The effectiveness of trauma-focused psychotherapy for complex post-traumatic stress disorder: A retrospective study.

OBJECTIVE: We retrospectively evaluated the effectiveness of trauma-focused psychotherapy (TF-P) versus stabilization and waiting in a civilian cohort of patients with an 11th version of the international classification of disease (ICD-11) diagnosis of complex post-traumatic stress disorder (CPTSD). METHODS: We identified patients with CPTSD treated at a specialist trauma service over a 3-year period by triangulating evidence from self-report questionnaires, file review, and expert-clinician opinion. Patients completed a phase-based treatment: stabilization consisting of symptom management and establishing safety, followed by waiting for treatment (phase 1); individual TF-P in the form of trauma-focused cognitive behavioral therapy (TF-CBT), or eye movement desensitization and reprocessing (EMDR) or TF-CBT plus EMDR (phase 2). Our primary outcome was PTSD symptoms during phase 2 versus phase 1. Secondary outcomes included depressive symptoms, functional impairment, and a proxy CPTSD measure. Exploratory analysis compared outcomes between treatments. Adverse outcomes were recorded. RESULTS: Fifty-nine patients were included. Compared to receiving only phase 1, patients completing TF-P showed statistically significant reductions in PTSD [t(58) = -3.99, p < 0.001], depressive symptoms [t(58) = -4.41, p < 0.001], functional impairment [t(58) = -2.26, p = 0.028], and proxy scores for CPTSD [t(58) = 4.69, p < 0.001]. There were no significant differences in outcomes between different treatments offered during phase 2. Baseline depressive symptoms were associated with higher PTSD symptoms and functional impairment. CONCLUSIONS: This study suggests that TF-P effectively improves symptoms of CPTSD. However, prospective research with validated measurements is necessary to evaluate current and new treatments and identify personal markers of treatment effectiveness for CPTSD.

Predicting the Need for Phototherapy After Discharge.

BACKGROUND AND OBJECTIVES: Bilirubin screening before discharge is performed to identify neonates at risk for future hyperbilirubinemia. The American Academy of Pediatrics recommends using a graph of bilirubin levels by age (the Bhutani Nomogram) to guide follow-up and a different graph to determine phototherapy recommendations. Our objective was to evaluate predictive models that incorporate the difference between the last total serum bilirubin (TSB) before discharge and the American Academy of Pediatrics phototherapy threshold (Δ-TSB) to predict a postdischarge TSB above the phototherapy threshold by using a single graph. METHODS: We studied 148 162 infants born at ≥35 weeks' gestation at 11 Kaiser Permanente Northern California facilities from 2012 to 2017 whose TSB did not exceed phototherapy levels and who did not receive phototherapy during the birth hospitalization. We compared 3 logistic models (Δ-TSB; Δ-TSB-Plus, which included additional variables; and the Bhutani Nomogram) by using the area under the receiver operating characteristic curve (AUC) in a 20% validation subset. RESULTS: A total of 2623 infants (1.8%) exceeded the phototherapy threshold postdischarge. The predicted probability of exceeding the phototherapy threshold after discharge ranged from 56% for a predischarge Δ-TSB 0 to 1 mg/dL below the threshold to 0.008% for Δ-TSB >7 mg/dL below the threshold. Discrimination was better for the Δ-TSB model (AUC 0.93) and the Δ-TSB-Plus model (AUC 0.95) than for the Bhutani Nomogram (AUC 0.88). CONCLUSIONS: The use of Δ-TSB models had excellent ability to predict postdischarge TSB above phototherapy thresholds and may be simpler to use than the Bhutani Nomogram.

Hyperbilirubinemia, Phototherapy, and Childhood Asthma.

