Developmental care pathway for hospitalised infants with CHD: on behalf of the Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative.

Infants and children born with CHD are at significant risk for neurodevelopmental delays and abnormalities. Individualised developmental care is widely recognised as best practice to support early neurodevelopment for medically fragile infants born premature or requiring surgical intervention after birth. However, wide variability in clinical practice is consistently demonstrated in units caring for infants with CHD. The Cardiac Newborn Neuroprotective Network, a Special Interest Group of the Cardiac Neurodevelopmental Outcome Collaborative, formed a working group of experts to create an evidence-based developmental care pathway to guide clinical practice in hospital settings caring for infants with CHD. The clinical pathway, "Developmental Care Pathway for Hospitalized Infants with Congenital Heart Disease," includes recommendations for standardised developmental assessment, parent mental health screening, and the implementation of a daily developmental care bundle, which incorporates individualised assessments and interventions tailored to meet the needs of this unique infant population and their families. Hospitals caring for infants with CHD are encouraged to adopt this developmental care pathway and track metrics and outcomes using a quality improvement framework.

Assessment and management of feeding difficulties for infants with complex CHD.

Early surgical intervention in infants with complex CHD results in significant disruptions to their respiratory, gastrointestinal, and nervous systems, which are all instrumental to the development of safe and efficient oral feeding skills. Standardised assessments or treatment protocols are not currently available for this unique population, requiring the clinician to rely on knowledge based on neonatal literature. Clinicians need to be skilled at evaluating and analysing these systems to develop an appropriate treatment plan to improve oral feeding skill and safety, while considering post-operative recovery in the infant with complex CHD. Supporting the family to re-establish their parental role during the hospitalisation and upon discharge is critical to reducing parental stress and oral feeding success.

Disruptions in the development of feeding for infants with congenital heart disease.

Congenital heart disease (CHD) is the most common birth defect for infants born in the United States, with approximately 36,000 affected infants born annually. While mortality rates for children with CHD have significantly declined, there is a growing population of individuals with CHD living into adulthood prompting the need to optimise long-term development and quality of life. For infants with CHD, pre- and post-surgery, there is an increased risk of developmental challenges and feeding difficulties. Feeding challenges carry profound implications for the quality of life for individuals with CHD and their families as they impact short- and long-term neurodevelopment related to growth and nutrition, sensory regulation, and social-emotional bonding with parents and other caregivers. Oral feeding challenges in children with CHD are often the result of medical complications, delayed transition to oral feeding, reduced stamina, oral feeding refusal, developmental delay, and consequences of the overwhelming intensive care unit (ICU) environment. This article aims to characterise the disruptions in feeding development for infants with CHD and describe neurodevelopmental factors that may contribute to short- and long-term oral feeding difficulties.

Successful gastrostomy tube weaning program using an intensive multidisciplinary team approach.

OBJECTIVES: The present study evaluated the effectiveness of a multidisciplinary intensive inpatient model for gastrostomy tube (GT) weaning. METHODS: A retrospective chart review was completed on 30 GT-dependent children, ages 3.9 (±1.4) years, admitted to the inpatient feeding program (length of stay 19 days) from May 2009 to December 2011. Administered GT calories were decreased on admission by an average of 73% from home regimen. Patients were offered 3 meals and 2 to 3 snacks/day, including 3 intensive feeding therapy sessions (Monday to Friday), along with psychosocial support, nutrition guidance, and behavioral therapy. Daily calorie counts and weights were recorded. Patients returned for a postdischarge feeding evaluation at an average of 4 months and a clinic visit at 1 year. Data were analyzed using paired samples t tests. RESULTS: Before admission, patients received 69% (±25) of goal calories by GT and 22% (±19) of goal calories orally. During admission, average caloric intake by mouth as a percentage of goal increased during the course of weeks 1, 2, and 3 (68%, 77%, and 82%, respectively), with a statistically significant increase between weeks 1 and 2 (P = 0.001) and 1 and 3 (P = 0.011). At discharge, 90% had discontinued GT feedings. Average percent weight change during admission was 0.2% (±4). At 1 year follow-up, 83% remained successfully off GT feedings. CONCLUSIONS: Children who are GT dependent can be weaned off GT feedings during a 3-week admission using a multidisciplinary feeding model. The therapeutic gains were maintained at 1 year postdischarge.

