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Pope Benedict XVI seemed an unlikely fellow to declare Hildegard of Bingen a Doctor of the Church in 2012. Yet Joseph Ratzinger’s studies as a medievalist disposed him to the symbolist tendencies of Hildegard and her contemporaries in reflecting on the relationship among scripture, history, and the Church. Deeply affected by the abuse of political power and corruption within the Church, both Ratzinger and Hildegard developed prophetic outlooks on the nature of the Church and its mission in the world, centered on the singular light of Christ’s Incarnation. We find, across the centuries, a shared embrace of the enigmatic tension between the Church’s corrupted institutions and their prophetic renewal. Ironically, Hildegard came to distrust the authority of the papacy and prophesied its ending, even as Benedict would be, as pope, her greatest champion.

In the last ~30 years, scientists have made great strides in understanding the biological function of group I metabotropic glutamate receptors (mGlu) in health and disease, as well as developing a broad array of potent and selective agents able to activate or inhibit these receptors. This article provides a comprehensive review of the most recent group I mGlu modulators published in patent and non-patent literatures from 2014 to May, 2015, including design, structure-activity relationship, in silico, in vitro and in vivo properties of key compounds. The current status of clinical mGlu5 negative allosteric modulators (NAMs) and the development of mGlu1 and mGlu5 PET ligands are also highlighted. While the therapeutic potential for group I mGlu modulating agents appears high, significant challenges remain. Strategies to reduce clinical development risks and mitigate important side effects, including psychotomimetic events observed with several mGlu5 NAMs and cellular toxicity associated with mGlu5 positive allosteric modulators (PAMs), while retaining therapeutic efficacy through approaches such as biased ligand signaling are discussed.

Solid-state heterojunction solar cells formed from binary blends of conjugated polymers and fullerenes provide a promising class of organic devices. We demonstrate that ternary blends incorporating porphyrins can be of similar morphology to the binary mixture and retain full device functionality. They allow, for the first time, the construction of efficient devices containing less than 10% polymer. By analyzing the absorption spectra as a function of concentration, we determine the proportion of light absorbed by each individual component in both binary and ternary mixtures. This analysis reveals that the majority of the light is absorbed by the fullerene in 1:4 polymer/C60-fullerene blends, with over 50% of the photocurrent produced under AM 1.5 conditions occurring subsequent to C60-fullerene absorption. This result provides for a consistent understanding of the origin of primary charge separation in general polymer/C60-fullerene blends, polymer/C70-fullerene blends, and polymer-fullerene dyad molecules. Porphyrins are demonstrated to add broad-band character to the device and may be used to tune for particular wavelengths; they also are shown to initiate primary charge separation through electron-transfer to the fullerene. Finally, addition of the porphyrin is shown to increase the internal quantum efficiency following polymer absorption from ca. 60 to 80%.

Novel dihydropyrrolopyrazole-substituted benzimidazoles were synthesized and evaluated in vitro as inhibitors of transforming growth factor-β type I receptor (TGF-β RI), TGF-β RII, and mixed lineage kinase-7 (MLK-7). These compounds were found to be potent TGF-β RI inhibitors and selective versus TGF-β RII and MLK-7 kinases. Benzimidazole derivative : was active in an in vivo target (TGF-β RI) inhibition assay.

OBJECTIVES: To assess variation in the quality of care in general practice and identify factors associated with high quality care. DESIGN: Observational study. SETTING: Stratified random sample of 60 general practices in six areas of England. OUTCOME MEASURES: Quality of management of chronic disease (angina, asthma in adults, and type 2 diabetes) and preventive care (rates of uptake for immunisation and cervical smear), access to care, continuity of care, and interpersonal care (general practice assessment survey). Multiple logistic regression with multilevel modelling was used to relate each of the outcome variables to practice size, routine booking interval for consultations, socioeconomic deprivation, and team climate. RESULTS: Quality of clinical care varied substantially, and access to care, continuity of care, and interpersonal care varied moderately. Scores for asthma, diabetes, and angina were 67%, 21%, and 17% higher in practices with 10 minute booking intervals for consultations compared with practices with five minute booking intervals. Diabetes care was better in larger practices and in practices where staff reported better team climate. Access to care was better in small practices. Preventive care was worse in practices located in socioeconomically deprived areas. Scores for satisfaction, continuity of care, and access to care were higher in practices where staff reported better team climate. CONCLUSIONS: Longer consultation times are essential for providing high quality clinical care. Good teamworking is a key part of providing high quality care across a range of areas and may need specific support if quality of care is to be improved. Additional support is needed to provide preventive care to deprived populations. No single type of practice has a monopoly on high quality care: different types of practice may have different strengths.

