Paving the way for application of next generation risk assessment to safety decision-making for cosmetic ingredients.

Next generation risk assessment (NGRA) is an exposure-led, hypothesis-driven approach that has the potential to support animal-free safety decision-making. However, significant effort is needed to develop and test the in vitro and in silico (computational) approaches that underpin NGRA to enable confident application in a regulatory context. A workshop was held in Montreal in 2019 to discuss where effort needs to be focussed and to agree on the steps needed to ensure safety decisions made on cosmetic ingredients are robust and protective. Workshop participants explored whether NGRA for cosmetic ingredients can be protective of human health, and reviewed examples of NGRA for cosmetic ingredients. From the limited examples available, it is clear that NGRA is still in its infancy, and further case studies are needed to determine whether safety decisions are sufficiently protective and not overly conservative. Seven areas were identified to help progress application of NGRA, including further investments in case studies that elaborate on scenarios frequently encountered by industry and regulators, including those where a 'high risk' conclusion would be expected. These will provide confidence that the tools and approaches can reliably discern differing levels of risk. Furthermore, frameworks to guide performance and reporting should be developed.

Localization of aquaporin 1 water channel in the Schmidt-Lanterman incisures and the paranodal regions of the rat sciatic nerve.

Aquaporin 1 (AQP1) is a member of a family of small, integral membrane water-transporting proteins, which facilitate water movement across cell membranes in response to osmotic gradients. Several papers have studied the expression and function of the AQPs in the central nervous system. However, little is known about the AQPs in the peripheral nervous system (PNS). In the PNS, AQP1, AQP2 and AQP4 have been reported in both peripheral neurons and glial cells. In this work we studied the expression and localization of AQP1 in the rat sciatic nerve. We found that from the four AQPs we studied (AQP1, AQP2, AQP4 and AQP9) only AQP1 is expressed in the nerve by reverse transcription polymerase chain reaction (RT-PCR). AQP1 is also observed at the protein level by Western blot analysis. We also studied the localization of AQP1 in the sciatic nerve by immunohistochemistry. The results show that AQP1 is present in both myelinating and non-myelinating Schwann cells. In myelin internodes AQP1 is enriched in the Schmidt-Lanterman incisures and in some internodes it is also present in the abaxonal membrane. At the nodes of Ranvier, AQP1 co-localizes with actin in the paranodal regions of the nerve. Therefore, AQP1 might play an important role in myelin homeostasis maintaining the thermodynamic equilibrium across the plasma membrane in myelinated axons during electrical activity. Also the expression of AQP1 in non-myelinating Schwann cells supports the involvement of AQP1 in pain perception.

Prophylaxis of impacted teeth using MRI and focal ultra-sound ablation? a feasible hypothesis.

UNLABELLED: Teeth start as bi-layered epithelial soft tissue follicles within bony jaws. Follicles grow into teeth and erupt. Early third molar follicles are detectable 8-9 years (±9 months). Intra-oral dental arches of jaws have finite space accommodating formed crowns. The last teeth to erupt are third molars. When the space needed by all the teeth exceeds the total arch space available, wisdom teeth may become impacted in bone. Lower impactions are more prevalent due to the mandible shape, and impaction associated pathologies with erupting partially or totally impacted teeth are common. Impacted third molars are universally prevalent from 17 to 23 years. Third molar impactions are sources of infection, pain, cyst formation and contribute to malocclusions and other pathologies. Surgical removal of third molars is traumatic, invasive and painful and may produce complicating morbidities. Magnetic resonance imaging (MRI) is used to locate lesions with clear definition and accurate targeting, both in soft and hard tissue organs. Focused ultrasound (FUS) is used to ablate hard and soft tissue structures and stops growth of targeted pathologies. For example, FUS is used to ablate CNS brain tumours, cell causing Parkinson's disease, prostatic growths and thrombolysis in strokes. HYPOTHESIS: Modern imaging techniques, like MRI, can accurately locate third molar follicles at age 9, before wisdom teeth form and grow. MRI in combination with FUS could be used to ablate follicles of third molars, stop tooth growth (both crown and root) and so avoid later impactions.

Safety profile of Hoodia gordonii extract: mouse prenatal developmental toxicity study.

