Evaluation of the EMA log kow trigger for fish BCF testing based on data for several human pharmaceuticals.

In the European Medicines Agency (EMA) "Guideline for Environmental Risk Assessment of Medicinal Products for Human Use," a fish bioconcentration factor (BCF) study is triggered in Phase I for pharmaceuticals having log Kow >4.5, to support Persistence, Bioaccumulation and Toxicity (PBT) screening, and in Phase II to assess secondary poisoning and bioaccumulation ('B') potential when log Kow ≥3. The standard sampling schedule outlined in OECD Test Guideline 305 (TG305) may require assessment of approximately 200 fish following exposure to low- and high-test concentrations and a negative control. We report experimental log Kow and BCF values for 64 human pharmaceuticals that were used to evaluate the current BCF testing trigger of log Kow ≥3, and whether a single BCF exposure concentration allows accurate classification of bioaccumulation potential. Our data support raising the BCF testing trigger to log Kow ≥4, and use of a single test concentration. The resulting reduction in the use of fish is consistent with the 3 R s principle and did not adversely affect classification accuracy. An assessment of potential risk of secondary poisoning was also conducted for three drugs classified as either B or vB, and no risks were identified.

Design of greener drugs: aligning parameters in pharmaceutical R&D and drivers for environmental impact.

Active pharmaceutical ingredients (APIs) in the environment, primarily resulting from patient excretion, are of concern because of potential risks to wildlife. This has led to more restrictive regulatory policies. Here, we discuss the 'benign-by-design' approach, which encourages the development of environmentally friendly APIs that are also safe and efficacious for patients. We explore the challenges and opportunities associated with identifying chemical properties that influence the environmental impact of APIs. Although a straightforward application of greener properties could hinder the development of new drugs, more nuanced approaches could lead to drugs that benefit both patients and the environment. We advocate for an enhanced dialogue between research and development (R&D) and environmental scientists and development of a toolbox to incorporate environmental sustainability in drug development.

Minimizing Experimental Testing on Fish for Legacy Pharmaceuticals.

There was no regulatory requirement for ecotoxicological testing of human pharmaceuticals authorized before 2006, and many of these have little or no data available to assess their environmental risk. Motivated by animal welfare considerations, we developed a decision tree to minimize in vivo fish testing for such legacy active pharmaceutical ingredients (APIs). The minimum no observed effect concentration (NOECmin, the lowest NOEC from chronic Daphnia and algal toxicity studies), the theoretical therapeutic water concentration (TWC, calculated using the fish plasma model), and the predicted environmental concentration (PEC) were used to derive API risk quotients (PEC/NOECmin and PEC/TWC). Based on a verification data set of 96 APIs, we show that by setting a threshold value of 0.001 for both risk quotients, the need for in vivo fish testing could potentially be reduced by around 35% without lowering the level of environmental protection. Hence, for most APIs, applying an assessment factor of 1000 (equivalent to the threshold of 0.001) to NOECmin substituted reliably for NOECfish, and TWC acted as an effective safety net for the others. In silico and in vitro data and mammalian toxicity data may further support the final decision on the need for fish testing.

Young People's Experiences of Returning to Physical Leisure Activities after a Severe Acquired Brain Injury.

AIMS: To understand the experiences of young people returning to physical leisure activities following a severe acquired brain injury (ABI). METHODS: Seven young people (5 male; 14-19 years) participated. Semi-structured interviews were conducted with young people who sustained a severe ABI 1-3 years prior to the study. Data thematically analyzed using Braun and Clarke's six-phase approach. RESULTS: Three main themes were created: My changing sense of identity around physical activity after my brain injury (how important physical activity was to them, how participation changed following their ABI); Why I take part in physical leisure activities (fun, friendships, help with recovery and physical and emotional health); and I can't do it alone (need for trusted adults to practically and emotionally support them to try and activities and continue to participate). DISCUSSION: Returning to physical leisure activities after ABI was important to young people, especially if they were active prior to their injury. However, participating with changed abilities was practically and emotionally challenging. Services need a multidisciplinary approach to ensure young people are supported with psychological processes of loss, adjustment, identity and resilience in addition to the practical help necessary to enable meaningful participation in activities they consider fun.

A new model to guide identity-focused multidisciplinary rehabilitation for children and young people following acquired brain injury: I-FoRM.

A complexity of biological, psychological, environmental and systemic factors influences a child's adaption after acquired brain injury (ABI), all of which transform as the child matures. Multidisciplinary rehabilitation teams are challenged by balancing family system needs and the child's needs, whilst promoting the child's functional skills in difficult or unappealing tasks. This paper presents the conceptual basis for a model for use in childhood ABI neurorehabilitation to address these challenges. A non-systematic narrative review of literature pertinent to integrated neurorehabilitation of pediatric ABI was conducted. Contemporary models of adult and pediatric psychosocial adaptation involving identity following ABI were reviewed. Key findings were then synthesized with models of pediatric resilience and self-concept development. The resulting model describes a cyclical adaptation process whereby the child learns experientially about their self and their world after ABI. Processes of identity development play a central role - particularly emotive processes of self-evaluation - by influencing the child's motivation for participation, tolerance for challenge, self-regulation and emerging self-awareness. The model directs clinicians to use the psychosocial processes of identity development to enhance the child's willingness and capacity to engage in the daily challenges of rehabilitation. Further systematic development and evaluation of the model is needed.