OBJECTIVES: To describe the menstrual experience of women referred for menstrual problems, in particular menorrhagia (excessive menstrual loss), and to assess associations with reasons for referral given by their general practitioners, the women's understanding of the reasons for their attendance at the hospital clinics, and clinic outcome. DESIGN: Questionnaire survey, with partial review of case notes after 8 months. SETTING: Three hospital gynaecology clinics in Glasgow and Edinburgh. PARTICIPANTS: 952 women completed the questionnaire, and the first 665 were reviewed. OUTCOME MEASURES: Reason for referral, women's reported menstrual problems and reason for clinic attendance, diagnosis, and treatment. RESULTS: Only 38% (95% confidence interval 34% to 41%) of women reported excessive menstrual loss as a severe problem. However 60% (57-63%) gave it as reason for attending a clinic, and 76% (73-79%) of general practitioners gave it as reason for referral. Reason for referral was significantly biased towards bleeding (McNemar odds ratio 4.01, 3.0 to 5.3, P<0.001) and against pain (0.54, 0.4 to 0.7, P<0.001). Dysfunctional uterine bleeding was diagnosed in 37% (31-42%) of the 259 women who gave as reason for attendance something other than bleeding. Women who were economically disadvantaged differed in prevalence of the main diagnoses and were more likely to fail to reattend. Hysterectomy was associated with referral for bleeding (relative risk 4.9, 1.6 to 15.6, P<0.001) but not with the patient stating bleeding as the reason for clinic attendance. CONCLUSIONS: Intolerance of the volume of their bleeding is not a key feature among women attending clinics for bleeding problems. Broad menstrual complaint tends to be reframed as excessive bleeding at referral and during management. This may result in women receiving inappropriate care. Conceptualisation and assessment of menorrhagia requires reconsideration.

OBJECTIVES: To identify prescribing indicators based on prescribing analysis and cost (PACT) data that have face validity for measuring quality or cost minimisation. DESIGN: Modified two round Delphi questionnaire requiring quantitative and qualitative answers. Setting: Health authorities in England. PARTICIPANTS: All health authority medical and pharmaceutical advisers in the first round and lead prescribing advisers for each health authority in the second round. MAIN OUTCOME MEASURES: Face validity (median rating of 7-9 on a nine point scale without disagreement) and reliability (rating 8 or 9) of indicators for assessing quality and cost minimisation. RESULTS: Completed second round questionnaires were received from 79 respondents out of 99. The median rating was 7 for cost minimisation and 6 for quality, and in all except four cases individual respondents rated indicators significantly higher for cost than for quality. Of the 41 indicators tested, only seven were rated valid and reliable for cost minimisation and five for quality. CONCLUSION: The 12 indicators rated as valid by leading prescribing advisers had a narrow focus and would allow only a limited examination of prescribing at a general practice, primary care group, or health authority level.

The effects of i.m. injections of (+)-HA-966, a glycine-site antagonist at the N-methyl-D-aspartate (NMDA) subtype of the glutamate receptor, its enantiomer (-)-HA-966, the competitive glutamate antagonist CGS-19755, the uncompetitive glutamate antagonists phencyclidine and dizocilpine, and the micro opioid agonist morphine were evaluated in a repeated acquisition task in pigeons. All of the drugs produced dose-dependent decreases in rates of responding. The NMDA receptor and channel blockers and (+)-HA-966 appeared to have a greater effect on acquisition than did morphine at doses that did not fully suppress responding. The rate suppression and learning impairment produced by a large dose of (+)-HA-966 (100 mg/kg) were completely prevented by coadministration of the glycine-site agonist D-serine (560 mg/kg) but not by its enantiomer, L-serine (1000 mg/kg). D-Serine, however, produced incomplete antagonism of the effects of dizocilpine and phencyclidine and failed to alter those of CGS-19755. These findings provide evidence that reducing the activity of the NMDA subtype of the glutamate receptor through pharmacological action at any of three sites produces similar decrements in acquisition, and those produced through antagonism of the glycine site are differentially sensitive to the glycine-site agonist D-serine.