Hoodia gordonii extract (0, 5, 15 or 50mg/kg body weight/day, n=24 mice/group) was orally administered by gavage to female CD-1 mice from gestation days 5-17. On gestation day 18 the females were euthanized and examined. Treatment at 50mg/kg/day caused a marked reduction in feed intake and body weight gain. Feed consumption was sporadically reduced at 15 mg/kg/day. At 50 or 15 mg/kg/day fetal weights, ossification of some bones and full and empty uterus weights were reduced. There were no clear maternal or fetal effects at 5mg/kg/day. Reproductive indices were unaffected at all doses and there were no treatment-related malformations, anomalies or variations. The overall study no-observed-adverse-effect level was set at 5mg/kg/day. In summary, at doses that reduced maternal feed consumption, H. gordonii extract delayed fetal development. The fetal effects seen could be consequent to reduced maternal feed consumption, the desired biological activity of the test item.

Safety profile of Hoodia gordonii extract: rabbit prenatal developmental toxicity study.

Hoodia gordonii extract was orally administered by gavage to groups of 22 female New Zealand white rabbits from day 3-28 after mating at doses of 0 (control), 3, 6 or 12 mg/kg bodyweight/day. These doses were reached by a dose escalation phase between days 3 and 7 after mating. As well as a vehicle control group, a control group pair-fed to the high dose was also included. On day 29 after mating the females were euthanized and examined. Treatment at 6 or 12 mg/kg/day was associated with a dose-related reduction in feed intake and bodyweight gain. Feed consumption and bodyweight gain was unaffected at 3mg/kg/day. In spite of marked maternal effects at 12 mg/kg/day, reproductive indices were unaffected at all doses and there were no effects on fetal or placental weights and no morphological changes in the fetuses. The no-observed-effect level (NOEL) for developmental effects was therefore 12 mg/kg/day, and the maternal NOEL was 3mg/kg/day. At doses that caused marked maternal effects, H. gordonii extract did not affect embryonic or fetal development in a species that is considered predictive of developmental toxicity in man.

The development of medical-manager roles in European hospital systems: a framework for comparison.

A central motif of health reforms around the world has been the drive to persuade doctors and other clinical professionals to become more actively engaged in the management of services. Examples include moves to extend the commissioning role of primary care doctors (such as general practitioners in the UK) and the introduction of 'clinical directorates' in secondary care. This strategy has been seen as a means of controlling professionals, turning 'poachers into game keepers', especially with regard to resource allocation. However, there is also a mounting body of evidence pointing to how clinical leadership may play a role in stimulating quality improvement and new innovations inservice design, with positive consequences for patient safety and satisfaction (1). Focusing on the top 100 hospitals in the US Goodall (2) finds a strong positive association between the ranked quality of hospitals and whether the chief executive officer was a clinician. A survey of 1200 hospitals across seven countries (UK, US, Germany, France, Italy,Canada and Sweden) conducted by McKinsey and LSE also finds that clinically qualified managers improve both the effectiveness of management decisions and clinical performance of hospitals overall (3).

Chronic disease management: teaching medical students to incorporate community.

BACKGROUND AND OBJECTIVES: As a response to the growing prevalence of chronic disease, models of chronic care have emerged as salient approaches to address dynamic health care changes and to manage the burden of suffering of these diseases. Concurrently, there has been a growing call to address chronic disease management within medical school curricula. This article describes the development and evaluation of a curricular intervention designed to prepare students to integrate patient-centered care with an understanding of the patients' community, provide care within rural settings, and experience clinical education specific to chronic disease management. METHODS: Second-year medical students completed a chronic disease management project as part of a 4-week community visit in rural and/or medically underserved sites. Paired pre- and post-survey data were collected using the Community Oriented Health Care Competency Scale to assess the student's knowledge, intent to practice, and attitudes toward incorporating community-oriented primary care into future practice. RESULTS: Matched pre- and post-project surveys were identified for 170 respondents out of 219 students (77.6% response rate). Post-assessment items were found to be statistically different from measures collected prior to the students' entrance into the community: all knowledge questions indicated significant advancements toward community responsiveness, as did one question related to attitude and three of the intent to practice community-oriented health care questions. CONCLUSIONS: Community-based rotations can play a positive role in developing the competencies needed for future practice. The development of curricular opportunities designed to train future physicians on the value of incorporating models of chronic care within rural and underserved communities should remain at the forefront of medical education.

