General access to cubanes as benzene bioisosteres.

The replacement of benzene rings with sp3-hybridized bioisosteres in drug candidates generally improves pharmacokinetic properties while retaining biological activity1-5. Rigid, strained frameworks such as bicyclo[1.1.1]pentane and cubane are particularly well suited as the ring strain imparts high bond strength and thus metabolic stability on their C-H bonds. Cubane is the ideal bioisostere as it provides the closest geometric match to benzene6,7. At present, however, all cubanes in drug design, like almost all benzene bioisosteres, act solely as substitutes for mono- or para-substituted benzene rings1-7. This is owing to the difficulty of accessing 1,3- and 1,2-disubstituted cubane precursors. The adoption of cubane in drug design has been further hindered by the poor compatibility of cross-coupling reactions with the cubane scaffold, owing to a competing metal-catalysed valence isomerization8-11. Here we report expedient routes to 1,3- and 1,2-disubstituted cubane building blocks using a convenient cyclobutadiene precursor and a photolytic C-H carboxylation reaction, respectively. Moreover, we leverage the slow oxidative addition and rapid reductive elimination of copper to develop C-N, C-C(sp3), C-C(sp2) and C-CF3 cross-coupling protocols12,13. Our research enables facile elaboration of all cubane isomers into drug candidates, thus enabling ideal bioisosteric replacement of ortho-, meta- and para-substituted benzenes.

Metallaphotoredox: The Merger of Photoredox and Transition Metal Catalysis.

The merger of photoredox catalysis with transition metal catalysis, termed metallaphotoredox catalysis, has become a mainstay in synthetic methodology over the past decade. Metallaphotoredox catalysis has combined the unparalleled capacity of transition metal catalysis for bond formation with the broad utility of photoinduced electron- and energy-transfer processes. Photocatalytic substrate activation has allowed the engagement of simple starting materials in metal-mediated bond-forming processes. Moreover, electron or energy transfer directly with key organometallic intermediates has provided novel activation modes entirely complementary to traditional catalytic platforms. This Review details and contextualizes the advancements in molecule construction brought forth by metallaphotocatalysis.

Direct arylation of strong aliphatic C-H bonds.

Despite the widespread success of transition-metal-catalysed cross-coupling methodologies, considerable limitations still exist in reactions at sp3-hybridized carbon atoms, with most approaches relying on prefunctionalized alkylmetal or bromide coupling partners1,2. Although the use of native functional groups (for example, carboxylic acids, alkenes and alcohols) has improved the overall efficiency of such transformations by expanding the range of potential feedstocks3-5, the direct functionalization of carbon-hydrogen (C-H) bonds-the most abundant moiety in organic molecules-represents a more ideal approach to molecular construction. In recent years, an impressive range of reactions that form C(sp3)-heteroatom bonds from strong C-H bonds has been reported6,7. Additionally, valuable technologies have been developed for the formation of carbon-carbon bonds from the corresponding C(sp3)-H bonds via substrate-directed transition-metal C-H insertion8, undirected C-H insertion by captodative rhodium carbenoid complexes9, or hydrogen atom transfer from weak, hydridic C-H bonds by electrophilic open-shell species10-14. Despite these advances, a mild and general platform for the coupling of strong, neutral C(sp3)-H bonds with aryl electrophiles has not been realized. Here we describe a protocol for the direct C(sp3) arylation of a diverse set of aliphatic, C-H bond-containing organic frameworks through the combination of light-driven, polyoxometalate-facilitated hydrogen atom transfer and nickel catalysis. This dual-catalytic manifold enables the generation of carbon-centred radicals from strong, neutral C-H bonds, which thereafter act as nucleophiles in nickel-mediated cross-coupling with aryl bromides to afford C(sp3)-C(sp2) cross-coupled products. This technology enables unprecedented, single-step access to a broad array of complex, medicinally relevant molecules directly from natural products and chemical feedstocks through functionalization at sites that are unreactive under traditional methods.

Decompensated cirrhosis: targeted training of acute medical teams to improve quality of care in first 24 hours.

BACKGROUND: A quality improvement project in a secondary care centre was initiated to investigate and evaluate the impact of staff education and the use of the British Society of Gastroenterology/British Association for the Study of the Liver cirrhosis care bundle in improving care of patients admitted to hospital with decompensated liver cirrhosis. METHOD: A staff training programme was implemented, involving around 30 health professionals consisting of consultants, junior doctors, physician associates and nurses from the acute medical unit. A review of electronic documentation and analysis of key clinical parameters, pre- and post-intervention, was carried out. RESULTS: The data show that the intervention has led to an improvement in patient management and clinical outcomes. CONCLUSION: This project illustrates that collaboration between hepatology and medical teams, with emphasis on education and training, benefits patients who present to hospital with decompensated liver cirrhosis.