OBJECTIVES: To evaluate two different methods of improving adherence to antidepressant drugs. DESIGN: Factorial randomised controlled single blind trial of treatment leaflet, drug counselling, both, or treatment as usual. SETTING: Primary care in Wessex PARTICIPANTS: 250 patients starting treatment with tricyclic antidepressants. MAIN OUTCOME MEASURES: Adherence to drug treatment (by confidential self report and electronic monitor); depressive symptoms and health status. RESULTS: 66 (63%) patients continued with drugs to 12 weeks in the counselled group compared with 42 (39%) of those who did not receiving counselling (odds ratio 2.7, 95% confidence interval 1.6 to 4.8; number needed to treat=4). Treatment leaflets had no significant effect on adherence. No differences in depressive symptoms were found between treatment groups overall, although a significant improvement was found in patients with major depressive disorder receiving drug doses of at least 75 mg (depression score 4 (SD 3.7) counselling v 5.9 (SD 5.0) no counselling, P=0.038). CONCLUSIONS: Counselling about drug treatment significantly improved adherence, but clinical benefit was seen only in patients with major depressive disorder receiving doses >/=75 mg. Further research is required to evaluate the effect of this approach in combination with appropriate targeting of treatment and advice about dosage.

Several new ferrocene-functionalised porphyrins and a ruthenocene-functionalised porphyrin have been synthesized and studied using electrochemistry, electronic absorbance and resonance Raman spectroelectrochemical techniques. The porphyrin and ferrocene are observed to have limited effect on each other with the properties of the porphyrin dominating the spectroscopy of these molecules.

[(S)-Alpha-phenyl-2-pyridine-ethanamine dihydrochloride] (ARL 15896AR) is a low affinity uncompetitive N-methyl-D-aspartic acid receptor antagonist that was tested in animal models of anoxia and ischemia. Pretreatment of rodents with ARL 15896AR extended survival time during exposure to hypoxia. With the rat four-vessel occlusion model of global ischemia (20 min), oral dosing commencing at reflow, resulted in significant protection of the CA1 hippocampal neurons. ARL 15896AR was, however, ineffective in the rat two-vessel occlusion model and in the gerbil models of forebrain ischemia, the latter due to an inability to attain suitable plasma levels. In the spontaneously hypertensive rat model of middle cerebral artery occlusion (MCAO) (2 hr plus 22 hr reflow), acute dosing with ARL 15896AR (i.p.) beginning from 30 min before or up to 1 hr post-MCAO significantly reduced cortical infarct volume. The ability of ARL 15896AR to influence infarct size, as well as functional correlates was examined in SHR after 90 min of MCAO. T2 weighted magnetic resonance images taken at 2 and 6 days post-MCAO revealed significantly smaller lesion sizes in the group receiving injections with ARL 15896AR beginning 30 min after occlusion. Spontaneously hypertensive rats were subsequently tested (30-42 days post-MCAO) and found to be deficient in skilled use of the forepaws (staircase test). The contralateral forepaw was most severely impaired, however, ARL 15896AR treatment prevented motor impairment in only the ipsilateral forepaw. Histopathological examination of cortical infarct size was unremarkable between treated and control rats. The findings indicate that ARL 15896AR exhibits neuroprotection in global and focal models of ischemia