A history of being prescribed controlled substances and risk of drug overdose death.

OBJECTIVE: The abuse of prescription drugs has increased dramatically since 1990. Persons who overdose on such drugs frequently consume large doses and visit multiple providers. The risk of fatal overdose for different patterns of use of opioid analgesics and sedative/hypnotics has not been fully quantified. DESIGN: Matched case-control study. Cases were 300 persons who died of unintentional drug overdoses in New Mexico during 2006-2008, and controls were 5,993 patients identified through the state prescription monitoring program with matching 6-month exposure periods. OUTCOME MEASURES: Death from drug overdose or death from opioid overdose. Exposures were demographic variables and characteristics of prescription history. Crude and adjusted odds ratios (AOR) were calculated. RESULTS: Increased risk was associated with male sex (AOR 2.4, 95% confidence interval [CI] 1.8-3.1), one or more sedative/hypnotic prescriptions (AOR 3.0, CI 2.2-4.2), greater age (AOR 1.3, CI 1.2-1.4 for each 10-year increment), number of prescriptions (AOR 1.1, CI 1.1-1.1 for each additional prescription), and a prescription for buprenorphine (AOR 9.5, CI 3.0-30.0), fentanyl (AOR 3.5, CI 1.7-7.0), hydromorphone (AOR 3.3, CI 1.4-7.5), methadone (AOR 4.9, CI 2.5-9.6), or oxycodone (AOR 1.9, CI 1.4-2.6). Patients receiving a daily average of >40 morphine milligram equivalents had an OR of 12.2 (CI 9.2-16.0). CONCLUSIONS: Patients being prescribed opioid analgesics frequently or at high dosage face a substantial overdose risk. Prescription monitoring programs might be the best way for prescribers to know their patients' prescription histories and accurately assess overdose risk.

Synthesis and SAR studies of novel 2-(6-aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) antagonists are described. 2-(6-Aminomethylaryl-2-aryl-4-oxo-quinazolin-3(4H)-yl)acetamide have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and OT. Optimised compound 16 shows a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

Synthesis and SAR studies of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V1b receptor antagonists.

Synthesis and structure-activity relationships (SAR) of a novel series of vasopressin V(1b) (V(3)) antagonists are described. 2-(4-Oxo-2-aryl-quinazolin-3(4H)-yl)acetamides have been identified with low nanomolar affinity for the V(1b) receptor and good selectivity with respect to related receptors V(1a), V(2) and oxytocin (OT). Optimised compound 12j demonstrates a good pharmacokinetic profile and activity in a mechanistic model of HPA dysfunction.

Prescription drug monitoring programs and death rates from drug overdose.

OBJECTIVE: Drug overdoses resulting from the abuse of prescription opioid analgesics and other controlled substances have increased in number as the volume of such drugs prescribed in the United States has grown. State prescription drug monitoring programs (PDMPs) are designed to prevent the abuse of such drugs. This study quantifies the relation of PDMPs to rates of death from drug overdose and quantities of opioid drugs distributed at the state level. DESIGN: Observational study of the United States during 1999-2005. OUTCOME MEASURES: Rates of drug overdose mortality, opioid overdose mortality, and opioid consumption by state. RESULTS: PDMPs were not significantly associated with lower rates of drug overdose or opioid overdose mortality or lower rates of consumption of opioid drugs. PDMP states consumed significantly greater amounts of hydrocodone (Schedule III) and nonsignificantly lower amounts of Schedule II opioids. The increases in overdose mortality rates and use of prescription opioid drugs during 1999-2005 were significantly lower in three PDMP states (California, New York, and Texas) that required use of special prescription forms. CONCLUSIONS: While PDMPs are potentially an important tool to prevent the nonmedical use of prescribed controlled substances, their impact is not reflected in drug overdose mortality rates. Their effect on overall consumption of opioids appears to be minimal. PDMP managers need to develop and test ways to improve the use of their data to affect the problem of prescription drug overdoses.

