Panel sequencing links rare, likely damaging gene variants with distinct clinical phenotypes and outcomes in juvenile-onset SLE.

OBJECTIVES: Juvenile-onset systemic lupus erythematosus (jSLE) affects 15-20% of lupus patients. Clinical heterogeneity between racial groups, age groups and individual patients suggests variable pathophysiology. This study aimed to identify highly penetrant damaging mutations in genes associated with SLE/SLE-like disease in a large national cohort (UK JSLE Cohort Study) and compare demographic, clinical and laboratory features in patient sub-cohorts with 'genetic' SLE vs remaining SLE patients. METHODS: Based on a sequencing panel designed in 2018, target enrichment and next-generation sequencing were performed in 348 patients to identify damaging gene variants. Findings were integrated with demographic, clinical and treatment related datasets. RESULTS: Damaging gene variants were identified in ∼3.5% of jSLE patients. When compared with the remaining cohort, 'genetic' SLE affected younger children and more Black African/Caribbean patients. 'Genetic' SLE patients exhibited less organ involvement and damage, and neuropsychiatric involvement developed over time. Less aggressive first line treatment was chosen in 'genetic' SLE patients, but more second and third line agents were used. 'Genetic' SLE associated with anti-dsDNA antibody positivity at diagnosis and reduced ANA, anti-LA and anti-Sm antibody positivity at last visit. CONCLUSION: Approximately 3.5% of jSLE patients present damaging gene variants associated with younger age at onset, and distinct clinical features. As less commonly observed after treatment induction, in 'genetic' SLE, autoantibody positivity may be the result of tissue damage and explain reduced immune complex-mediated renal and haematological involvement. Routine sequencing could allow for patient stratification, risk assessment and target-directed treatment, thereby increasing efficacy and reducing toxicity.

Predictive validity of developmental screening in young children with sickle cell disease: a longitudinal follow-up study.

AIM: To assess the predictive validity of developmental screenings in children with sickle cell disease (SCD) for academic outcomes and stroke risk. METHOD: Parent questionnaires and medical record data were collected for a cohort receiving developmental screenings between September 2004 and May 2008 as toddlers or early school age. Screening outcomes were dichotomized (positive, negative) by a priori criteria. Questionnaires assessed school and social functioning, services received, and quality of life. Medical record data assessed general SCD morbidity and stroke risk. RESULTS: Forty-one toddlers (mean age 2y 5mo; 25 males, 16 females) and 49 early school-age children (mean age 6y 5mo; 26 males, 23 females) completed follow-up. The mean follow-up period was 8 years 6 months (range 6.1-10.8y). For toddlers, positive screenings for language delays predicted lower academic performance (p=0.023). For older children, positive screenings for cognitive delays predicted more frequent academic/attentional problems at school (p<0.001), grade retention (p=0.007), and lower academic performance (p=0.001). Positive screenings were associated with an earlier onset of school problems and lower quality of life. Positive screenings for language/cognitive delays predicted increased stroke risk (both p<0.05). INTERPRETATION: Screening for language or cognitive development in young children with SCD predicts academic outcomes and stroke risk. WHAT THIS PAPER ADDS: Developmental screening predicts academic outcomes in sickle cell disease. Children with concerning language/cognitive screenings have early-onset school difficulties. Developmental screenings may help predict cerebrovascular complications.

Comorbid obstructive sleep apnea and increased risk for sickle cell disease morbidity.