Medical education for a healthier population: reflections on the Flexner Report from a public health perspective.

Abraham Flexner's 1910 report is credited with promoting critical reforms in medical education. Because Flexner advocated scientific rigor and standardization in medical education, his report has been perceived to place little emphasis on the importance of public health in clinical education and training. However, a review of the report reveals that Flexner presciently identified at least three public-health-oriented principles that contributed to his arguments for medical education reform: (1) The training, quality, and quantity of physicians should meet the health needs of the public, (2) physicians have societal obligations to prevent disease and promote health, and medical training should include the breadth of knowledge necessary to meet these obligations, and (3) collaborations between the academic medicine and public health communities result in benefits to both parties. In this article, commemorating the Flexner Centenary, the authors review the progress of U.S. and Canadian medical schools in addressing these principles in the context of contemporary societal health needs, provide an update on recent efforts to address what has long been perceived as a deficit in medical education (inadequate grounding of medical students in public health), and provide new recommendations on how to create important linkages between medical education and public health. Contemporary health challenges that require a public health approach in addition to one-on-one clinical skills include containing epidemics of preventable chronic diseases, reforming the health care system to provide equitable high-quality care to populations, and responding to potential disasters in an increasingly interconnected world. The quantitative skills and contextual knowledge that will prepare physicians to address these and other population health problems constitute the basics of public health and should be included throughout the continuum of medical education.

Vital signs screening for alcohol misuse in a rural primary care clinic: a feasibility study.

CONTEXT: Alcohol misuse is more common in rural areas, and rural problem drinkers are less likely to seek alcohol treatment services. Rural clinics face unique challenges to implementing routine alcohol screening and intervention. PURPOSE: To assess the feasibility of using the single alcohol screening question (SASQ) during routine nursing vital signs in a rural clinic, and to determine its effect on alcohol screening and intervention rates. METHODS: Patient exit interviews were used to identify alcohol misuse and to measure changes in screening and intervention rates. Chi-square tests were used to compare rates of screening across study phases, while odds ratios from logistic regression analyses were used to quantify association between nurse screening and clinician intervention. FINDINGS: Exit interviews were completed by 126 current drinkers (41 before vital signs screening implementation and 85 afterward). Screening rates for alcohol misuse rose from 14.6% at baseline to 20.0% (P = .027) after screening implementation. Clinician intervention rates among alcohol misusers rose from 6.3% to 11.8% (P = .039). Nurse screening increased the odds of clinician intervention (OR 1.47; 95% CI 1.10-1.95). CONCLUSIONS: Vital signs screening proved to be feasible in this rural clinic and produced modest but significant increases in alcohol screening by nurses and brief interventions by clinicians. Additional studies are needed to define effective strategies for further increasing these rates.

Expression of interleukin-6 receptor alpha in normal and injured rat sciatic nerve.

Interleukin-6 (IL-6) is a pleiotropic cytokine synthesized by many different cells after appropriate stimulation. IL-6 binds first to the interleukin-6 receptor alpha (IL6-Ralpha) and then this complex binds to the signal-transducing gp130 receptor, forming a functional hexameric receptor complex. We observed by Western blot analysis with anti-IL6-Ralpha two bands of approximately 80 kDa and approximately 110 kDa in the rat sciatic nerve, cerebral cortex, spleen, pancreas and liver, corresponding to the mature glycosylated form and possibly to the dimer of the non-glycosylated precursor protein. By immunohistochemistry, high levels of IL6-Ralpha expression are observed in non-myelinating Schwann cells. In myelinating Schwann cells IL6-Ralpha is present as discrete dots in the perinuclear region, in distinct membrane domains of the Schwann cell sheath and at the nodes of Ranvier, suggesting that IL6-Ralpha is clustered both on the axonal side of the node and within the Schwann cells. After sciatic nerve crush injury IL6-Ralpha is upregulated in denervated Schwann cells between the myelin ovoids during the period of Schwann cell proliferation. The expression of IL6-Ralpha continues during the period of remyelination, suggesting that IL6-Ralpha might be involved in both Schwann cell proliferation and remyelination of the rat sciatic nerve.