Identification and optimization of novel 2-(4-oxo-2-aryl-quinazolin-3(4H)-yl)acetamide vasopressin V3 (V1b) receptor antagonists.

The discovery, synthesis, and preliminary structure-activity relationship (SAR) of a novel class of vasopressin V3 (V1b) receptor antagonists is described. Compound 1, identified by high throughput screening of a diverse, three million-member compound collection, prepared using ECLiPS technology, had good activity in a V3 binding assay (IC50=0.20 microM), but less than desirable physicochemical properties. Optimization of compound 1 yielded potent analogs 19 (IC50=0.31 microM) and 24 (IC50=0.12 microM) with improved drug-like characteristics.

Novel pyrrolidine heterocycles as CCR1 antagonists.

A novel series of pyrrolidine heterocycles was prepared and found to show potent inhibitory activity of CCR1 binding and CCL3 mediated chemotaxis of a CCR1-expressing cell line. A potent, optimized triazole lead from this series was found to have acceptable pharmacokinetics and microsomal stability in rat and is suitable for further optimization and development.

Discovery of novel quinolinone adenosine A2B antagonists.

A novel series of quinolinone-based adenosine A(2B) receptor antagonists was identified via high throughput screening of an encoded combinatorial compound collection. Synthesis and assay of a series of analogs highlighted essential structural features of the initial hit. Optimization resulted in an A(2B) antagonist (2i) which exhibited potent activity in a cAMP accumulation assay (5.1 nM) and an IL-8 release assay (0.4 nM).

Quality of life in Indian women with fertility problems as assessed by the FertiQoL questionnaire: a single center cross sectional study.

PURPOSE: Infertility and its treatment can significantly impact an individual's physical and psychological health; however, this has not been well-studied in the Indian population. This study aimed to assess the quality of life in women with infertility at a teaching hospital in Hyderabad, India. METHODS: In this cross sectional study of women with infertility, the quality of life was measured using the 'FertiQoL International' questionnaire (English/Hindi). RESULTS: The age ranged from 20 to 38 years and polycystic ovary syndrome was the most common cause of infertility. Core FertiQoL scores were analyzed in 215 women and Treatment FertiQoL in 156. The mean Total FertiQoL score in the study population was 66.1 (SD 13.0) and this overall score was not influenced by socio-demographic or infertility-specific factors. However, on subscale analysis, women who had living children and were university-educated had significantly better emotional scores while obese (≥35 kg/m2) women and those on ovulation induction treatment had poorer mind body and relational scores, respectively. Women with associated co-morbidities had worse quality of life on the Treatment Environment scale than those without. CONCLUSIONS: The results provide a baseline quality of life score in these women. Infertility had the greatest impact on the emotional domain.

Novel pyrrolidine ureas as C-C chemokine receptor 1 (CCR1) antagonists.

Monocyte infiltration is implicated in a variety of diseases including multiple myeloma, rheumatoid arthritis, and multiple sclerosis. C-C chemokine receptor 1 (CCR1) is a chemokine receptor that upon stimulation, particularly by macrophage inflammatory protein 1alpha (MIP-1alpha) and regulated on normal T-cell expressed and secreted (RANTES), mediates monocyte trafficking to sites of inflammation. High throughput screening of our combinatorial collection identified a novel, moderately potent CCR1 antagonist 3. The library hit 3 was optimized to the advanced lead compound 4. Compound 4 inhibited CCR1 mediated chemotaxis of monocytes with an IC(50) of 20 nM. In addition, the compound was highly selective over other chemokine receptors. It had good microsomal stability when incubated with rat and human liver microsomes and showed no significant cytochrome P450 (CYP) inhibition. Pharmacokinetic evaluation of the compound in the rat showed good oral bioavailability.