PURPOSE: Sickle cell disease (SCD) imparts an increased risk for obstructive sleep apnea (OSA) in childhood. Studies of pediatric SCD have identified an increased risk for pain and neurologic complications with comorbid OSA. We determined the rate of a broad range of SCD-related medical complications to better characterize the spectrum of SCD complications related to OSA. METHODS: Retrospective chart review at a single hematology clinic identified 641 youth with SCD who received consistent screenings for OSA as part of routine hematological health maintenance visits over an 11-year period. Medical complication rates in the 136 children with OSA determined by polysomnography exams were compared to 136 matched controls at lower risk for OSA due to negative OSA screenings or exams. RESULTS: Children with SCD and OSA had higher overall rates of SCD complications than low OSA-risk controls; lung morbidity showed the largest effect size. Infection, cardiovascular, and neurologic complications occurred at higher rates in children with OSA. Children with comorbid OSA had higher rates of SCD complications both before and after OSA diagnosis. CONCLUSIONS: OSA in children with SCD is associated with higher rates of a broad range of SCD complications, including pneumonia and acute chest syndrome. Routine screenings, diagnosis, and increased therapeutic intervention for children with comorbid OSA could decrease SCD morbidity.

Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia-TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial.

BACKGROUND: For children with sickle cell anaemia and high transcranial doppler (TCD) flow velocities, regular blood transfusions can effectively prevent primary stroke, but must be continued indefinitely. The efficacy of hydroxycarbamide (hydroxyurea) in this setting is unknown; we performed the TWiTCH trial to compare hydroxyurea with standard transfusions. METHODS: TWiTCH was a multicentre, phase 3, randomised, open-label, non-inferiority trial done at 26 paediatric hospitals and health centres in the USA and Canada. We enrolled children with sickle cell anaemia who were aged 4-16 years and had abnormal TCD flow velocities (≥ 200 cm/s) but no severe vasculopathy. After screening, eligible participants were randomly assigned 1:1 to continue standard transfusions (standard group) or hydroxycarbamide (alternative group). Randomisation was done at a central site, stratified by site with a block size of four, and an adaptive randomisation scheme was used to balance the covariates of baseline age and TCD velocity. The study was open-label, but TCD examinations were read centrally by observers masked to treatment assignment and previous TCD results. Participants assigned to standard treatment continued to receive monthly transfusions to maintain 30% sickle haemoglobin or lower, while those assigned to the alternative treatment started oral hydroxycarbamide at 20 mg/kg per day, which was escalated to each participant's maximum tolerated dose. The treatment period lasted 24 months from randomisation. The primary study endpoint was the 24 month TCD velocity calculated from a general linear mixed model, with the non-inferiority margin set at 15 cm/s. The primary analysis was done in the intention-to-treat population and safety was assessed in all patients who received at least one dose of assigned treatment. This study is registered with ClinicalTrials.gov, number NCT01425307. FINDINGS: Between Sept 20, 2011, and April 17, 2013, 159 patients consented and enrolled in TWiTCH. 121 participants passed screening and were then randomly assigned to treatment (61 to transfusions and 60 to hydroxycarbamide). At the first scheduled interim analysis, non-inferiority was shown and the sponsor terminated the study. Final model-based TCD velocities were 143 cm/s (95% CI 140-146) in children who received standard transfusions and 138 cm/s (135-142) in those who received hydroxycarbamide, with a difference of 4·54 (0·10-8·98). Non-inferiority (p=8·82 × 10(-16)) and post-hoc superiority (p=0·023) were met. Of 29 new neurological events adjudicated centrally by masked reviewers, no strokes were identified, but three transient ischaemic attacks occurred in each group. Magnetic resonance brain imaging and angiography (MRI and MRA) at exit showed no new cerebral infarcts in either treatment group, but worsened vasculopathy in one participant who received standard transfusions. 23 severe adverse events in nine (15%) patients were reported for hydroxycarbamide and ten serious adverse events in six (10%) patients were reported for standard transfusions. The most common serious adverse event in both groups was vaso-occlusive pain (11 events in five [8%] patients with hydroxycarbamide and three events in one [2%] patient for transfusions). INTERPRETATION: For high-risk children with sickle cell anaemia and abnormal TCD velocities who have received at least 1 year of transfusions, and have no MRA-defined severe vasculopathy, hydroxycarbamide treatment can substitute for chronic transfusions to maintain TCD velocities and help to prevent primary stroke. FUNDING: National Heart, Lung, and Blood Institute, National Institutes of Health.

