Update to RIFM fragrance ingredient safety assessment, 2,4-dimethylbenzyl acetate, CAS Registry Number 62346-96-7.

The MOE is greater than 100. Without adjustment for specific uncertainty factors related to inter-species and intra-species variation, the material exposure by inhalation at 0.0040 mg/day is deemed to be safe under the most conservative consumer exposure scenario.

The RIFM approach to evaluating Natural Complex Substances (NCS).

The Research Institute for Fragrance Materials, Inc. (RIFM) has evaluated safety data for fragrance materials for 55 years. The safety assessment of Natural Complex Substances (NCS) is similar to that of discrete fragrance materials; all of the same endpoints are evaluated. A series of decision trees, reflecting advances in risk assessment approaches of mixtures and toxicological methodologies, follows a tiered approach for each endpoint using a 4-step process with testing only as a last resort: 1) evaluate available data on NCS; 2) verify whether the Threshold of Toxicological Concern (TTC) can be applied; 3) verify whether the NCS risk assessment can be achieved on a component basis; and 4) determine whether data must be generated. Using in silico tools, RIFM examined NCS similarities based on the plant part, processing, and composition of materials across 81 plant families to address data gaps. Data generated from the Creme RIFM Aggregate Exposure Model for over 900 fragrance NCS demonstrate that dermal exposure is the primary route of human exposure for NCS fragrance uses. Over a third of materials are below the most conservative TTC limits. This process aims to provide a comprehensive Safety Assessment of NCS used as a fragrance ingredient.

The value of peer support for self-management of diabetes among veterans in the Empowering Patients In Chronic care intervention.

AIM: To examine the value of peer support in the self-management of diabetes among veterans in an integrated health care system. METHODS: We conducted semi-structured in-depth interviews with veterans and clinicians 6 months after their participation in Empowering Patients in Chronic Care (EPIC), a group-based diabetes intervention with a peer-support component. Interviews elicited clinicians' narratives of how peer support unfolded in the groups and veterans' experiences of giving and receiving support from their peers. Data analysis was guided by principles of framework analysis using Heisler's peer-support model. RESULTS: Findings support Heisler's peer-support model and provide evidence supporting professional-led group visits with peer exchange. Clinicians and veterans endorsed informational and emotional support received in EPIC groups. Clinicians often referred to EPIC as an open forum or a support group where veterans could both give and receive help. Veterans noted the benefits of shared problem-solving and the support they received. Clinicians and veterans perceived the peer-support component of EPIC as facilitating increased empowerment in terms of self-efficacy, increased perceived social support and increased understanding of self-care. Ultimately, many veterans acknowledged that their participation in EPIC facilitated improved health-related quality of life, improved health behaviours and improved chronic disease control. CONCLUSIONS: Findings emphasize the value of peer support in managing chronic illness. Peer-support programmes may address veterans' unique challenges and have the potential to improve physical and mental health.

RIFM fragrance ingredient safety assessment, p-tolyl acetate, CAS Registry Number 140-39-6.

The existing information supports the use of this material as described in this safety assessment. p-Tolyl acetate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl p-tolyl carbonate (CAS # 22719-81-9) show that p-tolyl acetate is not expected to be genotoxic. Data on read-across materials p-cresol (CAS # 106-44-5) and acetic acid (CAS # 64-19-7) provide a calculated MOE >100 for the repeated dose and reproductive toxicity endpoints. The skin sensitization endpoint was completed using DST for reactive materials (64 µg/cm2); exposure is below the DST. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; p-tolyl acetate is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material, and the exposure to p-tolyl acetate is below the TTC (1.4 mg/day).The environmental endpoints were evaluated; p-tolyl acetate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, hydroxycitronellal dimethyl acetal, CAS Registry Number 141-92-4.

Hydroxycitronellal dimethyl acetal was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that hydroxycitronellal dimethyl acetal is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material and the exposure to hydroxycitronellal dimethyl acetal is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from hydroxycitronellal dimethyl acetal and from read-across material hydroxycitronellal diethyl acetal (CAS # 7779-94-4) show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; hydroxycitronellal dimethyl acetal is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; hydroxycitronellal dimethyl acetal was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, 4-(p-hydroxyphenyl)-2-butanone, CAS Registry Number 5471-51-2.

