complications at 30-days following ERPT. Secondary outcomes included timing and type of operative intervention as well as postoperative enterocolitis diagnosed within 6-months of ERPT. RESULTS: Forty-nine children were identified; inflammation was present on diagnostic biopsy for 17 children. Those with inflammation were more likely to have clinical evidence of enterocolitis at the time of biopsy (p = 0.001) and were more likely to undergo leveling colostomy before ERPT (p = 0.01). Children with inflammation had a higher anastomotic leak rate (p = 0.04). Subgroup analysis of patients with inflammation undergoing primary ERPT versus leveling colostomy demonstrated no significant difference in outcomes following definitive ERPT. CONCLUSIONS: Our study suggests inflammation on diagnostic rectal biopsy for HSCR is associated with increased anastomotic leak rates. While additional prospective studies are indicated, attention to methods of mitigating inflammation and confirming its resolution before definitive pull-through may be of benefit for improving clinical outcomes in patients found with inflammation on diagnostic rectal biopsy.

Comparison of Outcomes Between Surveillance Ultrasound and Completion Lymph Node Dissection in Children and Adolescents With Sentinel Lymph Node-Positive Cutaneous Melanoma.

OBJECTIVE: To determine the impact of nodal basin ultrasound (US) surveillance versus completion lymph node dissection (CLND) in children and adolescents with sentinel lymph node (SLN) positive melanoma. BACKGROUND: Treatment for children and adolescents with melanoma are extrapolated from adult trials. However, there is increasing evidence that important clinical and biological differences exist between pediatric and adult melanoma. METHODS: Patients ≤18 years diagnosed with cutaneous melanoma between 2010 and 2020 from 14 pediatric hospitals were included. Data extracted included demographics, histopathology, nodal basin strategies, surveillance intervals, and survival information. RESULTS: Of 252 patients, 90.1% (n=227) underwent SLN biopsy (SLNB), 50.9% (n=115) had at least 1 positive node. A total of 67 patients underwent CLND with 97.0% (n=65/67) performed after a positive SLNB. In contrast, 46 total patients underwent US observation of nodal basins with 78.3% (n=36/46) of these occurring after positive SLNB. Younger patients were more likely to undergo US surveillance (median age 8.5 y) than CLND (median age 11.3 y; P =0.0103). Overall, 8.9% (n=21/235) experienced disease recurrence: 6 primary, 6 nodal, and 9 distant. There was no difference in recurrence (11.1% vs 18.8%; P =0.28) or death from disease (2.2% vs 9.7%; P =0.36) for those who underwent US versus CLND, respectively. CONCLUSIONS: Children and adolescents with cutaneous melanoma frequently have nodal metastases identified by SLN. Recurrence was more common among patients with thicker primary lesions and positive SLN. No significant differences in oncologic outcomes were observed with US surveillance and CLND following the identification of a positive SLN.

Implementation of Standardized Educational Material in Outpatient Pediatric Surgery: A Pilot Study.

INTRODUCTION: Caregiver health literacy is affected by both personal knowledge and education provided by clinicians. Literature on implementation of educational materials into pediatric surgical clinical practice is scarce. We developed plain-language picture-based educational material and implemented it in a pediatric surgery clinic. We assessed both caregiver and clinician satisfaction before and after implementation. METHODS: Picture-based educational material was developed for epigastric/umbilical/inguinal hernias/hydroceles, gastrostomy/gastrojejunostomy tube creation, and soft tissue masses and implemented in an academic pediatric surgery clinic. Pediatric surgeons (n = 12), clinic nurses (n = 4), and physician extenders (n = 2) were surveyed before and after a 4-week pilot implementation period. In parallel, parents of children (0-18 y) completed a 19-item postpre electronic survey capturing demographics, self-professed level of prior knowledge, and opinions regarding the material. Descriptive statistics were performed. RESULTS: Clinician response rate was 88% (pre) and 72% (post). Preimplementation, clinicians overwhelmingly reported repetitive parental counseling, need to redraw diagrams, and anticipation of improvement in workflow with standardized materials. Postimplementation, most clinicians felt the material was easy to use (76%), beneficial (77%), and perceived satisfaction in parents they were counseling (77%). Caregiver response rate was 100%. The majority reported their understanding improved after reviewing the material, found the material easy to understand and helpful, were more comfortable managing their child's condition, and recommended continued use of the material during visits. CONCLUSIONS: Results indicate clinician satisfaction and willingness to use standardized educational material during outpatient visits, as well as caregiver satisfaction and self-reported improved understanding. These findings support further development and use of standardized educational material for pediatric surgical conditions and procedures.