Effects of hydroxyurea treatment for patients with hemoglobin SC disease.

Although hemoglobin SC (HbSC) disease is usually considered less severe than sickle cell anemia (SCA), which includes HbSS and HbS/ß(0) -thalassemia genotypes, many patients with HbSC experience severe disease complications, including vaso-occlusive pain, acute chest syndrome, avascular necrosis, retinopathy, and poor quality of life. Fully 20 years after the clinical and laboratory efficacy of hydroxyurea was proven in adult SCA patients, the safety and utility of hydroxyurea treatment for HbSC patients remain unclear. Recent NHLBI evidence-based guidelines highlight this as a critical knowledge gap, noting HbSC accounts for ∼30% of sickle cell patients within the United States. To date, only 5 publications have reported short-term, incomplete, or conflicting laboratory and clinical outcomes of hydroxyurea treatment in a total of 71 adults and children with HbSC. We now report on a cohort of 133 adult and pediatric HbSC patients who received hydroxyurea, typically for recurrent vaso-occlusive pain. Hydroxyurea treatment was associated with a stable hemoglobin concentration; increased fetal hemoglobin (HbF) and mean corpuscular volume (MCV); and reduced white blood cell count (WBC), absolute neutrophil count (ANC), and absolute reticulocyte count (ARC). Reversible cytopenias occurred in 22% of patients, primarily neutropenia and thrombocytopenia. Painful events were reduced with hydroxyurea, more in patients >15 years old. These multicenter data support the safety and potentially salutary effects of hydroxyurea treatment for HbSC disease; however, a multicenter, placebo-controlled, Phase 3 clinical trial is needed to determine if hydroxyurea therapy has efficacy for patients with HbSC disease.

Examining Biopsychosocial Factors in Relation to Multiple Pain Features in Pediatric Sickle Cell Disease.

OBJECTIVE: To examine biopsychosocial variables in relation to multiple pain features in pediatric sickle cell disease (SCD). METHODS: 76 children with SCD (M = 14.05, SD = 3.26), ages 8-19 years, and 70 caregivers completed measures of coping, mood, and family functioning and reported on multiple pain features via retrospective interviews during routine hematological visits. Sickle cell genotype and health care utilization were collected via medical record review. Using hierarchical regression, biological (genotype), child psychological (coping and mood), and social factors (caregiver coping and family functioning) were evaluated in relation to multiple pain features. RESULTS: Genotype was associated with pain intensity, and child psychological factors were associated with pain frequency. Multiple biopsychosocial factors were related to health care utilization. CONCLUSIONS: Biopsychosocial factors may have distinct relationships with pain features in pediatric SCD. Understanding these relationships may refine the biopsychosocial model and inform integrated medical and psychosocial approaches in SCD.

Information-seeking coping behaviors during painful procedures in African-American children with sickle cell disease.

This study examined the frequency of information-seeking coping behaviors in 37 African-American children (ages 5-17 years) with sickle cell disease during venipuncture. The relationships between coping behaviors and child- and parent-reported pain and observational distress were also assessed. The majority of children attended to the procedure, but did not seek information via questions. This pattern of coping was only partially effective at reducing distress and had no relation to pain. This pattern of coping is discussed within the context of cultural factors that may be important in understanding responses to procedural pain in pediatric sickle cell disease.

Responsiveness of the PedsQL to pain-related changes in health-related quality of life in pediatric sickle cell disease.

OBJECTIVE: To determine if caregiver report of the pediatric quality of life inventory (PedsQL) is responsive to changes in health-related quality of life (HRQL) associated with pain episodes in pediatric sickle cell disease (SCD). METHODS: 81 caregivers of children ages 2-19 years with SCD completed the PedsQL as part of routine psychosocial screenings at 2 time points, ranging from 6 to 18 months apart. Frequency of SCD-related pain episodes between time points was assessed using medical chart review. RESULTS: The frequency of pain episodes between time points was a significant predictor of decreases in physical, psychosocial, and total HRQL, even after controlling for time interval, demographic, and medical variables. CONCLUSIONS: The caregiver report of the PedsQL appears to be a useful tool for capturing changes in HRQL over time associated with pain episodes in SCD.