The existing information supports the use of this material as described in this safety assessment. 4-(p-Hydroxyphenyl)-2-butanone was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that 4-(p-hydroxyphenyl)-2-butanone is not genotoxic. Data on 4-(p-hydroxyphenyl)-2-butanone provide a calculated MOE >100 for the repeated dose toxicity endpoint. The developmental and reproductive toxicity and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to 4-(p-hydroxyphenyl)-2-butanone is below the TTC (0.03 mg/kg/day and 1.4 mg/day, respectively). Data from 4-(p-hydroxyphenyl)-2-butanone show that there are no safety concerns for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; 4-(p-hydroxyphenyl)-2-butanone is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; 4-(p-hydroxyphenyl)-2-butanone was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, isobutyl alcohol, CAS Registry Number 78-83-1.

The existing information supports the use of this material as described in this safety assessment. Isobutyl alcohol was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that isobutyl alcohol is not genotoxic. Data on isobutyl alcohol provide a calculated MOE >100 for the repeated dose toxicity and reproductive toxicity endpoints. Data from read-across material isoamyl alcohol (CAS # 123-51-3) show that there are no safety concerns for isobutyl alcohol for skin sensitization under the current declared levels of use. The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; isobutyl alcohol is not expected to be phototoxic/photoallergenic. The local respiratory toxicity endpoint was evaluated using the TTC for a Cramer Class I material and the exposure to isobutyl alcohol is below the TTC (1.4 mg/day). The environmental endpoints were evaluated; isobutyl alcohol was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, methyl 2-octynoate, CAS Registry Number 111-12-6.

Methyl 2-octynoate was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data show that methyl 2-octynoate is not genotoxic. Data provided methyl 2-octynoate a NESIL of 110 µg/cm2 for the skin sensitization endpoint. The repeated dose, developmental and reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class II material, and the exposure to methyl 2-octynoate is below the TTC (0.009 mg/kg/day, 0.009 mg/kg/day, and 0.47 mg/day, respectively). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; methyl 2-octynoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-octynoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, methyl ionone (mixture of isomers), CAS registry number 1335-46-2.

Methyl ionone (mixture of isomers) was evaluated for genotoxicity, repeated dose toxicity, developmental and reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from methyl ionone (mixture of isomers) show that the material is not genotoxic and provided a NESIL of 70,000 µg/cm2 for the skin sensitization endpoint. Data provided a calculated MOE >100 for the repeated dose toxicity and developmental toxicity endpoints, and data from read-across material (E)-ß-ionone (CAS # 79-77-6) provided a calculated MOE >100 for the reproductive toxicity endpoint. For the local respiratory endpoint, a calculated MOE >100 was provided by the read-across material ß-ionone (CAS # 14901-07-6). The phototoxicity/photoallergenicity endpoints were evaluated based on data and UV spectra; the material is not phototoxic/photoallergenic. The environmental endpoints were evaluated with data from the target chemical and read-across material α-allylionone (CAS # 79-78-7), and the material was not found to be PBT; its risk quotients, based on current volume of use in Europe and North America (PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, methyl 2-nonenoate, CAS Registry Number 111-79-5.

The existing information supports the use of this material as described in this safety assessment. Methyl 2-nonenoate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog ethyl trans-2,cis-4-decadienoate (CAS # 3025-30-7) show that methyl 2-nonenoate is not expected to be genotoxic. The repeated dose, reproductive, and local respiratory toxicity endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to methyl 2-nonenoate is below the TTC (0.03 mg/kg/day, 0.03 mg/kg/day, and 1.4 mg/day, respectively). Data from the target and read-across analog isobutyl-2-butenoate (CAS # 589-66-2) do not indicate the material is a sensitizer. The phototoxicity/photoallergenicity endpoints were evaluated based on data and UV spectra; methyl 2-nonenoate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; methyl 2-nonenoate was found not to be PBT as per the IFRA Environmental Standards, and its risk quotients, based on its current volume of use in Europe and North America (i.e., PEC/PNEC), are <1.

RIFM fragrance ingredient safety assessment, isobutyl propionate, CAS Registry Number 540-42-1.