OBJECTIVE: To compare the outcome of out of hours care given by general practitioners from patients' own practices and by commercial deputising services. DESIGN: Randomised controlled trial. SETTING: Four urban areas in Manchester, Salford, Stockport, and Leicester. SUBJECTS: 2152 patients who requested out of hours care, and 49 practice doctors and 183 deputising doctors (61% local principals in general practice) who responded to the requests. MAIN OUTCOME MEASURES: Health status outcome, patient satisfaction, and subsequent health service use. RESULTS: Patients seen by deputising doctors were less satisfied with the care they received. The mean overall satisfaction score for practice doctors was 70.7 (95% confidence interval 68.1 to 73.2) and for deputising doctors 61.8 (59.9 to 63.7). The greatest difference in satisfaction was with the delay in visiting. There were no differences in the change in health or overall health status measured 24 to 120 hours after the out of hours call or subsequent use of the health service in the two groups. CONCLUSIONS: Patients are more satisfied with the out of hours care provided by practice doctors than that provided by deputising doctors. Organisation of doctors into large groups may produce lower levels of patient satisfaction, especially when associated with increased delays in the time taken to visit. There seem to be no appreciable differences in health outcome between the two types of service.

OBJECTIVE: To examine the effects of a financial incentive scheme on prescribing in non-fundholding general practices. DESIGN: Observational study. SETTING: Non-fundholding general practices in former Northern region in 1993-4. INTERVENTION: Target savings were set for each group of practices; those that achieved them were paid a portion of the savings. MAIN OUTCOME MEASURES: Financial performance; prescribing patterns in major therapeutic groups and some specific therapeutic areas; rates of generic prescribing; and performance against a measure of prescribing quality. SUBJECTS: 459 non-fundholding general practices, grouped into three bands according to the ratio of their indicative prescribing amount to the local average (band A > or = 10% above average, B between average and 10% above, C below average). RESULTS: 102 (23%) of 442 practices achieved their target savings (18%, 19%, and 27% of bands A, B, and C respectively). Band C practices that achieved their target had a lower per capita prescribing frequency for gastrointestinal drugs, inhaled steroids, antidepressants, and hormone replacement therapy. There were no other significant differences in prescribing frequency, and no reduction in the quality of prescribing in achieving practices. Total savings of pounds 1.54 m on indicative prescribing amounts were achieved. Payments from the incentive scheme and discretionary quality awards resulted in pounds 463,000 being returned to practices for investment in primary care. CONCLUSIONS: The prescribing behaviour of non-fundholding general practitioners responded to financial incentives in a similar way to that of fundholding practitioners. The incentive scheme did not seem to reduce the quality of prescribing.

Activation by opioid receptors of cell proliferation was examined with fibroblast cell lines stably expressing either delta-opioid or mu-opioid receptors. Addition of [D-Ala2, D-Leu5]-enkephalin or [D-Pen2,D-Pen5]-enkephalin to Chinese hamster ovary (CHO) cells transfected with delta-opioid receptor cDNA resulted in an agonist concentration-dependent potentiation of fetal calf serum (FCS)-stimulated cell proliferation. This potentiation by delta-opioid agonists was antagonized by naloxone and was not observed with the kappa-opioid receptor selective agonist U50,488 or the mu-opioid receptor selective agonist [D-Ala2,N-MePhe4, Gly-ol5]-enkephalin. This delta-opioid agonist effect was not observed at FCS concentrations > 0.1% and could be blocked by pretreating cells with pertussis toxin, indicating that Gi/Go were involved in this action. In addition, delta-opioid agonists could potentiate CHO cell proliferation stimulated by those growth factors that are mediated by tyrosine kinase receptors (i.e., insulin, insulin-like growth factor 1, and fibroblast-derived growth factor b). This delta-opioid agonist potentiation of growth apparently was dependent on the level of delta-opioid receptors that were expressed and had cell-line selectivity. Activation of delta-opioid receptors expressed in Rat-1 or NIH3T3 fibroblast did not result in a modulation of the cell growth induced by FCS or by growth factors. Interestingly, in CHO cells transfected with mu-opioid receptor cDNA, activation with agonists did not produce a potentiation of FCS-stimulated proliferation. This lack of mu-opioid receptor effect was not due to the differences among CHO clones. In a CHO cell line transfected with both delta-opioid receptor cDNA and mu-opioid receptor cDNA, activation of delta-but not mu-opioid receptors resulted in a potentiation of growth. These data suggest that delta- and mu-opioid receptors in CHO cells activate similar but divergent second messenger pathways, resulting in the differential regulation of cell growth.

