Establishing a natural history of X-linked dystonia parkinsonism.

X-linked dystonia parkinsonism is a neurodegenerative movement disorder that affects men whose mothers originate from the island of Panay, Philippines. Current evidence indicates that the most likely cause is an expansion in the TAF1 gene that may be amenable to treatment. To prepare for clinical trials of therapeutic candidates for X-linked dystonia parkinsonism, we focused on the identification of quantitative phenotypic measures that are most strongly associated with disease progression. Our main objective is to establish a comprehensive, quantitative assessment of movement dysfunction and bulbar motor impairments that are sensitive and specific to disease progression in persons with X-linked dystonia parkinsonism. These measures will set the stage for future treatment trials. We enrolled patients with X-linked dystonia parkinsonism and performed a comprehensive oromotor, speech and neurological assessment. Measurements included patient-reported questionnaires regarding daily living activities and both neurologist-rated movement scales and objective quantitative measures of bulbar function and nutritional status. Patients were followed for 18 months from the date of enrollment and evaluated every 6 months during that period. We analysed a total of 87 men: 29 were gene-positive and had symptoms at enrollment, seven were gene-positive and had no symptoms at enrollment and 51 were gene-negative. We identified measures that displayed a significant change over the study. We used principal variables analysis to identify a minimal battery of 21 measures that explains 67.3% of the variance over the course of the study. These measures included patient-reported, clinician-rated and objective quantitative outcomes that may serve as endpoints in future clinical trials.

Biomarkers of Thrombotic Status Predict Spontaneous Reperfusion in Patients With ST-Segment Elevation Myocardial Infarction.

BACKGROUND: Spontaneous reperfusion, seen in ∼20% of patients with ST-segment elevation myocardial infarction (STEMI), manifests as normal epicardial flow in the infarct-related artery, with or without ST-segment resolution, before percutaneous coronary intervention (PCI). The drivers mediating this are unknown. OBJECTIVES: The authors sought to relate spontaneous reperfusion to the thrombotic profile. METHODS: In a prospective study, blood from STEMI patients (n = 801) was tested pre-PCI to assess in vitro, point-of-care, occlusion times (OT) and endogenous lysis times (LT). Spontaneous reperfusion was defined as infarct-related artery Thrombolysis In Myocardial Infarction flow grade 3 before PCI. Patients were followed for major cardiovascular events (death, myocardial infarction, or stroke). RESULTS: Spontaneous reperfusion was associated with a longer OT (435 seconds vs 366 seconds; P < 0.001) and a shorter LT (1,257 seconds vs 1,616 seconds; P < 0.001), lower troponin, and better left ventricular function. LT was superior to OT for predicting spontaneous reperfusion (area under the curve for LT: 0.707; 95% CI: 0.661-0.753; area under the curve for OT: 0.629; 95% CI: 0.581-0.677). Among patients with spontaneous reperfusion, those with complete, vs partial ST-segment resolution, had a longer OT (P = 0.002) and a shorter LT (P < 0.001). Spontaneous reperfusion was unrelated to clinical characteristics or pain-to-angiography times. Over 4 years, patients with spontaneous reperfusion experienced fewer major adverse cardiovascular events than those without (4.1% vs 10.6%; P = 0.013), especially in those with both spontaneous reperfusion and complete ST-segment resolution (1.5% vs 10.1%; P = 0.029). CONCLUSIONS: We demonstrate a novel hematological signature in STEMI patients with spontaneous reperfusion, namely, decreased platelet reactivity and faster endogenous fibrinolysis, relating to smaller infarcts and improved survival. This finding indicates a role for modulating thrombotic status early after STEMI onset, to facilitate spontaneous reperfusion and improve outcomes.

A Pilot Study to Examine the Effect of Passive Straight Leg Raise Performed During Cardiopulmonary Resuscitation on Cerebral Perfusion Measured by Noninvasive Cerebral Oximetry.