Surgical methods in the treatment of congenital anomalies of the uterine cervix.

PURPOSE OF REVIEW: Cervical agenesis is an extremely rare congenital anomaly of the female reproductive tract. There are many anatomical forms that constitute this type of cervical abnormality and the literature is replete with attempts to surgically restore a patent outflow tract and preserve fertility in these patients. There are no carefully designed cohort or randomized trials to support a best surgical practice; past reports are descriptive only. RECENT FINDINGS: Of late, there has been renewed interest in the surgical treatment of cervical dysgenesis with techniques both through laparotomy with hysterotomy and more recently, minimally invasive approaches, which have attempted to restore a patent outflow tract without perineal dissection or graft harvesting in an attempt to avoid uterovaginal scarring if further surgery is necessary. To maintain consistency in the field of surgical reconstruction of the female reproductive tract, there has been a call for streamlined classifications of the anatomical abnormalities observed to better compare patient findings and the outcome of their surgical reconstruction in the literature. SUMMARY: The authors discuss the embryological development of this rare reproductive tract abnormality and have proposed a systematic surgical strategy for each anatomic finding. Ultimately, counseling patients on the best surgical approach requires a discussion on the potential postoperative complications, the degree of cervical abnormality, and the patient's desired treatment outcome. Whether the patient desires definitive treatment with a hysterectomy to avoid the risk of further surgery or, when anatomically appropriate, she wants to pursue a patent outflow tract and the possibility of future childbearing, evidence-based medicine must become the source for surgical strategies.

Cerebral blood flow velocity and language functioning in pediatric sickle cell disease.

We investigated the association of increased cerebral blood flow velocity with specific language abilities in children with sickle cell disease (SCD). Thirty-nine children ages 5 to 8 years old with high-risk genotypes of SCD underwent cognitive testing, which included tests of language skills, visual motor skills, and attention/working memory as part of a routine hematology health-maintenance visit. Transcranial Doppler (TCD) velocities were obtained from review of medical records, with the velocities that were in closest temporal proximity to the cognitive assessment used in the analysis. TCD velocities predicted scores on tests of syntactical skills, even when controlling for anemia severity. Semantic and phonological ability and other cognitive skills were not strongly related to TCD velocities. Elevated blood flow velocities in children with high-risk SCD may contribute to a specific language impairment or to a broader dysfunction of short-term and/or working memory. This study underscores the need for clinicians to monitor language skills of children with SCD who have elevated TCD velocities, as these cognitive abilities might be particularly sensitive to cerebrovascular disruption related to their disease.

Relationships between somatic growth and cognitive functioning in young children with sickle cell disease.

OBJECTIVE: Children with sickle cell disease (SCD) exhibit poor somatic growth due to nutritional and metabolic effects, but potential relationships between growth and other areas of development are unclear. We examined whether growth is related to cognition and whether growth might be one marker of neurocognitive risk. METHODS: Sixty-four children with SCD and eighty-one demographically similar controls, ages 4 to 8 years, completed cognitive and anthropometric measures. RESULTS: Height-for-age partially accounted for cognitive decrements related to SCD on all cognitive measures. Higher body-mass-index was a significant predictor of higher visual-motor and academic achievement scores in children with SCD, but not in controls. CONCLUSIONS: In some children with SCD, especially those with HbSS and Hb Sbeta(0), low height-for-age may help to explain neurocognitive risk. Higher body-mass-index may be related to better cognitive outcomes in children with SCD. Nutrition deficits in SCD could explain the association between somatic growth and cognitive deficits.

Use of handheld wireless technology for a home-based sickle cell pain management protocol.