Acute Large Ovarian Cyst After Surgical Resection of Juvenile Granulosa Cell Tumor Stage 1C.

Juvenile granulosa cell tumors (JGCTs) are rare, though carry significant burden of morbidity and mortality. A 15-year-old menstruating female with abdominal pain was diagnosed with a large 22.3 cm pelvic mass. CA-125 and LDH were elevated. Exploratory laparotomy was undertaken due to lesion size, and left salpingo-oophorectomy with omentectomy was completed. Pathology confirmed JGCTs with focal disruption, consistent with Stage IC disease. Six weeks postoperatively, the patient experienced recurrent abdominal pain and ultrasound revealed a 7.9 cm right ovarian cystic structure. Given size and nodularity, management was discussed with a multidisciplinary team. Serial ultrasounds demonstrated resolution of the cyst. Workup for ovarian masses in pediatric patients has added complexity of fertility preservation. Once ovarian torsion is ruled out, imaging and laboratory studies are completed to characterize the mass. In pediatric patients with cancer of the Mullerian structures and risk of infertility, decision-making can be challenging and is best managed with a multidisciplinary approach.

Beyond Parity: Gender Diversity of National and International Pediatric Surgery Societal Leadership.

PURPOSE: Despite trends toward equal gender representation among medical school graduates, surgical trainees and fellows, diversity in higher levels of pediatric surgery is largely unstudied. This study aims to quantify gender diversity among leadership of pediatric surgical associations and societies across the globe. METHODS: National and international pediatric surgical organizations were identified from the websites of the American Pediatric Surgical Association (APSA) and World Federation of Associations of Pediatric Surgery (WOFAPS). Compositional gender data of current and past organizational leadership was collected by examining publicly available archives of executive membership rosters. If roster pictures were not available, member names were input into social media sites and other search engines to ensure accurate gender denotation. Univariate analyses of organizational metrics and aggregate data of 5-year time intervals were performed via Fischer's Exact Test with significance of p < 0.05. RESULTS: Nineteen pediatric surgical organizations were included for study analysis. Of 189 current organizational leaders, 50 (26.4%) are women. Eight organizations (42.1%) have less than 20% of leadership positions filled by women members, while two executive boards have no women members. Four organizations (22.2%) have a current woman seated as president/chairperson. Historical gender distribution stratified by organization demonstrates a range of 0-7.8% (p = 0.99), with one organization having yet to elect a woman president/chairperson. Longitudinally, women presidential representation remained consistently low (5-11%) across all time intervals from 1993 to 2022 (p = 0.35). CONCLUSIONS: Despite advances in diversity in medical school graduates, surgical training, and workforce recruitment, there are still significant disparities in gender representation within pediatric surgery societal leadership. LEVEL OF EVIDENCE: IV.

Malrotation in Adult and Adolescent Patients.