The existing information supports the use of this material as described in this safety assessment. Isobutyl propionate was evaluated for genotoxicity, repeated dose toxicity, reproductive toxicity, local respiratory toxicity, phototoxicity/photoallergenicity, skin sensitization, and environmental safety. Data from read-across analog isobutyl acetate (CAS # 110-19-0) show that isobutyl propionate is not expected to be genotoxic. Data from read-across analog isoamyl acetate (CAS # 123-92-2) show that there are no safety concerns for isobutyl propionate for skin sensitization under the current declared levels of use. The repeated dose and reproductive endpoints were evaluated using the TTC for a Cramer Class I material, and the exposure to isobutyl propionate is below the TTC (0.03 mg/kg/day and 0.03 mg/kg/day, respectively). For the local respiratory endpoint, a calculated MOE >100 was provided by read-across analog butyl acetate (CAS # 123-86-4). The phototoxicity/photoallergenicity endpoints were evaluated based on UV spectra; isobutyl propionate is not expected to be phototoxic/photoallergenic. The environmental endpoints were evaluated; isobutyl propionate is not PBT as per the IFRA Environmental Standards. For the risk assessment, isobutyl propionate was not able to be risk screened as there were no reported volumes of use for North America or Europe in the 2015 IFRA Survey.

RIFM fragrance ingredient safety assessment, propanal diethyl acetal, CAS registry number 4744-08-5.

There are insufficient toxicity data on the target material propanal diethyl acetal (CAS # 4744-08-5). Hence, in silico evaluation was conducted to determine read-across analogs for this material. Based on structural similarity, reactivity, metabolism data, physical-chemical properties, and expert judgment, analogs acetal (CAS # 105-57-7) and butane, 1,1'-[methylenebis(oxy)]bis- (CAS # 2568-90-3) were identified as read-across materials with sufficient data for toxicological evaluation of genotoxicity.

Use of antibiotics in paediatric long-term care facilities.

BACKGROUND: Adult long-term care (LTC) facilities have high rates of antibiotic use, raising concerns about antimicrobial resistance. Few studies have examined antibiotic use in paediatric LTC facilities. AIM: To describe antibiotic use in three paediatric LTC facilities and to describe the factors associated with use. METHODS: A retrospective cohort study was conducted from September 2012 to December 2015 in three paediatric LTC facilities. Medical records were reviewed for demographics, healthcare-associated infections (HAIs), antimicrobial use and diagnostic testing. Logistic regression was used to identify predictors for antibiotic use. The association between susceptibility testing results and appropriate antibiotic coverage was determined using Chi-squared test. FINDINGS: Fifty-eight percent (413/717) of residents had at least one HAI, and 79% (325/413) of these residents were treated with at least one antibiotic course, totalling 2.75 antibiotic courses per 1000 resident-days. Length of enrolment greater than one year, having a neurological disorder, having a tracheostomy, and being hospitalized at least once during the study period were significantly associated with receiving antibiotics when controlling for facility (all P < 0.001). Diagnostic testing was performed for 40% of antibiotic-treated HAIs. Eighty-six percent of antibiotic courses for identified bacterial pathogens (201/233) provided appropriate coverage. Access to susceptibility testing was not associated with appropriate antibiotic choice (P = 0.26). CONCLUSION: Use of antibiotics in paediatric LTC facilities is widespread. There is further need to assess antibiotic use in paediatric LTC facilities. Evaluation of the adverse outcomes associated with inappropriate antibiotic use, including the prevalence of resistant organisms in paediatric LTC facilities, is critical.

Potassium titanyl phosphate (KTP) laser treatment for molluscum contagiosum.

We report a case of an immunocompromised 38-year-old Asian patient who developed several hundred atypical lesions of molluscum on her face and neck, resistant to conventional treatment. These lesions were treated successfully by potassium titanyl phosphate (KTP) laser without pigmentary disturbance. KTP laser is a novel treatment for molluscum contagiosum.

Cervical cancer among Vietnamese women: efforts to define the problem among Houston's population.