OBJECTIVES: Our aim was to quantify the associations of both hyperbilirubinemia and phototherapy with childhood asthma using a population-based cohort with total serum bilirubin (TSB) levels. METHODS: Retrospective cohort study of infants born at ≥35 weeks' gestation in the Kaiser Permanente Northern California health system (n = 109 212) from 2010 to 2014. Cox models were used to estimate hazard ratios (HRs) for a diagnosis of asthma. RESULTS: In the study, 16.7% of infants had a maximum TSB level of ≥15 mg/dL, 4.5% of infants had a maximum TSB level of ≥18 mg/dL, and 11.5% of infants received phototherapy. Compared with children with a maximum TSB level of 3 to 5.9 mg/L, children with a TSB level of 9 to 11.9 mg/dL, 12 to 14.9 mg/dL, and 15 to 17.9 mg/dL were at an increased risk for asthma (HR: 1.22 [95% confidence interval (CI): 1.11-1.3], HR: 1.18 [95% CI: 1.08-1.29], and HR: 1.30 [95% CI: 1.18-1.43], respectively). Children with a TSB level of ≥18 mg/dL were not at an increased risk for asthma (HR: 1.04; 95% CI: 0.90-1.20). In propensity-adjusted analyses, phototherapy was not associated with asthma (HR: 1.07; 95% CI: 0.96-1.20). CONCLUSIONS: Modest levels of hyperbilirubinemia were associated with an increased risk of asthma, but an association was not seen at higher levels. No dose-response relationship was seen. Using phototherapy to prevent infants from reaching these modest TSB levels is unlikely to be protective against asthma.

Accuracy of international classification of diseases, ninth revision, codes for postpartum hemorrhage among women undergoing cesarean delivery.

BACKGROUND: Determining the accuracy of International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9) codes for postpartum hemorrhage (PPH) is vital for reaching valid conclusions about the epidemiology of PPH. Our primary objectives were to assess the performance characteristics of ICD-9 PPH codes against a reference standard using estimated blood loss (EBL) among a cohort undergoing Cesarean delivery. STUDY DESIGN AND METHODS: We analyzed maternal discharge and EBL data from women who underwent Cesarean delivery at Kaiser Permanente Northern California facilities between 2010 and 2013. We defined PPH as an EBL of at least 1000 mL. In a secondary analysis, ICD-9 performance characteristics were assessed using an EBL of at least 1500 mL to classify severe PPH. RESULTS: We identified 35,614 hospitalizations for Cesarean delivery. Using EBL of at least 1000 mL as the "gold standard," PPH codes had a sensitivity of 27.8%, specificity of 97%, positive predictive value (PPV) of 74.5%, and a negative predictive value (NPV) of 80.9%. The prevalence of a PPH code (9%) was lower than the prevalence using a blood loss of at least 1000 mL (24%). Using a reference standard of EBL of at least 1500 mL, PPH codes had a sensitivity of 61.7%, specificity of 93.8%, PPV of 34.2%, and NPV of 97.9%. CONCLUSION: PPH ICD-9 codes have high specificity, moderately high PPVs and NPVs, and low sensitivity. An EBL of at least 1500 mL as a reference standard has higher sensitivity. Our findings suggest that, for women undergoing Cesarean delivery, quality improvement efforts are needed to enhance PPH ICD-9 coding accuracy in administrative data sets.

Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Reducing Bronchiolitis Hospitalizations Among High-Risk Infants.

We sought to determine the real-world effectiveness of respiratory syncytial virus (RSV) immunoprophylaxis in a population-based cohort to inform policy. The study population included infants born during 1996-2008 and enrolled in the Kaiser Permanente Northern California integrated health-care delivery system. During the RSV season (November-March), the date of RSV immunoprophylaxis administration and the following 30 days were defined as RSV immunoprophylaxis protected period(s), and all other days were defined as unprotected period(s). Numbers of bronchiolitis hospitalizations were determined using International Classification of Diseases, Ninth Revision, codes during RSV season. We used a proportional hazards model to estimate risk of bronchiolitis hospitalization when comparing infants' protected period(s) with unprotected period(s). Infants who had ever received RSV immunoprophylaxis had a 32% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.68, 95% confidence interval: 0.46, 1.00) when protected periods were compared with unprotected periods. Infants with chronic lung disease (CLD) had a 52% decreased risk of bronchiolitis hospitalization (adjusted hazard ratio = 0.48, 95% confidence interval: 0.25, 0.94) when protected periods were compared with unprotected periods. Under the new 2014 American Academy of Pediatrics (AAP) guidelines, 48% of infants eligible for RSV immunoprophylaxis on the basis of AAP guidelines in place at birth would no longer be eligible, but nearly all infants with CLD would remain eligible. RSV immunoprophylaxis is effective in decreasing hospitalization. This association is greatest for infants with CLD, a group still recommended for receipt of RSV immunoprophylaxis under the new AAP guidelines.

Outcomes of Admissions for Preterm Labor.