BACKGROUND: Malrotation in children presents with bilious emesis and can be life threatening. Data on adults is lacking. METHODS: Single institution, retrospective 20-year data collection on adult (>18 years) and adolescent patients (12-18) with symptomatic malrotation. We evaluated demographics, surgical approach, hospital stay, time to feed, and type of surgeon with descriptive statistics to analyze each group. RESULTS: Adult (n=17) and adolescent patients (n=8) primarily presented with acute abdominal pain (82% adult, 100% adolescent), and non-bilious emesis (0%), and had elective repair. CT scan was diagnostic for 82% adults and 71% adolescents. Overall, 88% had improvement in symptoms. CONCLUSION: In this single institution series comparing adults and adolescent patients with malrotation, 88% have resolution of pain after repair, despite atypical presentations. CT scan is diagnostic and laparoscopic approach should be considered.

Procalcitonin and Pediatric Traumatic Brain Injury: Differentiating Neuro-storming From Infection.

INTRODUCTION: Recurrent febrile episodes represent a diagnostic challenge in the pediatric traumatic brain injury (TBI) population as they may indicate presence of infection versus sterile neuro-storming. Procalcitonin (PCT) is a promising biomarker used in pediatric sepsis; however, data are limited regarding use in TBI. We hypothesized PCT helps discern neuro-storming from sepsis in children with TBI. MATERIALS AND METHODS: A single-institution retrospective review (2014-2021) identified pediatric patients (aged 0-18 y) with moderate-to-severe TBI and intensive care unit admission > 2 d. Patients with multiple febrile events who underwent infectious evaluation including cultures and PCT drawn within 48 h of fever were included. Demographics, vital signs, infectious biomarkers including PCT, and culture data were captured. Univariate and multivariate analyses were performed to determine variables associated with culture positive status. RESULTS: One hundred and fifty six patients were admitted to the intensive care unit with moderate-to-severe TBI during the study period. Eighty five patients (54%) experienced recurrent febrile episodes. Twenty four (28%) met inclusion criteria, undergoing 32 total infectious workups. Twenty one workups were culture-positive (66%) in a total of 18 patients. Median PCT levels were not statistically different between culture-positive and culture-negative workups (P = 0.94). In multivariate modeling, neither PCT [odds ratio 0.89 (confidence interval: 0.75-1.05)] nor temperature [odds ratio 7.34 (confidence interval: 0.95-57.16)] correlated with positive bacterial cultures. CONCLUSIONS: In this small pilot analysis, recurrent febrile episodes were common and PCT did not correlate with sepsis or neuro-storming in pediatric TBI patients. Prospective protocols are needed to better understand the utility of PCT and identify predictors of bacterial infection to improve early diagnosis of sepsis in this population.

Ultrasound assessment of abdominal adhesions in neonates: data over dogma for re-operative timing.

INTRODUCTION: Neonatal abdominal reoperation is difficult and can be complicated by abdominal adhesions. Identifying patients who could safely undergo early reoperation would save TPN and central line days, decrease associated infection and liver injury, and NICU and hospital length of stay. We sought to determine if ultrasound (US) could accurately assess the location and severity of adhesions in neonates as an objective dynamic marker capable of informing reoperation timing. METHODS: After IRB approval, we conducted a prospective observational study including neonates undergoing abdominal operations. Patients received surgeon-performed US approximately every 2 weeks until reoperation or discharge. Adhesions were assessed in five zones: right upper quadrant (RUQ), right lower quadrant (RLQ), left upper quadrant (LUQ), left lower quadrant (LLQ) and peri-incision (INC). RESULTS: Over a 6-month study period, 16 neonates were enrolled. Median gestational age was 34 weeks at birth and median weight 2.2 kg. 6 underwent reoperation within initial NICU admission. At time of operation US correctly identified the absence or presence and severity of adhesions in: RUQ (3/3); RLQ (6/6); LUQ (4/5); LLQ (6/6); and INC (5/5). CONCLUSION: US can identify location and severity of post-operative adhesions in neonates, potentially identifying patients who can safely undergo reoperation earlier than predetermined wait periods. LEVEL OF EVIDENCE: IV.

A Pilot Study: Transcriptional Profiling, Functional Analysis, and Organoid Modeling of Intestinal Mucosa in Hirschsprung Disease.