INTRODUCTION: Asian American/Pacific Islanders (AAPIs) in the United States (US) continue to bear a disproportionate burden of cancer. This report focuses on the interviews with local health-care delivery providers, directors, administrators, and community outreach liaisons in the Vietnamese community in Houston, Texas. METHODS: The Center for Minority Health (CMRH) at the University of Texas M.D. Cancer Center interviewed 17 leaders, as defined above, to identify factors that have a negative impact on screening practices among Vietnamese women. RESULTS: The results show that some of the barriers to cervical cancer screening include: lack of knowledge, lack of female physicians, language barriers, lack of insurance, and embarrassment. Interviews established that "prevention" is a Western concept that the Vietnamese community has not yet adopted. Vietnamese women used their churches, community physicians (licensed or not), circle of friends, and families for their health information. Many patients used herbs as alternative or complementary therapies. CONCLUSION: Cultural factors play a vital role in limiting Vietnamese women in the use of cervical screening. Further research needs to focus on identifying specific barriers and how they can be overcome.

Clopidogrel used in combination with aspirin compared with aspirin alone in the treatment of non-ST-segment-elevation acute coronary syndromes: a systematic review and economic evaluation.

OBJECTIVES: To review systematically the clinical effectiveness and the cost-effectiveness of clopidogrel used in combination with standard therapy including aspirin, compared with standard therapy alone for the treatment of non-ST-segment elevation acute coronary syndromes (ACS). DATA SOURCES: Electronic databases. Manufacturers' submissions. REVIEW METHODS: Studies were selected using rigorous criteria. The quality of randomised controlled trials (RCTs) was assessed according to criteria based on NHS CRD Report No. 4, and the quality of systematic reviews was assessed according to the guidelines for the Database of Reviews of Effect (DARE) criteria. The quality of economic evaluations was assessed according to a specifically tailored checklist. The clinical effectiveness and cost-effectiveness of clopidogrel in combination with standard therapy compared with standard therapy alone were synthesised through a narrative review with full tabulation of the results of the included studies. In the economic evaluations, a cost-effectiveness model was constructed using the best available evidence to determine cost-effectiveness in a UK setting. RESULTS: One RCT (the CURE trial) was a randomised, double-blind, placebo-controlled trial of high quality and showed that clopidogrel in addition to aspirin was significantly more effective than placebo plus aspirin in patients with non-ST-segment elevation ACS for the composite outcome of death from cardiovascular causes, non-fatal myocardial infarction or stroke over the 9-month treatment period. However, clopidogrel was associated with a significantly higher number of episodes of both major and minor bleeding. The results from the five systematic reviews that assessed the adverse events associated with long-term aspirin use showed that aspirin was associated with a significantly higher incidence of haemorrhagic stroke, extracranial haemorrhage and gastrointestinal haemorrhage compared with placebo. Of the cost-effectiveness evidence reviewed, only the manufacturer's submission was considered relevant from the perspective of the NHS. The review of this evidence highlighted potential limitations within the submission in its use of data and in the model structure used. These limitations led to the development of a new model with the aim of providing a more reliable estimate of the cost-effectiveness from the perspective of the UK NHS. This model indicated that clopidogrel appears cost-effective compared with standard care alone in patients with non-ST-elevation ACS as long as the NHS is willing to pay GBP6078 per quality of life year (QALY). The results were most sensitive to the inclusion of additional strategies that assessed alternative treatment durations with clopidogrel. Although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. CONCLUSIONS: The results of the CURE trial indicate that clopidogrel in combination with aspirin was significantly more effective than placebo combined with aspirin in a wide range of patients with ACS. This benefit was largely related to a reduction in Q-wave myocardial infarction. There was no statistically significant benefit in relation to mortality. The trial data suggested that a substantial part of the benefit derived from clopidogrel is achieved by 3 months, with a further small benefit over the remaining 9 months of chronic treatment. The results from the base-case model suggest that treatment with clopidogrel as an adjunct to standard therapy (including aspirin) for 12 months, compared with standard therapy alone, is cost-effective in non-ST elevation ACS patients as long as the health service is willing to pay GBP6078 per additional QALY. However, although treatment with clopidogrel for 12 months remained cost-effective for the overall cohort, provisional findings indicate that the shorter treatment durations may be more cost-effective in patients at low risk. To estimate the exact length of time that clopidogrel in addition to standard therapy should be prescribed for patients with non-ST-segment ACS would require a prospective trial that randomised patients to various durations of therapy. This would accurately assess whether a 'rebound' phenomenon occurs in patients if clopidogrel were stopped after 3 months of treatment.