Passive leg raise (PLR) during cardiopulmonary resuscitation (CPR) is simple and noninvasive maneuver, which can potentially improve patient-related outcomes. Initial CPR guidelines have previously advocated "elevation of the lower extremities to augment artificial circulation during CPR." There is lack of supporting evidence for this recommendation. DESIGN: This was a double cross-over physiologic efficacy randomized study. SETTING AND PATIENTS: Study in 10 subjects with in-hospital cardiac arrest for whom CPR was undertaken. INTERVENTION: Subjects were randomized to receive two cycles of CPR with PLR followed by two cycles of CPR without PLR (Group I) or vice-versa (Group II). Subjects had their foreheads (right and left) fitted with near infrared spectroscopy (NIRS) electrodes (O3 System-Masimo, Masimo corporation Forty Parker, Irvine CA) while undergoing CPR during the study. NIRS readings, a measure of mixed venous, arterial, and capillary blood oxygen saturation, act as a surrogate measure of cerebral blood perfusion during CPR. MEASUREMENT AND MAIN RESULTS: PLR was randomly used "first" in five of them, whereas it was used "second" in the remaining five subjects. In subjects in whom PLR was performed during first two cycles (Group I), NIRS values were initially significantly greater. The performance of PLR during CPR in Group II attenuated the decline in NIRS readings during CPR. CONCLUSIONS: PLR during CPR is feasible and leads to augmentation of cerebral blood flow. Furthermore, the expected decline in cerebral blood flow over time during CPR may be attenuated by this maneuver. The clinical significance of these findings will require further investigations.

Neurovascular structure-adjacent frozen-section examination robotic-assisted radical prostatectomy: outcomes from 500 consecutive cases in the UK.

The purpose is to report the United Kingdom's largest single-centre experience of robotically assisted laparoscopic radical prostatectomies (RALP), using the neurovascular structure-adjacent frozen-section (NeuroSAFE) technique. We describe the utilisation and outcomes of this technique. This is a retrospective study from 2012 to 2019 on 520 patients undergoing NeuroSAFE RALP at our Institution. Our Institution's database was analysed for false-positive frozen-section (FS) margins as confirmed on paraffin histopathological analysis: functional outcomes of potency, continence, and biochemical recurrence (BCR). The median (range) of console time was 145 (90-300) min. In our cohort, positive FS was seen in 30.7% (160/520) of patients, with a confirmatory paraffin analysis in 91.8% of our patients' cohort (147/160). The neurovascular bundles (NVBs) that underwent secondary resection contained tumour in 26.8% (43/160) of the cases. Biochemical recurrence (BCR) was 6.7% (35/520), of which FS was positive in 40% (14/35) of those cases. There were insufficient evidence of a statistical association of urinary incontinence and positive surgical margin rates according to NS or NVB resection. NeuroSAFE enables intraoperative confirmation of the oncologic safety of a NS procedure. Patients with a positive FS on NeuroSAFE can be converted to a negative surgical margin (NSM) by ipsilateral wide resection. This spared 1 in 4 men from positive margins posterolaterally in our series. Limitations are the absence of a matched contemporary cohort of NS RALP without NeuroSAFE in our centre.

Determinants of Endogenous Fibrinolysis in Whole Blood Under High Shear in Patients With Myocardial Infarction.

Hypofibrinolysis is a recently-recognized risk factor for recurrent cardiovascular events in patients with ST-segment elevation myocardial infarction (STEMI), but the mechanistic determinants of this are not well understood. In patients with STEMI, we show that the effectiveness of endogenous fibrinolysis in whole blood is determined in part by fibrinogen level, high sensitivity C-reactive protein, and shear-induced platelet reactivity, the latter directly related to the speed of thrombin generation. Our findings strengthen the evidence for the role of cellular components and bidirectional crosstalk between coagulatory and inflammatory pathways as determinants of hypofibrinolysis.

Rapid onsite evaluation uses a very small proportion of total material aspirated at endobronchial or endoscopic ultrasound in the investigation of suspected thoracic malignancy.