Species differences in the identification of acoustic stimuli by birds.

The perceptual organization of auditory stimuli can reveal a great deal about how the brain naturally groups events. The current study uses identification techniques to investigate the abilities of two species of birds in identifying zebra finch song as well as synthetically generated speech stimuli. Budgerigars (Melopsittacus undulatus) and zebra finches (Taeniopygia guttata) were trained to differentially peck keys in response to the presentation of various complex stimuli. Although there were no clear differences in performance during the training paradigm between the two species, budgerigars were far more adept at learning to identify both sets of complex stimuli than were zebra finches, requiring far less trials to reach criterion. The non-singing but vocally plastic budgerigars vastly outperformed zebra finches at identifying both zebra finch song and synthetically designed human speech despite known similarities in auditory sensitivities between the two species and seemingly equivalent learning capacity. The flexibility that budgerigars seem to have at identifying various stimuli is highlighted by their enhanced performance in these tasks. These results are discussed in the context of what is known about both general and specialized processes which may contribute to any differences or similarities in performance.

Strengths and limitations of using repeat-dose toxicity studies to predict effects on fertility.

The upcoming European chemicals legislation REACH (Registration, Evaluation, and Authorisation of Chemicals) will require the risk assessment of many thousands of chemicals. It is therefore necessary to develop intelligent testing strategies to ensure that chemicals of concern are identified whilst minimising the testing of chemicals using animals. Xenobiotics may perturb the reproductive cycle, and for this reason several reproductive studies are recommended under REACH. One of the endpoints assessed in this battery of tests is mating performance and fertility. Animal tests that address this endpoint use a relatively large number of animals and are also costly in terms of resource, time, and money. If it can be shown that data from non-reproductive studies such as in-vitro or repeat-dose toxicity tests are capable of generating reliable alerts for effects on fertility then some animal testing may be avoided. Available rat sub-chronic and fertility data for 44 chemicals that have been classified by the European Union as toxic to fertility were therefore analysed for concordance of effects. Because it was considered appropriate to read across data for some chemicals these data sets were considered relevant for 73 of the 102 chemicals currently classified as toxic to reproduction (fertility) under this system. For all but 5 of these chemicals it was considered that a well-performed sub-chronic toxicity study would have detected pathology in the male, and in some cases, the female reproductive tract. Three showed evidence of direct interaction with oestrogen or androgen receptors (linuron, nonylphenol, and fenarimol). The remaining chemicals (quinomethionate and azafenidin) act by modes of action that do not require direct interaction with steroid receptors. However, both these materials caused in-utero deaths in pre-natal developmental toxicity studies, and the relatively low NOAELs and the nature of the hazard identified in the sub-chronic tests provides an alert for possible effects on fertility (or early embryonic development), the biological significance of which can be ascertained in a littering (e.g. 2-generation) study. From the chemicals reviewed it would appear that where there are no alerts from a repeat-dose toxicity study, a pre-natal developmental toxicity study and sex steroid receptor binding assays, there exists a low priority for animal studies to address the fertility endpoint. The ability for these types of tests to provide alerts for effects on fertility is clearly dependent on the mode of action of the toxicant in question. Further work should therefore be performed to determine the 'failure rate' of this type of approach when applied to a larger group of chemicals with diverse modes of action.

A 90-day subchronic toxicity study and reproductive toxicity studies on ACE-inhibiting lactotripeptide.

In recent years there has been an increasing body of literature describing the antihypertensive effects of peptides produced from milk protein. The tripeptides isoleucine-proline-proline (IPP) and valine-proline-proline (VPP), isolated from hydrolysed casein have been shown to lower blood pressure by inhibiting angiotensin I-converting enzyme (ACE). This has led to the use of these tripeptides, collectively referred to as lactotripeptide (LTP) as ingredients of functional foods intended to help control blood pressure. A programme of studies including a 90-day repeat-dose oral gavage toxicity study in the rat and an embryo-fetal (pre-natal) development study in the rabbit was conducted to ensure the safety of this ACE-inhibiting ingredient. In addition, a non-standard pre- and post-natal development study in the rat was performed. This study included direct dosing of the neonates, and was designed specifically to investigate renal development and to ensure that the bioactive peptides were not associated with the same type of fetopathy exhibited by ACE inhibiting drugs. These studies showed that there were no adverse effects of treatment at the highest doses tested.