Objective This study aims to quantitate the incidence of preterm labor (PTL) admissions and determine the frequency and predictors of preterm delivery (PTD) during these admissions. Study Design Retrospective cohort of singleton pregnancies within Kaiser Permanente Northern California, 2001 to 2011. PTL admissions were defined as inpatient encounters > 24 hours with an International Classification of Diseases, 9th Revision code for PTL. Results Total study population was 365,897 with PTL admission rate 11%. PTD occurred in 85% of pregnancies with PTL admission. Delivery occurred within 48 hours of admission in 96% ≥34 weeks, 67% 31 to 33 weeks, and 51.9% <31 weeks. Predictors of delivery during PTL admission included gestational age 34 to 36 weeks (adjusted odds ratio [aOR], 6.90), chorioamnionitis (aOR, 105.58), and preterm rupture of membranes (aOR 19.29). Conclusion We demonstrate a high rate of PTD per PTL admission in a highly integrated health care system. More work is needed to determine optimal practices for hospitalization and treatment of women diagnosed with PTL.

A Quantitative, Risk-Based Approach to the Management of Neonatal Early-Onset Sepsis.

Importance: Current algorithms for management of neonatal early-onset sepsis (EOS) result in medical intervention for large numbers of uninfected infants. We developed multivariable prediction models for estimating the risk of EOS among late preterm and term infants based on objective data available at birth and the newborn's clinical status. Objectives: To examine the effect of neonatal EOS risk prediction models on sepsis evaluations and antibiotic use and assess their safety in a large integrated health care system. Design, Setting, and Participants: The study cohort includes 204 485 infants born at 35 weeks' gestation or later at a Kaiser Permanente Northern California hospital from January 1, 2010, through December 31, 2015. The study compared 3 periods when EOS management was based on (1) national recommended guidelines (baseline period [January 1, 2010, through November 31, 2012]), (2) multivariable estimates of sepsis risk at birth (learning period [December 1, 2012, through June 30, 2014]), and (3) the multivariable risk estimate combined with the infant's clinical condition in the first 24 hours after birth (EOS calculator period [July 1, 2014, through December 31, 2015]). Main Outcomes and Measures: The primary outcome was antibiotic administration in the first 24 hours. Secondary outcomes included blood culture use, antibiotic administration between 24 and 72 hours, clinical outcomes, and readmissions for EOS. Results: The study cohort included 204 485 infants born at 35 weeks' gestation or later: 95 343 in the baseline period (mean [SD] age, 39.4 [1.3] weeks; 46 651 male [51.0%]; 37 007 white, non-Hispanic [38.8%]), 52 881 in the learning period (mean [SD] age, 39.3 [1.3] weeks; 27 067 male [51.2%]; 20 175 white, non-Hispanic [38.2%]), and 56 261 in the EOS calculator period (mean [SD] age, 39.4 [1.3] weeks; 28 575 male [50.8%]; 20 484 white, non-Hispanic [36.4%]). In a comparison of the baseline period with the EOS calculator period, blood culture use decreased from 14.5% to 4.9% (adjusted difference, -7.7%; 95% CI, -13.1% to -2.4%). Empirical antibiotic administration in the first 24 hours decreased from 5.0% to 2.6% (adjusted difference, -1.8; 95% CI, -2.4% to -1.3%). No increase in antibiotic use occurred between 24 and 72 hours after birth; use decreased from 0.5% to 0.4% (adjusted difference, 0.0%; 95% CI, -0.1% to 0.2%). The incidence of culture-confirmed EOS was similar during the 3 periods (0.03% in the baseline period, 0.03% in the learning period, and 0.02% in the EOS calculator period). Readmissions for EOS (within 7 days of birth) were rare in all periods (5.2 per 100 000 births in the baseline period, 1.9 per 100 000 births in the learning period, and 5.3 per 100 000 births in the EOS calculator period) and did not differ statistically (P = .70). Incidence of adverse clinical outcomes, including need for inotropes, mechanical ventilation, meningitis, and death, was unchanged after introduction of the EOS calculator. Conclusions and Relevance: Clinical care algorithms based on individual infant estimates of EOS risk derived from a multivariable risk prediction model reduced the proportion of newborns undergoing laboratory testing and receiving empirical antibiotic treatment without apparent adverse effects.

Phototherapy and Risk of Type 1 Diabetes.