INTRODUCTION: The objectives were: to measure the proportion of aspirated material used to make direct slides for rapid onsite evaluation (ROSE) at endobronchial (EBUS) and endoscopic ultrasound (EUS) in suspected thoracic malignancy; and to correlate pass weights with ROSE category and needle size. METHOD: All EBUS and EUS cases for possible thoracic malignancy October 2018-May 2019 were included. All material from each pass was expelled into a Petri dish. One drop of material was placed on each of two slides; one used for ROSE, the other fixed and remaining material processed to cell block. Dish and slides were weighed before and after this procedure on a sensitive balance and weight of aspirate and slide material calculated. When ROSE identified malignancy, slide production ceased but target sampling for ancillary studies continued. RESULTS: ROSE accuracy was 96.8%. Mean percentage by target of aspirated material used to make direct slides for ROSE was 1.9% in malignant cases and 3.6% in non-malignant cases (P = .027 for difference). Mean percentage by pass was 5.9%. Mean weight of a single aspirate was 128.8 mg. Mean weight of aspirates insufficient on ROSE (175.7 mg) was significantly higher than the mean weight of benign or malignant aspirates (117.1 and 114.0 mg, respectively). Mean weight of aspirates using 22G needles (132.6 mg) was significantly higher than that for 25G needles (87.1 mg). CONCLUSION: Material made into direct slides at EBUS and EUS and used in part for ROSE uses a tiny proportion of aspirated material with over 98% processed to cell block and available for ancillary testing in malignant cases.

Can Medical Humanities impart Empathy and Resilience skills to Medical Students?

This article was migrated. The article was marked as recommended. The contribution of the Medical Humanities to a comprehensive medical education has been discussed elsewhere ( Schamroth, 2018), but what has been difficult to demonstrate is whether it has any measurable quantitative impact on improving student's empathy or resilience. This small project was an attempt to further explore this question. Medical students at University College London Medical School spend approximately one day a month during their first clinical year within a primary care setting in a programme called "Medicine in the Community" (MIC). The structure of the day involves students seeing patients under the supervision of primary care physicians. In this ethically approved research project (University College London, 2017) conducted over the academic year 2017-2018, a non-selected group of 24 students, received a compressed version of this MIC programme in the morning and in the afternoon were exposed to medical humanities. This included discussing poetry with a medical focus, creative writing based on the students own clinical experiences, watching and listening to carefully selected opera scenes where a health-related issue was illustrated and finally an experiential group based psychotherapy process using body mapping which facilitated the exploration of the interrelationship between mind and body. A second group of 18 medical students who received the conventional MIC experience acted as the control. Both groups were given empathy and resilience questionnaires at the beginning and end of the academic year. The results showed that the students who experienced the afternoon humanities programme scored significantly higher in 3 of the 20 empathy questions than the control group and better in the resilience questionnaire, although the latter did not reach statistical significance.

Socioeconomic Differences and the Potential Role of Tribes in Young People's Food and Drink Purchasing Outside School at Lunchtime.

Socioeconomic deprivation has been linked to food consumption practices, but studies investigating the food environment around schools provide mixed findings. Peer influence and marketing cues are considered important influencers of young people's behaviors. This study used a tribal theory lens to investigate the factors affecting pupils' purchasing and consumption of food/drinks outside schools at lunchtime. A survey was conducted with 243 pupils from seven UK secondary schools of differing socioeconomic status (SES). A purchasing recall questionnaire (PRQ) was developed and administered online at the participating schools to capture food and drink purchasing, intake, and expenditure. No significant differences were found in terms of energy and nutrients consumed or food/drink expenditure between pupils from schools of lower and higher SES. Enjoyment of food shopping with friends was linked with higher food energy intake and spend. Higher susceptibility to peer influence was associated with greater influence from food advertising and endorsements. Without ignoring the impact that SES can have on young people's food choices, we suggest that tribal theory can be additionally used to understand pupils' eating behaviors and we present implications for social marketers and policy makers.

Prevalence of drug-herb and drug-supplement interactions in older adults: a cross-sectional survey.