Do volunteer community-based preceptors value students' feedback?

PURPOSE: A key component of educational practice is to provide feedback and evaluation to teachers and learners to improve the teaching and learning process. The purpose of this study was to determine whether volunteer community preceptors value evaluation and feedback by students as much as they value other resources or rewards. METHOD: In Fall 1999, a questionnaire concerning the resources and rewards of preceptorship was mailed to 236 community preceptors affiliated with the Mercer University School of Medicine, Macon, Georgia. Preceptors were asked to rate 20 factors on a five-point Likert scale (5 = very important to 1 = not very important). The mean values were compared using t-tests. RESULTS: One hundred sixty-eight preceptors (71%) completed questionnaires. Preceptors rated evaluation and feedback from students significantly higher (p < .001) than all other factors (mean = 4.02, standard deviation [SD] = .87). Continuing medical education for teaching was the next most highly valued factor (mean = 3.67, SD = 1.14). Preceptors rated financial compensation the lowest (mean = 2.01, SD = 1.19) of all factors. The high rank of feedback and evaluation from students persisted across gender, specialty, length of time as a preceptor, practice location, and years practicing medicine. CONCLUSION: This study demonstrates that feedback and evaluation from students is highly valued. The knowledge that community-based preceptors highly value feedback and evaluation from students should stimulate medical school programs to provide feedback and evaluation to preceptors that will enhance the educational outcomes for both faculty and learners.

Abdominal obesity defined as a larger than expected waist girth is associated with racial/ethnic differences in risk of hypertension.

OBJECTIVE: Waist circumference (WC) cut-points of > or =102 cm and > or =88 cm for men and women, respectively, representing abdominal obesity have been recommended for determining obesity related co-morbidities. However, these cut-points carry the component of generalised obesity estimated by body mass index (BMI). The aim of this investigation was to determine whether abdominal obesity free of the influence of overall heaviness is associated with increased risk of hypertension in a representative sample of white and black Americans. METHODS: Data (n = 11114) from the Third US National Health and Nutrition Examination Survey were used in this investigation. Standardised residual values from the linear regression of WC on BMI were used to define abdominal obesity status. The risk of hypertension associated with abdominal obesity was estimated from the logistic regression model, adjusting for age, smoking and alcohol. We also estimated the public health consequences of abdominal obesity from the population attributable fraction of hypertension. RESULTS: Relative to white, black race/ethnicity was associated with approximately 1.8 and approximately 2.7 greater risk of hypertension in men and women, respectively, adjusting for abdominal obesity, age, smoking and alcohol consumption. Having larger than expected waist girths were associated with 1.58 and 1.39 increased risk of hypertension in black men and black women, respectively, adjusting for confounders. Population attributable risks of hypertension due to abdominal obesity were approximately 24.9% and 15.9%, in black men and black women, respectively. CONCLUSIONS: In Americans, hypertension is a public health problem that is closely linked to abdominal adiposity. An important research challenge therefore is to determine the best way to regulate body weight under conditions of food abundance. There is a need to clarify how lifestyle habits promote large waist sizes leading to abdominal adiposity and associated cardiovascular disease in the US, particularly among black Americans.

Masking by harmonic complexes in birds: behavioral thresholds and cochlear responses.

Thresholds for pure tones embedded in harmonic complexes were measured behaviorally and physiologically for three species of birds, and physiologically in gerbils. The harmonic maskers were generated using the Schroeder-phase algorithm, characterized by monotonically increasing or decreasing phase across frequency. Previous work has shown that these stimuli produce large differences in masking in humans but not budgerigars. In this study, we show that for two additional species of birds, the patterns of masking were similar to those shown for budgerigars, with masking differing only slightly for the two Schroeder-phase waveforms, and in the opposite direction from that demonstrated in humans. Amounts of masking among species corresponded qualitatively to differences in their critical ratios. Evoked potential measurements in birds and gerbils indicated responses that were consistent with the behaviorally measured thresholds in birds and humans. Results are interpreted in light of differences in frequency selectivity and cochlear temporal processing across species.