BACKGROUND AND OBJECTIVE: Increases in both phototherapy use and the incidence of type 1 diabetes mellitus (DM-1) have been reported. One large study has suggested a strong association between them. Our objective was to quantify any association between neonatal phototherapy and DM-1 in a northern California integrated health care system. METHODS: This retrospective cohort study included 499 642 children born at ≥35 weeks' gestation in 15 Kaiser Permanente Northern California hospitals from 1995 to 2011 and followed until March 31, 2014. We ascertained phototherapy, bilirubin levels, and other covariates from electronic records. We identified DM-1 cases using a diabetes registry and inpatient and outpatient diagnoses. We used traditional and propensity-adjusted Cox models to quantify associations. RESULTS: Phototherapy use increased from 2.7% in 1995 to 16.0% in 2011. DM-1 was diagnosed in 37 of 39 406 children who had received phototherapy (15.1 per 100 000 person-years; mean follow-up 6.2 years) and 712 of 460 236 who had not (18.8 per 100 000 person-years; mean follow-up 8.2 years). There was no evidence of increasing diabetes incidence. We found no association between phototherapy and DM-1 in either unadjusted analyses (incidence rate ratio 0.81; 95% confidence interval, 0.56 to 1.12) or analyses adjusted for hyperbilirubinemia and other covariates (hazard ratio 1.06; 95% confidence interval, 0.78 to 1.45). DM-1 incidence was most strongly associated with race and ethnicity, with whites at highest risk (25.6 per 100 000) and Asians at lowest risk (8.9 per 100 000). CONCLUSIONS: We found no evidence of increased DM-1 risk in children who had received phototherapy.

Risk of Autism Associated With Hyperbilirubinemia and Phototherapy.

OBJECTIVE: Whether neonatal hyperbilirubinemia and/or phototherapy increase the risk of autism spectrum disorder (ASD) is unclear. We sought to quantify the risk of ASD associated with elevated total serum bilirubin (TSB) levels and with phototherapy. METHODS: In a retrospective cohort study of 525 409 infants born at ≥35 weeks' gestation in 15 Kaiser Permanente Northern California (KPNC) hospitals, 1995-2011, we obtained all TSB levels and determined which infants received phototherapy. From the KPNC Autism Registry, we identified patients with ASD diagnosed at a KPNC Autism Center, by a clinical specialist, or by a pediatrician. We calculated Cox proportional hazard ratios (HRs) for time to diagnosis of ASD, adjusting for confounding factors. RESULTS: Among infants in the birth cohort, 2% had at least 1 TSB level ≥20 mg/dL, and 8% received phototherapy. The rate of ASD was 13 per 1000 births. Crude analyses revealed an association between TSB ≥20 and ASD (relative risk: 1.4; 95% confidence interval [CI]: 1.1-1.6), and between phototherapy and ASD (relative risk: 1.7; 95% CI: 1.5-1.8). After adjusting for confounders, TSB ≥20 (HR: 1.09; 95% CI: 0.89-1.35) and phototherapy (HR: 1.10; 95% CI: 0.98-1.24) were no longer significantly associated with ASD. Independent risk factors for ASD included maternal and paternal age; maternal and paternal higher education; male sex; birth weight <2500 g or ≥4200 g; and later year of birth. CONCLUSIONS: After adjustment for the effects of sociodemographic factors and birth weight, neither hyperbilirubinemia nor phototherapy was an independent risk factor for ASD.

Retrospective Cohort Study of Phototherapy and Childhood Cancer in Northern California.

OBJECTIVE: To investigate the association between neonatal phototherapy use and childhood cancer. METHODS: This retrospective cohort study included 499 621 children born at ≥35 weeks' gestation from 1995 to 2011 in Kaiser Permanente Northern California hospitals, who survived to hospital discharge and were followed ≥60 days. We obtained data on home and inpatient phototherapy, covariates, and cancer incidence from electronic records. We used propensity-adjusted Cox and Poisson models to control for confounding and unequal follow-up times. RESULTS: There were 60 children with a diagnosis of cancer among 39 403 exposed to phototherapy (25 per 100 000 person-years), compared with 651 of 460 218 unexposed children (18 per 100 000 person-years; incidence rate ratio [IRR] 1.4; P = .01). Phototherapy was associated with increased rates of any leukemia (IRR 2.1; P = .0007), nonlymphocytic leukemia (IRR 4.0; P = .0004), and liver cancer (IRR 5.2; P = .04). With adjustment for a propensity score that incorporated bilirubin levels, chromosomal disorders, congenital anomalies, and other covariates, associations were no longer statistically significant: Adjusted hazard ratios (95% confidence intervals) were 1.0 (0.7-1.6) for any cancer, 1.6 (0.8-3.5) for any leukemia, 1.9 (0.6-6.9) for nonlymphocytic leukemia, and 1.4 (0.2-12) for liver cancer. Upper limits of 95% confidence intervals for adjusted 10-year excess risk were generally <0.1% but reached 4.4% for children with Down syndrome. CONCLUSIONS: Although phototherapy use was associated with increased cancer rates (particularly nonlymphocytic leukemia), control for confounding variables eliminated or attenuated the associations. Nonetheless, the possibility of even partial causality suggests that avoiding unnecessary phototherapy may be prudent.