BACKGROUND: Hirschsprung disease (HSCR) is a congenital colonic aganglionosis. Many HSCR patients develop enterocolitis despite surgical resection. The pathophysiology of this inflammatory process is poorly understood. We compared transcriptional profiles and function of ganglionic and aganglionic tissue in HSCR patients. METHODS: RNA sequencing was performed on mucosal tissues from HSCR patients (n = 6) and controls (n = 3). Function of matched ganglionic and aganglionic regions were investigated utilizing organoids generated from these tissues. RESULTS: Transcriptional differences observed in ganglionic and aganglionic regions of HSCR patients included upregulation of genes involving inflammation, cell differentiation and proliferation as well as decreased expression of genes encoding mucins compared to controls. Organoids derived from ganglionic and aganglionic regions of HSCR patients were similar in epithelial cell differentiation, epithelial barrier formation and response to stimulation with bacterial metabolites and pro-inflammatory cytokines. CONCLUSIONS: Despite normal ganglionic structure, the section of colon adjacent to the aganglionic region in HSCR patients has perturbed gene expression which resembles the aganglionic segment. Transcriptional and functional changes in colonic epithelium are persevered in the ganglionic colon used for pull-through surgery. This may explain persistence of enterocolitis despite surgical excision of aganglionic colon and subsequent endorectal pull-through performed with ganglionic colon during correction of HSCR. LEVEL OF EVIDENCE: N/A.

Meckel's Diverticulum, A Rare Presentation in a Neonate.

Meckel's diverticulum is commonly symptomatic the first 2 years of life. Complications associated with Meckel's diverticulum are due to gastrointestinal (GI) bleeding or obstruction. A 5-day-old male presented to the emergency department (ED) with an episode of bright red blood per rectum (BRBPR) associated with emesis. Vital signs were normal and abdomen soft and non-distended. Serial abdominal radiographs progressed to show distention of small bowel and air fluid levels. Operative intervention was undertaken with diagnosis of intestinal obstruction. On exploratory laparotomy, 24 cm of a fibrosed, ischemic closed-loop ileal segment densely adherent to the tip of a Meckel's diverticulum was identified and resected, followed by primary reanastamosis. Histologic findings confirmed ectopic gastric tissue. Symptomatic Meckel's diverticulum is often secondary to intestinal obstruction and hematochezia, findings which are caused by incarcerated inguinal hernia or ileocolic intussusception. Our patient presented with a closed loop, which has not been previously reported.

Visible Apical Blebs on CXR: Are Plain Radiographs Under-Utilized in Primary Spontaneous Pneumothorax?

A primary spontaneous pneumothorax (PSP) is caused by rupture of subpleural emphysematous blebs, without inciting event or pre-existing co-morbidity. A previously healthy 16-year-old male presented with upper chest pain. As expected, chest radiographs (CXR) demonstrated a 13 mm pneumothorax. Additionally, a 4.7 cm apical bleb was identified. After six-hours of observation and non-rebreather oxygen mask therapy, follow-up CXR confirmed stable findings. The patient was subsequently discharged home after symptoms improved. Follow-up CXR at 2-weeks confirmed persistent visible apical bleb. After lengthy discussion addressing patient and parental concerns, elective surgical management was pursued. Current literature suggests blebs are not routinely identified on CXR. While there is no universally accepted management algorithm for PSP in children, visible apical blebs on CXR may influence the decision to pursue surgical intervention. Shared decision making should involve counseling regarding the recurrence risk following surgery, and consideration of patient-specific factors including patient and parental anxiety.

Histologic type predicts disparate outcomes in pediatric hepatocellular neoplasms: A Pediatric Surgical Oncology Research Collaborative study.