Alcohol-related harm: developing a drug and alcohol liaison team.

The City of Wolverhampton has much higher rates of accident and emergency (emergency department) attendance and hospital admission for alcohol-related harm than in neighbouring health authorities and double the national death rate from alcohol-related liver disease. Recovery Near You, the local addiction service, in partnership with The Royal Wolverhampton NHS Trust, initiated a nurse-led drug and alcohol liaison team to address these health issues. This resulted in a tenfold increase in screening and engagement with patients in the acute hospital, the creation of guidelines, protocols and training available for staff in the Trust and an accessible service that has impacted positively on patient experience. This article describes the development of the team, outlining the challenges, successes and outcomes.

Copper-Catalyzed Enantioselective Addition of Styrene-Derived Nucleophiles to Imines Enabled by Ligand-Controlled Chemoselective Hydrocupration.

The copper-catalyzed intermolecular enantioselective addition of styrenes to imines has been achieved under mild conditions at ambient temperature. This process features the use of styrenes as latent carbanion equivalents via the intermediacy of catalytically generated benzylcopper derivatives, providing an effective means for accessing highly enantiomerically enriched amines bearing contiguous stereocenters. Mechanistic studies shed light on the origin of the preferential styrene hydrocupration in the presence of an imine with the Ph-BPE-derived copper catalyst.

Workload involved in vital signs-based monitoring & responding to deteriorating patients: A single site experience from a regional New Zealand hospital.

Objective: This study aimed to quantify the workload involved in patient monitoring by vital signs and early warning scores (EWS), and the time spent by a rapid response team locally known as the Patient-at-Risk (PaR) team in responding to deteriorating patients. Methods: The workload involved in the measurement and the documentation of vital signs and EWS was quantified by time and motion study using electronic stopwatch application in 167 complete sets of vital signs observations taken by nursing staff on general hospital wards at Taranaki Base Hospital, New Plymouth, New Zealand. The workload involved in responding to deteriorating patients was measured by the PaR team in real-time and recorded in an electronic logbook specifically designed for this purpose. Dependent variables were studied using analysis of variance (ANOVA), post hoc Tukey, Kruskal Wallis test, Mann-Whitney test and correlation tests. Results: The mean time to measure and record a complete set of vital signs including interruptions was 4:18 (95% CI: 4:07-4:28) minutes. After excluding interruptions, the mean time taken to measure and record a set of vital signs was 3:24 (95% CI: 3:15-3:33) minutes. We found no statistical difference between the observer, location of the patient, staff characteristics or experience and patient characteristics. PaR nurses' mean time to provide rapid response was 47:36 (95% CI: 44:57-50:15) minutes. Significantly more time was spent on patients having severe degrees of deterioration (higher EWS) < 0.001. No statistical difference was observed between ward specialty, and nursing shifts. Conclusions: Patient monitoring and response to deterioration consumed considerable time. Time spent in monitoring was not affected by independent and random factors studied; however, time spent on the response was greater when patients had higher degrees of deterioration.

Will the Affordable Care Act make health insurance affordable?

Using a budget-based approach to measuring affordability, this issue brief explores whether the subsidies available through the Affordable Care Act are enough to make health insurance affordable for low-income families. Drawing from the Consumer Expenditure Survey, the authors assess how much "room" people have in their budget, after paying for other necessities, to pay for health care needs. The results show that an overwhelming majority of households have room in their budgets for the necessities, health insurance premiums, and moderate levels of out-of-pocket costs established by the Affordable Care Act. Fewer than 10 percent of families above the federal poverty level do not have the resources to pay for premiums and typical out-of-pocket costs, even with the subsidies provided by the health reform law. Affordability remains a concern for some families with high out-of-pocket spending, suggesting that this is the major risk to insurance affordability.

Establishing the added benefit of measuring MMP9 in FOB positive patients as a part of the Wolverhampton colorectal cancer screening programme.