Association Between Laboratory Calibration of a Serum Bilirubin Assay, Neonatal Bilirubin Levels, and Phototherapy Use.

IMPORTANCE: The American Academy of Pediatrics treatment recommendations for neonatal jaundice are based on age-specific total serum bilirubin (TSB) levels. In May 2012, Ortho Clinical Diagnostics adjusted the calibrator values for Vitros Chemistry Products BuBc Slides (Ortho Clinical Diagnostics), a widely used method to quantify TSB, after concerns of positively biased results. OBJECTIVE: To investigate the association between recalibration of a reflectance spectrophotometry serum bilirubin assay and TSB levels and phototherapy use among newborns. DESIGN, SETTING, AND PARTICIPANTS: Descriptive study comparing TSB levels and phototherapy use before and after recalibration at Kaiser Permanente Northern California, a large, integrated health care delivery system. The study evaluated live births at or after 35 weeks' gestation at 12 facilities that used universal serum bilirubin screening before (January 1, 2010, through April 30, 2012; n = 61 677) and after (July 1, 2012, through December 31, 2013; n = 42 571) recalibration. The analysis took place in December 2015. INTERVENTION: Recalibration of bilirubin testing instruments. MAIN OUTCOMES AND MEASURES: Proportions of newborns with (1) at least 1 TSB value at or above 15 mg/dL; (2) at least 1 TSB level exceeding the American Academy of Pediatrics phototherapy threshold; (3) phototherapy during the birth hospitalization; and (4) at least 1 readmission for phototherapy. RESULTS: In 104 420 infants (61 677 in the prerecalibration period and 42 511 in the postrecalibration period), a TSB was obtained in 99.2% of infants during birth and in 99.5% of infants within the first 30 days after birth. The postrecalibration period was associated with a 1.25 mg/dL (95% CI, 1.19-1.31; P < .001) decrease in mean maximum TSB, which led to a 39% relative reduction (from 20.4% to 12.4%) in infants with a TSB level of 15 mg/dL or more and a 51% relative reduction (from 9.3% to 4.5%) in infants with a TSB level that was at or above the American Academy of Pediatrics phototherapy threshold. Phototherapy during birth hospitalizations was reduced by 59% (absolute risk reduction, 5.5%; 95% CI, 4.7%-6.1%) and readmissions for phototherapy by 53% (absolute risk reduction, 1.8%; 95% CI, 1.4%-2.3%). CONCLUSIONS AND RELEVANCE: Modest recalibration-induced reductions in mean TSB concentrations was associated with a significant reduction in the percentage of infants with clinically significant hyperbilirubinemia. Current laboratory accuracy standards are insufficient to detect biases that can have significant clinical effect. These data underline the need for increased integration of laboratory expertise into clinical guidelines and to support international initiatives to standardize laboratory measurements.

Risk for cerebral palsy in infants with total serum bilirubin levels at or above the exchange transfusion threshold: a population-based study.