PURPOSE: To evaluate use of a handheld electronic wireless device to implement a pain management protocol for participants with sickle cell disease (SCD). METHODS: Participants were 19 patients with SCD aged 9-20 who experienced vaso-occlusive pain. A single-session training on the use of cognitive-behavioral coping skills was followed by instruction on how to practice these skills and monitor daily pain experience using the device. Daily pain experience and practice of coping skills were collected for the 8-week intervention period using wireless technology. RESULTS: High rates of participation, daily diary completion and consumer satisfaction support the use of handheld wireless devices to implement this protocol. A comparison of the rates of self and device-recorded skills practice provides important information about the use of electronic monitoring for behavioral interventions. CONCLUSION: Wireless data transfer technology has significant potential to become a practical method to improve symptom monitoring and communication between patients and providers.

Applications of estradiol and testosterone assays in the management of the infertile female patient.

A collaborative effort to improve steroid hormone measurements in patient care was convened by the Centers for Disease Control in March 2008 to discuss the need for enhanced performance and standardization of clinical estradiol and testosterone assays. This article discusses the current status of estradiol and testosterone assays in the treatment of infertile women to include the assessment of ovarian reserve, ovulation induction and follicle tracking, ovarian hyperstimulation syndrome, and the role of testosterone in fertility management.

Validity of the Pediatric Quality Of Life Inventory for youth with sickle cell disease.

OBJECTIVE: Evaluate the validity of the Pediatric Quality of Life Inventory (PedsQL) for sickle cell disease (SCD). METHODS: Sixty-eight parent-child dyads (children 5-18 years) completed the PedsQL. Medical record review assessed history of specific morbidities. RESULTS: Internal consistency of the scales varied. The strongest reliability was for parent proxy-report for specific domains or for global functioning scores with either informant. Modest internal consistency was found for specific domains with child informants, particularly for younger children. Moderate convergent validity was found between informants. History of neurologic problems or major pain episodes indicated criterion validity for specific scales. CONCLUSIONS: The PedsQL appears to validly assess quality of life in youth with SCD. Domain-specific measurement of quality of life was limited by (a) low reliability for youth-report and (b) lack of discriminant validity. Choice of informant may be important when evaluating quality of life effects from pain or neurologic problems in SCD.

Neurodevelopmental screening in toddlers and early preschoolers with sickle cell disease.

Sickle cell disease is associated with an elevated risk for neurologic complications beginning in early childhood. Detecting higher-risk cases with developmental screening instruments may be a cost-effective method for identifying young children in need of more frequent or intensive assessment. We evaluated the validity of the Denver II test as a tool to detect lower levels of developmental attainment and their association with neurologic risk in 50 young children with sickle cell disease. Children with suspect Denver II outcomes showed lower scores for functional communication skills, had lower hematocrit percentage, higher mean velocities on transcranial Doppler ultrasound imaging, and were more likely to have had preterm birth. Validity of age equivalencies from specific Denver II areas was demonstrated for Language and Fine Motor scores, suggesting the instrument could be used to index children's developmental levels in these domains. The Denver II may be a useful behavioral screening tool for neurodevelopmental risk in sickle cell disease.

Parent Perspectives on Pain Management in Preschool-Age Children With Sickle Cell Disease.

Pain episodes occur for many preschoolers with sickle cell disease (SCD), but little is known about parent perceptions of managing pain episodes in young children. We surveyed parents of young children with SCD who had managed pain episodes in the past year to assess their management and satisfaction with their strategies, challenges of pain management, and interest in additional education. Parents were recruited from health maintenance visits at a SCD specialty clinic. Forty-two of 51 parents (82%) of 2- to-6-year-olds reported managing pain over the past year. Parents who had managed pain primarily reported using medications. These parents reported at least moderate satisfaction with current management strategies and resources. At least one-third of parents found each facet of pain management queried as at least somewhat challenging. Identifying when their child was in pain, encouraging functional activities, and managing irritable behavior were reported as most challenging. Parents of young children with SCD reported interest in additional pain management education, which could promote better parent and child coping skills.