BACKGROUND: Bowel cancer is common and a major cause of death. The NHS is currently rolling out a national bowel cancer screening programme that aims to cover the entire population by 2010. The programme will be based on the Faecal Occult Blood test (FOBt) that reduces mortality from colon cancer by 16%. However, FOB testing has a relatively low positive predictive value, with associated unnecessary cost, risk and anxiety from subsequent investigation, and is unacceptable to a proportion of the target population. Increased levels of an enzyme called matrix metalloproteinase 9 (MMP9) have been found to be associated with colorectal cancer, and this can be measured from a blood sample. MMP9 has potential for detecting those at risk of having colorectal cancer. The aim of this study is to assess whether MMP9 estimation enhances the predictive value of a positive FOBt. METHODS AND DESIGN: FOBt positive people aged 60-69 years attending the Wolverhampton NHS Bowel Cancer Screening Unit and providing consent for colonoscopy will be recruited. Participants will provide a blood sample prior to colonoscopy and permission for collection of the clinical outcome from screening unit records. Multivariate logistic regression analyses will determine the independent factors (patient and disease related, MMP9) associated with the prediction of neoplasia. DISCUSSION: Colorectal cancer is a major cause of morbidity and mortality. Pilot studies have confirmed the feasibility of the national cancer screening programme that is based on FOBt. However, the test has high false positive rates. MMP9 has significant potential as a marker for both adenomas and cancers. This study is to examine whether using MMP9 as an adjunct to FOBt improves the accuracy of screening and reduces the number of false positive tests that cause anxiety and require invasive and potentially harmful investigation.

SLC11A1 is expressed in the human placenta across multiple gestational ages.

The human placenta functions as an innate immune barrier to prevent fetal infection. However, the molecular mechanisms accounting for placental resistance to pathogens are currently poorly understood. The solute carrier family 11 member 1 (SLC11A1) is a divalent cation transporter expressed primarily by macrophages and neutrophils that is essential for controlling infections by intracellular pathogens such as Salmonella, Leishmania and Mycobacteria. This report demonstrates that SLC11A1 is expressed in the syncytiotrophoblast of the human placenta at multiple gestational ages. These results suggest that SLC11A1 may play a role in blocking productive placental infections by certain intracellular pathogens.

Analysis of the capacity of Salmonella enterica Typhimurium to infect the human Placenta.

INTRODUCTION: Salmonella species are gram-negative facultative intracellular bacteria that are common causes of foodborne illness in North America. Infections by Salmonella during pregnancy are a significant cause of fetal loss in domestic livestock, and fetal and maternal mortality in mice. Furthermore, Salmonella infection is associated with miscarriage, stillbirth and preterm birth in pregnant women. Despite these collective associations, the extent to which Salmonella can infect the human placenta has not been investigated. METHODS: Human placental villous explants from several gestational ages were exposed to Salmonella enterica serovar Typhimurium (STm) ex vivo. Infection was assessed by colony forming unit assay and whole mount immunofluorescence (WMIF). RESULTS: Viable bacteria were recovered from placental villous explants of all gestational ages tested, but the bacterial burden was highest in 1st trimester explants. Bacterial numbers did not change appreciably with time post-infection in explants from any gestational age examined, suggesting that STm does not proliferate in placental villi. Exposure of villous explants to STm strains defective for the type III secretion systems revealed that Salmonella pathogenicity island 1 is essential for optimal invasion. In contrast to placental explants, STm infected and proliferated within villous cytotrophoblast cells isolated from term placentas. WMIF demonstrated that STm was restricted primarily to the syncytiotrophoblast layer in infected placentas. DISCUSSION: Our study demonstrates that STm can invade into the syncytiotrophoblast but does not subsequently proliferate. Thus, the syncytiotrophoblast may function as a barrier to STm infection of the fetus.

Copper-catalyzed asymmetric addition of olefin-derived nucleophiles to ketones.

Enantioenriched alcohols found in an array of bioactive natural products and pharmaceutical agents are often synthesized by asymmetric nucleophilic addition to carbonyls. However, this approach generally shows limited functional-group compatibility, requiring the use of preformed organometallic reagents in conjunction with a stoichiometric or substoichiometric amount of chiral controller to deliver optically active alcohols. Herein we report a copper-catalyzed strategy for the stereoselective nucleophilic addition of propargylic and other alkyl groups to ketones, using easily accessible (poly)unsaturated hydrocarbons as latent carbanion equivalents. Our method features the catalytic generation of highly enantioenriched organocopper intermediates and their subsequent diastereoselective addition to ketones, allowing for the effective construction of highly substituted stereochemical dyads with excellent stereocontrol. Moreover, this process is general, scalable, and occurs at ambient temperature.

Tumour necrosis factor-alpha in Barrett's oesophagus: a potential novel mechanism of action.