IMPORTANCE: Exchange transfusion is recommended for newborns with total serum bilirubin (TSB) levels thought to place them at risk for cerebral palsy (CP). However, the excess risk for CP among these infants is unknown. OBJECTIVE: To quantify the risks for CP and CP consistent with kernicterus that are associated with high TSB levels based on the 2004 American Academy of Pediatrics exchange transfusion threshold (ETT) guidelines. DESIGN, SETTING, AND PARTICIPANTS: We enrolled 2 cohorts from a population of 525,409 infants in the Late Impact of Getting Hyperbilirubinemia or Phototherapy (LIGHT) birth cohort. Eligible infants were born at a gestational age of at least 35 weeks at 15 hospitals within the Kaiser Permanente Northern California integrated medical care delivery system from January 1, 1995, through December 31, 2011. EXPOSURES: The exposed cohort included all 1833 infants with at least 1 TSB measurement at or above the ETT based on age at testing, gestational age, and results of direct antiglobulin testing. The unexposed cohort was a 20% random sample of 104 716 infants with TSB levels below the ETT. MAIN OUTCOMES AND MEASURES: A pediatric neurologist blinded to the TSB levels reviewed medical records to determine the presence of CP, defined as a nonprogressive congenital motor dysfunction with hypertonia or dyskinesia. Cerebral palsy was judged to be consistent with kernicterus if magnetic resonance imaging of the brain revealed bilateral globus pallidus injury in the setting of dyskinetic CP. RESULTS: We identified CP in 7 of 1833 exposed (0.4%) vs 86 of 104 716 unexposed (0.1%) infants (relative risk, 4.7 [95% CI, 2.2-10.0]). Absolute risk differences were 0.2% (95% CI, 0%-0.5%) for a TSB level 0 to 4.9 mg/dL above the ETT (n = 1705), 0.9% (95% CI, 0.1%-5.3%) for a TSB level 5.0 to 9.9 mg/dL above the ETT (n = 102), and 7.6% (95% CI, 2.1%-24.1%) for a TSB level 10 mg/dL or more above the ETT (n = 26). Cerebral palsy consistent with kernicterus occurred in 3 infants (incidence, 0.57 per 100,000 births); all 3 had TSB levels of more than 5.0 mg/dL above the ETT and at least 2 risk factors for neurotoxicity, such as prematurity, glucose-6-phosphate dehydrogenase deficiency, or hypoxia-ischemia. CONCLUSIONS AND RELEVANCE: Cerebral palsy consistent with kernicterus occurred only in infants with 2 or more risk factors for neurotoxicity and TSB levels of more than 5 mg/dL above the ETT. Among infants with lower degrees of TSB level elevation, the excess risk for CP is minimal.

Persistent recurring wheezing in the fifth year of life after laboratory-confirmed, medically attended respiratory syncytial virus infection in infancy.

BACKGROUND: Respiratory syncytial virus (RSV) infection in infancy is associated with subsequent recurrent wheezing. METHODS: A retrospective cohort study examined children born at ≥32 weeks gestation between 1996-2004. All children were enrolled in an integrated health care delivery system in Northern California and were followed through the fifth year of life. The primary endpoint was recurrent wheezing in the fifth year of life and its association with laboratory-confirmed, medically-attended RSV infection during the first year, prematurity, and supplemental oxygen during birth hospitalization. Other outcomes measured were recurrent wheezing quantified through outpatient visits, inpatient hospital stays, and asthma prescriptions. RESULTS: The study sample included 72,602 children. The rate of recurrent wheezing in the second year was 5.6% and fell to 4.7% by the fifth year. Recurrent wheezing rates varied by risk status: the rate was 12.5% among infants with RSV hospitalization, 8% among infants 32-33 weeks gestation, and 18% in infants with bronchopulmonary dysplasia. In multivariate analyses, increasing severity of respiratory syncytial virus infection was significantly associated with recurrent wheezing in year 5; compared with children without RSV infection in infancy, children who only had an outpatient RSV encounter had an adjusted odds ratio of 1.38 (95% CI,1.03-1.85), while children with a prolonged RSV hospitalization had an adjusted odds ratio of 2.59 (95% CI, 1.49-4.50). CONCLUSIONS: Laboratory-confirmed, medically attended RSV infection, prematurity, and neonatal exposure to supplemental oxygen have independent associations with development of recurrent wheezing in the fifth year of life.

Synthesis and evaluation of substituted benzoisoquinolinones as potent inhibitors of Chk1 kinase.

From HTS lead 1, a novel benzoisoquinolinone class of ATP-competitive Chk1 inhibitors was devised and synthesized via a photochemical route. Using X-ray crystallography as a guide, potency was rapidly enhanced through the installation of a tethered basic amine designed to interact with an acidic residue (Glu91) in the enzyme pocket. Further SAR was explored at the solvent front and near to the H1 pocket and resulted in the discovery of low MW, sub-nanomolar inhibitors of Chk1.