A Review of the Current Cervical Cancer Screening Guidelines.

For many decades, Pap smear screening has been synonymous with well-woman visits. Although Pap smears have greatly decreased the rates of cervical cancer, current guidelines support less frequent screening. This commentary reviews the currently recommended strategies for cervical cancer screening.

Implementation of a Preventive Services Bundle in Academic Pediatric Primary Care Centers.

BACKGROUND AND OBJECTIVES: Previous studies have documented poor rates of delivery of preventive services, 1 of the core services provided in the primary care medical home setting. We aimed to increase the reliability of delivering a bundle of preventive services to patients 0 to 14 months of age from 58% of patient visits to 95% of visits. The bundle includes administration of routine vaccinations, offering influenza vaccination, completed lead screening, completed developmental screening tool, screening for maternal depression and food insecurity, and documentation of gestational age. METHODS: The setting was 3 academic pediatric primary care clinics that serve 31,000 patients (>90% Medicaid). Quality improvement methodology was used and key driver diagram was determined. Patient "Ideal Visit Flow" and the Responsible, Accountable, Support, Consulted, and Informed Matrix were developed to drive accountability for components of the ideal flow. Plan, Do, Study, Act cycles were used to develop successful interventions. The percent of patients seen who received all bundle elements for which they were eligible was plotted weekly on a run chart, and statistical process control methods were used to determine a significant change in performance. RESULTS: The preintervention percentage of patient visits ages 0 to 14 months receiving all preventive service bundle elements was 58%. The postintervention percentage is 92%. CONCLUSIONS: Innovative redesign led to improvement in percentage of patients age 0 to 14 months who received the entire preventive services bundle. Key elements for success were multidisciplinary site-specific teams, redesigned visit flow, effective communication, and resources for data and project management.

Development of a bundle measure for preventive service delivery to infants in primary care.

RATIONALE, AIMS AND OBJECTIVES: In the United States, paediatric patients receive only 41% of indicated preventive services. Past improvement efforts have not bundled preventive services to measure the reliability with which infants' physical, developmental and emotional needs are all addressed. We aimed to create a comprehensive bundle measure that reflects reliable delivery of preventive services during primary care visits, as well as overall preventive service status of a population of patients served by three primary care centres. METHOD: Data were collected from electronic health records for cohorts of infants < 14 months old with at least one visit to one of three primary care centres. Immunizations, lead screening, developmental screening and screening for biopsychosocial risk factors (gestational age, parental depression, food insecurity) were chosen by local expert consensus for inclusion in the preventive services bundle measure. Monthly measures of preventive service status at 14 months of age were constructed. A visit-level bundle measure of preventive service delivery was also created. To obtain a baseline for improvement work, bundle completion rates were calculated for infants born in May 2011. Visit-level performance was measured for visits from July to August 2012. RESULTS: Among 278 patients born in May 2011, 22% of patients received the entire bundle of preventive services by 14 months of age. On a visit level, patients received all indicated services at 58% of visits. CONCLUSION: A novel bundle measure can be used to characterize delivery of preventive services and drive improvement at both an individual visit level and a population level.

FRA16D common chromosomal fragile site oxido-reductase (FOR/WWOX) protects against the effects of ionizing radiation in Drosophila.

Fragile sites are chromosomal structures that have been proposed to have a determining role in cancer-associated DNA instability. The human WWOX gene spans the FRA16D chromosomal fragile site, the common minimal region of homozygous deletion found in adenocarcinomas and three out of five translocation breakpoints in multiple myeloma. Transcripts from the alternatively spliced WWOX gene encode proteins with common N-terminal WW domains and variable homology to the oxidoreductase family of proteins. In this study, the Drosophila orthologue of the WWOX gene was identified and subjected to mutagenesis via homologous recombination. The resultant DmWWOX1 mutants were viable but exhibited an increased sensitivity to ionizing radiation. This radiation sensitivity was rescued by reintroduction and expression of either the wild-type Drosophila or human WWOX genes. Thus, the protective function of DmWWOX in response to irradiation in Drosophila is conserved with human WWOX (hWWOX). This is consistent with a protective role for hWWOX where aberrant expression, as a result of breakage at the associated fragile site, could contribute directly to cancer progression.

Cooperativity in long-range gene regulation by the lambda CI repressor.

Effective repression of cI transcription from PRM by the bacteriophage lambda CI repressor requires binding sites (OL) located 2.4 kb from the promoter. A CI tetramer bound to OL1.OL2 interacts with a tetramer bound near PRM (OR1.OR2), looping the intervening DNA. We previously proposed that in this CI octamer:DNA complex, the distant OL3 operator and the weak OR3 operator overlapping PRM are juxtaposed so that a CI dimer at OL3 can cooperate with a CI dimer binding to OR3. Here we show that OL3 is necessary for effective repression of PRM and that the repressor at OL3 appears to interact specifically with the repressor at OR3. The OL3-CI-OR3 interaction involves the same CI interface used for short-range dimer-dimer interactions and does not occur without the other four operators. The long-range interactions were incorporated into a physicochemical model, allowing estimation of the long-range interaction energies and showing the lysogenic state to be ideally poised for CI negative autoregulation. The results establish the lambda system as a powerful tool for examining long-range gene regulatory interactions in vivo.