The association of oral hydroxyurea therapy with improved cognitive functioning in sickle cell disease.

This study examined potential cognitive benefits of oral hydroxyurea therapy for children with sickle cell disease (SCD). Cognitive abilities of 15 children with SCD on hydroxyurea were compared to 50 other children with SCD, controlling for demographics and hematocrit. Children on hydroxyurea scored significantly higher on tests of verbal comprehension, fluid reasoning, and general cognitive ability than children not on the drug. The data therefore provide preliminary evidence of cognitive benefits of hydroxyurea. Mechanisms for this effect may be improved blood/oxygen supply to the brain or reduced fatigue and illness.

Developmental Screening in Pediatric Sickle Cell Disease: Disease-Related Risk and Screening Outcomes in 4 Year Olds.

OBJECTIVE: Studies of early child development in sickle cell disease (SCD) have found modest associations between disease-related risks and developmental status in infants and toddlers, but such associations are evident by early elementary school. We screened 4-year-old children with SCD using 2 screening strategies to assess if biomedical risk factors for neurologic disease are related to developmental screening outcomes at this intermediate age. METHODS: Seventy-seven 4-year-old children with SCD (M = 4.5 yrs, SD = 0.3 yrs) completed developmental screenings at routine hematology visits using child testing (Fluharty Preschool Speech and Language Screenings Test, 2nd edition) and parent-report (Ages and Stages Questionnaire, 2nd edition) procedures. Genotype and other biomedical variables were coded from medical records. RESULTS: Children with higher-risk SCD genotypes (n = 52) showed lower performance than children with lower-risk genotypes (n = 25) on a measure related to neurologic disease risk in older children (syntactic processing); genotype risk was also related to rates of positive screenings on parent-reported developmental milestones (52% positive screenings in high-risk genotypes vs 12% in low-risk genotypes). Screening outcomes were also related to transcranial Doppler ultrasound findings assessing cerebral blood flow. CONCLUSION: Developmental screening at age 4 may be a useful target age for identifying preschoolers with sickle cell-related neurodevelopmental concerns. Parent report of developmental milestones and behavioral testing each may have a role in screening for children in need of follow-up services to address potential neurodevelopmental effects from SCD.

Expert guidelines for the treatment of severe PMS, PMDD, and comorbidities: the role of SSRIs.

The hallmark feature of premenstrual syndrome (PMS) and premenstrual dysphoric disorder (PMDD) is the predictable, cyclic nature of symptoms or distinct on/offness that begins in the late luteal phase of the menstrual cycle and remits shortly after the onset of menstruation. PMDD is distinguished from PMS by the severity of symptoms, predominance of mood symptoms, and role dysfunction, particularly in personal relationships and marital/family domains. Several treatment modalities are beneficial in PMDD and severe PMS, but the selective serotonin reuptake inhibitors (SSRIs) have emerged as first-line therapy. The SSRIs can be administered continuously throughout the entire month, intermittently from ovulation to the onset of menstruation, or semi-intermittently with dosage increases during the late luteal phase. These guidelines present practical treatment algorithms for the use of SSRIs in women with pure PMDD or severe PMS, PMDD and underlying subsyndromal clinical features of mood or anxiety, or premenstrual exacerbation of a mood/anxiety disorder.

Association between somatic growth trajectory and cognitive functioning in young children with sickle cell disease.

Children with sickle cell disease are at risk of cognitive deficits and somatic growth delays beginning in early childhood. We examined growth velocity from age 2 years (height and body mass index progression over time) and cognitive functioning in 46 children with sickle cell disease 4 to 8 years of age. Height-for-age velocity was not associated with cognitive outcomes. Higher body mass index velocity was associated with higher scores on global cognitive and visual-motor abilities but not processing resources or academic achievement. Body mass index progression over time may be a clinically useful indicator of neurocognitive risk in sickle cell disease, as it may reflect multiple sickle cell disease-related risk factors.