In global health research and genomics research specifically, community engagement has gained prominence in enhancing ethical conduct, particularly in managing the risk of stigmatization, but there is minimal scientific evidence on how to do this effectively. This article reports on community engagement evaluation strategies in two African genomics studies: the Stigma in African Genomics Research study and the Genomics of Schizophrenia in South African Xhosa People (SAX) study. Within the Stigma in African Genomics Research study, a self-report rating scale and open-ended questions were used to track participant responses to an experiential theatre workshop. The workshop focused on participant experiences of living with schizophrenia or rheumatic heart disease (RHD). While the schizophrenia group reported more alienation and less stigma resistance than the RHD group, both groups demonstrated increased stigma resistance over time, after participating in the workshops. Hearing from others living with and managing the same illness normalised participants’ own experiences and encouraged them. Within the SAX study, a short rating scale and qualitative feedback methods were used to evaluate a Mental Health Literacy Day targeting mental health stigma. Information talks about (i) the symptoms of schizophrenia and treatment options and (ii) the illness experiences of a patient in recovery were rated as the most helpful on the day. Audience members reported that these talks challenged negative perceptions about severe mental illness. Three important learnings emerged from these evaluations: firstly, integration of evaluation strategies at the research study planning phase is likely to promote more effective community engagement. Secondly, a combination of quantitative and qualitative methods that draw on simple descriptive statistics and thematic analysis can provide nuanced perspectives about the value of community engagement. Thirdly, such evidence is necessary in establishing and promoting the science of community engagement in genomics research and health research more broadly.

In TiO2-based dye-sensitized nanocrystalline solar cells, efficiencies of up to 11% have been obtained using Ru dyes, but the limited availability of these dyes together with their undesirable environmental impact have led to the search for cheaper and safer organic-based dyes. In this Letter, we report the synthesis, electronic, and photovoltaic properties of novel green porphyrin sensitizers. All six porphyrin dyes give solar cell efficiencies of ≥5%, but the best performing dye under standard global AM 1.5 solar conditions gives a short circuit photocurrent density (jsc) of 14.0 ± 0.20 mA/cm2, an open circuit voltage of 680 ± 30 mV, and a fill factor of 0.74, corresponding to an overall conversion efficiency of 7.1%, which, for porphyrin-based sensitizers, is unprecedented. This same dye gives an efficiency of 3.6% in a solid-state cell with spiro-MeOTAD as the hole transporting component, comparable to solid-state cells incorporating the best performing ruthenium dyes.

OBJECTIVE: To compare the process of out of hours care provided by general practitioners from patients' own practices and by commercial deputising services. DESIGN: Randomised controlled trial. SETTING: Four urban areas in Manchester, Salford, Stockport, and Leicester. SUBJECTS: 2152 patients who requested out of hours care, and 49 practice doctors and 183 deputising doctors (61% local principals) who responded to those requests. MAIN OUTCOME MEASURES: Response to call, time to visit, prescribing, and hospital admissions. RESULTS: 1046 calls were dealt with by practice doctors and 1106 by deputising doctors. Practice doctors were more likely to give telephone advice (20.2% v 0.72% of calls) and to visit more quickly than deputising doctors (median delay 35 minutes v 52 minutes). Practice doctors were less likely than deputising doctors to issue a prescription (56.1% v 63.2% of patients) or to prescribe an antibiotic (43.7% v 61.3% of prescriptions issued) and more likely to prescribe genetic drugs (58.4% v 32.1% of drugs prescribed), cheaper drugs (mean cost per prescription pounds 3.28 v pounds 5.04), and drugs in a predefined out of hours formulary (49.8% v 41.1% of drugs prescribed). There was no significant difference in the number of hospital admissions. CONCLUSIONS: By contrast with practice doctors, deputising doctors providing out of hours care less readily give telephone advice, take longer to visit at home, and have patterns of prescribing that may be less discriminating.