Frequency discrimination in budgerigars (Melopsittacus undulatus): effects of tone duration and tonal context.

Studies of frequency resolving power in budgerigars (Melopsittacus undulatus) have shown that this species has excellent discrimination abilities for both simple and complex sounds falling in the region of 2 to 4 kHz--the frequency range of their contact call. In four experiments, frequency discrimination by budgerigars of short tones similar to elements found in the contact call was examined. Frequency difference limens (FDLs) for simple pure tones at 2.86 kHz were constant for tone durations above 20 ms but higher for shorter tones. Budgerigars generally showed larger FDLs for shorter duration 1-, 2-, and 4-kHz pure tones. FDLs in budgerigars for 20-ms tones embedded in a sequence of six other tones were similar to FDLs measured for tones of the same frequency presented in isolation. Moreover, there was no effect of introducing trial-by-trial variation in the location of the frequency change in the seven-tone complexes for budgerigars, a condition for which humans showed a large decrement in performance. Taken together, these results suggest budgerigars possess enhanced spectral resolving power for short duration pure tones when they are embedded in contact call-like tonal patterns.

Ethnic differences in the rates of low birth weight attributable to differences in early motherhood: a study from the Third National Health and Nutrition Examination Survey.

OBJECTIVE: To estimate the impact of early motherhood (being a mother at < 20 years of age) on ethnic differences in the risk of low birth weight (LBW) in a representative sample (n = 9141) of American infants and children. METHODS: Risks for LBW and the population-attributable fraction due to early motherhood were estimated adjusting for maternal smoking and education in logistic regression models. The contribution of early motherhood to ethnic differences in the risks of LBW was determined using a relative attributable risk estimate that compared Hispanics and Blacks with Whites. RESULTS: Early motherhood was independently associated with increased risk of LBW in each of the three ethnic groups, adjusting for maternal smoking during pregnancy and education. Hispanic and Black ethnicity were each associated with 15% and 123% increased risk of LBW relative to Whites. The population-attributable fractions of LBW due to early motherhood were 6.2%, 7.4%, and 2.3%, for Whites, Hispanics, and Blacks, respectively. The responses of early motherhood for LBW were different among the three ethnic groups (p < 0.05). Adjusting for maternal smoking and education, 4.8% and 7.4% of the differences in the risk of LBW between Whites and Hispanics and between Whites and Blacks, respectively, were due to differences in early motherhood. CONCLUSION: The result of this study underscores the risk of LBW due to early motherhood. Because early motherhood is preventable and avoidable, appropriate public health strategies to educate young women on the need to delay childbearing in these ethnic groups, particularly among Hispanics and Blacks, are warranted.

Masking by harmonic complexes in budgerigars (Melopsittacus undulatus).

In humans, masking by harmonic complexes is dependent not only on the frequency content of the masker, but also its phase spectrum. Complexes that have highly modulated temporal waveforms due to the selection of their component phases usually provide less masking than those with flatter temporal envelopes. Moreover, harmonic complexes that are created with negative Schroeder phases (component phases monotonically decreasing with increasing harmonic frequency) may provide more masking than those created with positive Schroeder phases (monotonically increasing phase), even though both temporal envelopes are equally flat. To date, there has been little comparative work on the masking effectiveness of harmonic complexes. Using operant conditioning and the method of constant stimuli, masking of pure tones by harmonic complexes was examined in budgerigars at several different masker levels for complexes constructed with two different fundamental frequencies. In contrast to humans, thresholds in budgerigars differed very little for the two Schroeder-phase waveforms. Moreover, when there was a difference in masking by these two waveforms, the positive Schroeder was the more effective masker--the reverse of that described for humans. Control experiments showed that phase selection was relevant to the masking ability of harmonic complexes in budgerigars. Release from masking occurred when the components were in coherent phase, compared with a complex with random phases selected for each component. It is suggested that these psychoacoustic differences may emerge from structural and functional differences between the avian and mammalian peripheral auditory systems involving traveling wave mechanics and spectral tuning characteristics.