Barrett's metaplasia (BM) is an early lesion in the progression from oesophageal inflammation through dysplasia to the development of Barrett's adenocarcinoma (BA). Previous work indicates that BM and BA are associated with reduced E-cadherin expression and increased cytoplasmic/nuclear pools of its associated protein beta-catenin. beta-catenin participates in Wnt signalling and activates oncogene transcription by complexing with T-cells factors (TCF). One such oncogene is c-myc. We have previously shown that TNF-alpha can down-regulate E-cadherin expression. Here, we assess TNF-alpha expression in Barrett's metaplasia and examine if TNF-alpha can promote beta-catenin mediated transcription of oncogenes in a gastrointestinal model system. Employing immunohistochemistry and Western blot analysis of oesophageal tissue, epithelial expression of TNF-alpha increases with progression along the metaplasia-dysplasia-carcinoma sequence (P<0.001). beta-catenin mediated transcription was then assessed in TNF-alpha stimulated cell lines using the TOPFLASH reporter system whilst c-myc expression was assessed by real time PCR. In a columnar intestinal cell model, TNF-alpha induces c-myc expression which is induced via beta-catenin mediated transcription (P<0.05). This beta-catenin mediated transcription is independent of NF-kappaB activation. Thus, TNF-alpha is up-regulated in the progression of Barrett's oesophagus and beta-catenin mediated transcription of c-myc is a novel pathway whereby elevated levels of TNF-alpha may lead to oncogene transcription and altered biology in gastrointestinal epithelia and metaplasia.

Tropical medicine and travel medicine: medical advice for aviation medical examiners concerning flight operations in tropical areas.

Medical stress factors in the tropics include the climate itself, factors related to travel (jet lag, means of transport), insects, low standards of hygiene, infectious diseases, socio-economic problems, and psychosocial stress. This chapter from the Joint Aviation Authority Aviation Medical Regulations explores these stresses as they relate to aircrew and the aviation medical examiners who treat them.

Gastropericardial fistula: a potential role for conservative treatment.

Gastropericardial fistulae are rare entities associated with considerable mortality and morbidity. Most commonly seen secondary to surgery and trauma, they also occur because of peptic ulcer disease. Surgical correction remains the definitive treatment and conservative management is normally associated with poor outcomes. We present the case of a woman with multiple comorbidities who presented with a pneumopericardium secondary to a benign peptic ulcer-related gastropericardial fistula. This case shows that early nasojejunal feeding in patients not fit for a surgical intervention can be associated with a good outcome. We therefore propose that in cases where surgery is not feasible, conservative management with antibiotics and nasojejunal feeding remains a viable alternative.

Shortness of breath: flushing out the diagnosis.

We report a 63-year-old man who presented with breathlessness and weight loss and was diagnosed on echocardiography to have carcinoid heart disease. It was later transpired that he underwent surgical removal of an ileal carcinoid tumour 19 years previously.

Detection of intestinal metaplasia in Barrett's esophagus: an observational comparator study suggests the need for a minimum of eight biopsies.

OBJECTIVES: Intestinal metaplasia (IM) and dysplasia in Barrett's esophagus are recognized surrogates for esophageal adenocarcinoma risk. While few would argue with the "hunt for dysplasia," there is a divide regarding the usefulness of the histological confirmation of intestinal metaplasia in endoscopically apparent long segment Barrett's esophagus. We aimed to assess the frequency of intestinal metaplasia in 125 consecutive patients with columnar-lined esophagus and to determine the optimal biopsy protocol to detect intestinal metaplasia. METHODS: Two-hundred ninety-six endoscopies were performed over a 4-yr period in Barrett's esophagus segments of mean length 4 cm (range 1-11 cm) at a single center and the resulting biopsies were analyzed retrospectively. Biopsies were all processed with routine hematoxylin and eosin (H&E) staining, and a subset (N=92) was subject to alcian blue/periodic-acid Schiff staining. RESULTS: Using H&E staining, we found that the optimum number of biopsies to diagnose intestinal metaplasia was 8 per endoscopy, mean 67.9% endoscopies having intestinal metaplasia. In contrast, if only four were taken the yield was 34.7% with intestinal metaplasia. Unless more than 16 biopsies were taken (100% yield of intestinal metaplasia), no additional significant detection was achieved. Using additional alcian blue/periodic-acid Schiff staining only had a marginal benefit, with 5.4% of new cases of intestinal metaplasia being identified. There is a proximal cephalo-caudal gradient of intestinal metaplasia, especially with increased chronological age, but doing repeat endoscopies on patients did not increase the detection of intestinal metaplasia. CONCLUSIONS: The data suggest that at least 8 random biopsies is the minimum to be taken and analyzed with conventional H&E staining to diagnose benign intestinal metaplasia. Taking more biopsies did not statistically increase the diagnosis of intestinal metaplasia except when greater than 16 were taken when 100% yield was obtained.