BACKGROUND: Hepatocellular carcinoma (HCC) is a rare cancer in children, with various histologic subtypes and a paucity of data to guide clinical management and predict prognosis. METHODS: A multi-institutional review of children with hepatocellular neoplasms was performed, including demographic, staging, treatment, and outcomes data. Patients were categorized as having conventional HCC (cHCC) with or without underlying liver disease, fibrolamellar carcinoma (FLC), and hepatoblastoma with HCC features (HB-HCC). Univariate and multivariate analyses identified predictors of mortality and relapse. RESULTS: In total, 262 children were identified; and an institutional histologic review revealed 110 cHCCs (42%; 69 normal background liver, 34 inflammatory/cirrhotic, 7 unknown), 119 FLCs (45%), and 33 HB-HCCs (12%). The authors observed notable differences in presentation and behavior among tumor subtypes, including increased lymph node involvement in FLC and higher stage in cHCC. Factors associated with mortality included cHCC (hazard ratio [HR], 1.63; P = .038), elevated α-fetoprotein (HR, 3.1; P = .014), multifocality (HR, 2.4; P < .001), and PRETEXT (pretreatment extent of disease) stage IV (HR, 5.76; P < .001). Multivariate analysis identified increased mortality in cHCC versus FLC (HR, 2.2; P = .004) and in unresectable tumors (HR, 3.4; P < .001). Disease-free status at any point predicted survival. CONCLUSIONS: This multi-institutional, detailed data set allowed a comprehensive analysis of outcomes for children with these rare hepatocellular neoplasms. The current data demonstrated that pediatric HCC subtypes are not equivalent entities because FLC and cHCC have distinct anatomic patterns and outcomes in concert with their known molecular differences. This data set will be further used to elucidate the impact of histology on specific treatment responses, with the goal of designing risk-stratified algorithms for children with HCC. LAY SUMMARY: This is the largest reported granular data set on children with hepatocellular carcinoma. The study evaluates different subtypes of hepatocellular carcinoma and identifies key differences between subtypes. This information is pivotal in improving understanding of these rare cancers and may be used to improve clinical management and subsequent outcome in children with these rare malignancies.

Genetic origins of the Minoans and Mycenaeans.

The origins of the Bronze Age Minoan and Mycenaean cultures have puzzled archaeologists for more than a century. We have assembled genome-wide data from 19 ancient individuals, including Minoans from Crete, Mycenaeans from mainland Greece, and their eastern neighbours from southwestern Anatolia. Here we show that Minoans and Mycenaeans were genetically similar, having at least three-quarters of their ancestry from the first Neolithic farmers of western Anatolia and the Aegean, and most of the remainder from ancient populations related to those of the Caucasus and Iran. However, the Mycenaeans differed from Minoans in deriving additional ancestry from an ultimate source related to the hunter-gatherers of eastern Europe and Siberia, introduced via a proximal source related to the inhabitants of either the Eurasian steppe or Armenia. Modern Greeks resemble the Mycenaeans, but with some additional dilution of the Early Neolithic ancestry. Our results support the idea of continuity but not isolation in the history of populations of the Aegean, before and after the time of its earliest civilizations.

A European population in Minoan Bronze Age Crete.

The first advanced Bronze Age civilization of Europe was established by the Minoans about 5,000 years before present. Since Sir Arthur Evans exposed the Minoan civic centre of Knossos, archaeologists have speculated on the origin of the founders of the civilization. Evans proposed a North African origin; Cycladic, Balkan, Anatolian and Middle Eastern origins have also been proposed. Here we address the question of the origin of the Minoans by analysing mitochondrial DNA from Minoan osseous remains from a cave ossuary in the Lassithi plateau of Crete dated 4,400-3,700 years before present. Shared haplotypes, principal component and pairwise distance analyses refute the Evans North African hypothesis. Minoans show the strongest relationships with Neolithic and modern European populations and with the modern inhabitants of the Lassithi plateau. Our data are compatible with the hypothesis of an autochthonous development of the Minoan civilization by the descendants of the Neolithic settlers of the island.

The accessible chromatin landscape of the human genome.

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ∼2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect ∼580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.