OBJECTIVE--To assess ability to distinguish between first rate malt whisky and brandy and between different brands of each. DESIGN--Crossover with two sessions of 12 blindfold tastings of two whiskies and two brandies before and after supper, repeated not more than seven days later. SETTING--Dundas, Ontario. PARTICIPANTS--4 volunteers aged 50-68 years, all moderate drinkers of alcohol and members of a wine club. MAIN OUTCOME MEASURES--Proportion of samples correctly identified (whisky v brandy) and, of those, the proportion of brands correctly identified. RESULTS--Only one participant produced irrefutable statistical evidence (P < 0.0001) of being able to distinguish between whisky and brandy, correctly identifying 50/51 (98%) samples. Two participants achieved some success in identification (72%, P = 0.0031 and 65% P = 0.031). The fourth participant's responses reflected pure guesswork. Brandy was no easier to identify than whisky (P = 0.84). The participant who was best able to distinguish between whisky and brandy was also best able to identify correctly the brand of whisky (100%, P < 0.0001). CONCLUSION--Despite the fact that not all participants completed the full number of tastings the results show that some participants could distinguish neither between malt whisky and brandy nor between different brands of whisky and brandy. However, the success of one participant shows that "it can be done" and that his whisky specific ability is acquired not innate.

Background. Perinatal HIV transmission is less than 1% with antiretroviral (ARV) prophylaxis. Transmission risk appears higher in “high risk” dyads, yet this is not well defined, possibly exposing more infants to combination ARV compared with standard care. Objective. To describe characteristics of mother-infant dyads where infants received ARVs and how these characteristics relate to specific ARV regimens. Methods. Retrospective chart review of ARV-receiving newborns at St. Michael’s Hospital from 2007 to 2012 (and their mothers). Numerical and categorical variables were analyzed using t-tests/ANOVA F-tests and Fisher’s exact tests, respectively. Results. Maternal HIV status at delivery was as follows: 69% positive and 24% unknown. Maternal factors significantly associated with newborn-triple therapy are Canadian origin, substance abuse, unstable housing, lost custody of previous children, and sex work. Neonatal factors are child protective services involvement, NICU, and lengthier admission. Maternal factors associated with monotherapy are African origin, HIV-positive, employment, and education. Further analysis based on maternal presentation at delivery demonstrated unequal distribution of many aforementioned factors. Discussion. This cohort revealed associations between particular factors and newborn-monotherapy or triple therapy that exist, suggesting that sociodemographic factors may influence the choice of ARV regimen. Canadian perinatal HIV transmission guidelines should qualify how to risk stratify newborns and consider use of rapid HIV antibody testing.

The condensation of a dipyrromethane with ferrocene aldehyde leads to a single atropisomer of α,α-5,15-bis(ferrocenyl)-2,8,12,18-tetrabutyl-3,7,13,17-tetramethylporphyrin 1; electrochemistry of 1 and Ni-1 reveals two consecutive ferrocene-based one-electron oxidation waves, which are separated by 0.19 and 0.41 V, respectively.

OBJECTIVE: To examine the association between hypertensive diseases of pregnancy (gestational hypertension and pre-eclampsia) and the development of circulatory diseases in later life. DESIGN: Cohort study of women who had pre-eclampsia during their first singleton pregnancy. Two comparison groups were matched for age and year of delivery, one with gestational hypertension and one with no history of raised blood pressure. SETTING: Maternity services in the Grampian region of Scotland. PARTICIPANTS: Women selected from the Aberdeen maternity and neonatal databank who were resident in Aberdeen and who delivered a first, live singleton from 1951 to 1970. MAIN OUTCOME MEASURES: Current vital and cardiovascular health status ascertained through postal questionnaire survey, clinical examination, linkage to hospital discharge, and mortality data. RESULTS: There were significant positive associations between pre-eclampsia/eclampsia or gestational hypertension and later hypertension in all measures. The adjusted relative risks varied from 1.13-3.72 for gestational hypertension and 1.40-3.98 for pre-eclampsia or eclampsia. The adjusted incident rate ratio for death from stroke for the pre-eclampsia/eclampsia group was 3.59 (95% confidence interval 1.04 to 12.4). CONCLUSIONS: Hypertensive diseases of pregnancy seem to be associated in later life with diseases related to hypertension. If greater awareness of this association leads to earlier diagnosis and improved management, there may be scope for reducing a proportion of the morbidity and mortality from such diseases.