Behavioural profiles of inbred mouse strains used as transgenic backgrounds. I: motor tests.

One of the characteristic manifestations in several neurodegenarative diseases is the loss of voluntary motor control and the development of involuntary movements. In order to determine the suitability of six mouse strains as transgenic background strains we investigated performance on a variety of tasks designed to identify subtle changes in motor control. On both the accelerating and the staggered speed rotarod all six mouse strains performed well. However, latency to fall from the rod was sensitive to both rotarod speed and repeated exposure to the apparatus. Performance of the DBA/2 mouse strain was highly variable across the time points used. On the acoustic startle test CBA mice showed the greatest degree of reactivity to the acoustic startle stimuli with both the C57 and DBA showing the least. Complex strain differences were also identified on measures of habituation to the startle stimuli and variations in the prepulse noise level, and prepulse/startle delay. Gait analysis using the footprint test did not reveal strain differences on measures of base width, overlap or stride length but the 129S2/Sv strain took significantly longer to traverse the runway than the other mouse strains. Finally, the swim tank test detected complex strain differences in swim speed, and the number of fore- and hindpaw paddles required to swim the length of the tank. These data taken together suggest that choice of background strain is a crucial consideration for the repeated behavioural assessment of motor deficits in transgenic mouse models of disease.

The interstitial nuclei of the human anterior hypothalamus: an investigation of variation with sex, sexual orientation, and HIV status.

The interstitial nuclei of the human anterior hypothalamus (INAH1-4) have been considered candidates for homology with the sexually dimorphic nucleus of the preoptic area of the rat. Volumetric sexual dimorphism has been described for three of these nuclei (INAH1-3), and INAH3 has been reported to be smaller in homosexual than heterosexual men. The current study measured the INAH in Nissl-stained coronal sections in autopsy material from 34 presumed heterosexual men (24 HIV- and 10 HIV+), 34 presumed heterosexual women (25 HIV- and 9 HIV+), and 14 HIV+ homosexual men. HIV status significantly influenced the volume of INAH1 (8% larger in HIV+ heterosexual men and women relative to HIV- individuals), but no other INAH. INAH3 contained significantly more neurons and occupied a greater volume in presumed heterosexual males than females. No sex difference in volume was detected for any other INAH. No sexual variation in neuronal size or density was observed in any INAH. Although there was a trend for INAH3 to occupy a smaller volume in homosexual men than in heterosexual men, there was no difference in the number of neurons within the nucleus based on sexual orientation.

Experience with a one-stop colorectal clinic.

BACKGROUND AND OBJECTIVE: Colorectal services have traditionally been arranged for the convenience of hospitals rather than patients. This model is not ideal, particularly for minor interventions and diagnostic procedures. In order to address this a one-stop colorectal clinic was set up. PATIENTS AND METHODS: Weekly clinics ran from 6.00 to 9.30 p.m. on Wednesdays for a period of 6 months. Patients with rectal bleeding, altered bowel habit, anorectal symptoms and those requesting screening advice were seen by a consultant or specialist registrar. Patients were asked to fill in a questionnaire at the end of their clinic attendance. RESULTS: 197 patients were seen in 17 clinics; 134 underwent proctoscopy, 72 had a rigid sigmoidoscopy and 85 had a flexible sigmoidoscopy carried out. Twenty-four patients subsequently had a barium enema and 3 were listed for colonoscopy. The main diagnosis was haemorrhoids (n = 104); 14 colorectal neoplasms were discovered (5 cancers and 9 polyps). During the study period the number of patients waiting for lower gastrointestinal endoscopy fell from 119 to 63; 2 months after ending the pilot scheme, the number had risen to 108. CONCLUSION: The clinic was found to have significantly improved patient care. The majority of patients were satisfied with an evening clinic. Flexible sigmoidoscopy without sedation was well tolerated and the ability to perform this at initial assessment had a marked effect on the number of patients awaiting lower gastrointestinal endoscopy.