BACKGROUND: Polypharmacy is common among older adults, with increasing numbers also using prescription drugs with herbal medicinal products (HMPs) and dietary supplements. There is no reliable evidence from the UK on concurrent use of HMPs and dietary supplements with prescription drugs in older adults. AIM: To establish prevalence of concurrent prescription drugs, HMPs, and dietary supplements among UK community-dwelling older adults and identify potential interactions. DESIGN AND SETTING: Cross-sectional survey of older adults registered at two general practices in South East England. METHOD: A questionnaire asking about prescription medications, HMPs, and sociodemographic information was posted to 400 older adults aged ≥65 years, identified as taking ≥1 prescription drug. RESULTS: In total 155 questionnaires were returned (response rate = 38.8%) and the prevalence of concurrent HMPs and dietary supplements with prescriptions was 33.6%. Females were more likely than males to be concurrent users (43.4% versus 22.5%; P = 0.009). The number of HMPs and dietary supplements ranged from 1 to 8, (mean = 3, median = 1; standard deviation = 1.65). The majority of concurrent users (78.0%) used dietary supplements with prescription drugs. The most commonly used dietary supplements were cod liver oil, glucosamine, multivitamins, and vitamin D. Others (20.0%) used only HMPs with prescription drugs. Common HMPs were evening primrose oil, valerian, and Nytol Herbal® (a combination of hops, gentian, and passion flower). Sixteen participants (32.6%) were at risk of potential adverse drug interactions. CONCLUSION: GPs should routinely ask questions regarding herbal and supplement use, to identify and manage older adults at potential risk of adverse drug interactions.

Rationalisation of a mechanism for sensing single point variants in target DNA using anthracene-tagged base discriminating probes.

The labelling of DNA oligonucleotides with signalling groups that give a unique response to duplex formation depending on the target sequence is a highly effective strategy in the design of DNA-based hybridisation sensors. A key challenge in the design of these so-called base discriminating probes (BDPs) is to understand how the local environment of the signalling group affects the sensing response. The work herein describes a comprehensive study involving a variety of photophysical techniques, NMR studies and molecular dynamics simulations, on anthracene-tagged oligonucleotide probes that can sense single base changes (point variants) in target DNA strands. A detailed analysis of the fluorescence sensing mechanism is provided, with a particular focus on rationalising the high dependence of this process on not only the linker stereochemistry but also the site of nucleobase variation within the target strand. The work highlights the various factors and techniques used to respectively underpin and rationalise the BDP approach to point variant sensing, which relies on different responses to duplex formation rather than different duplex binding strengths.

Association Between Experiencing Relational Bullying and Adolescent Health-Related Quality of Life.

BACKGROUND: Bullying is a public health concern for the school-aged population, however, the health outcomes associated with the subtype of relational bullying are less understood. The purpose of this study was to examine the association between relational bullying and health-related quality of life (HRQL) among young people. METHODS: This study utilized data from 5335 students aged 11-15 years, collected as part of the 2014 Health Behavior in School-aged Children (HBSC) study conducted in England. Data were collected through self-completed surveys. Multilevel analysis modeled the relationship between relational bullying and HRQL. Demographic variables (sex, age, ethnicity, socioeconomic status) and other forms of bullying were controlled for. RESULTS: Experiencing relational bullying had a significant negative association with HRQL whilst controlling for other forms of bullying. Weekly relational bullying resulted in an estimated 5.352 (95% confidence interval (CI), -4.178, -6.526) decrease in KIDSCREEN-10 score compared with those not experiencing relational bullying. CONCLUSION: Experiencing relational bullying is associated with poorer HRQL. The findings question the perception of relational bullying as being a predominantly female problem. Girls were more likely to report experiencing relational bullying, but the negative association with HRQL was equal for boys and girls.

Self-harm in adolescence: protective health assets in the family, school and community.

OBJECTIVES: The aim of this paper was to examine if the multiple environments of the adolescent including family, peers, school and neighbourhood might function as protective health assets against self-harming behaviour during adolescence. METHODS: The present study utilised data collected from 1608 respondents aged 15 years as part of the England WHO Health Behaviour in School-aged Children (HBSC) Study. Multilevel modelling was undertaken using the package MLwiN (version 2.33) to investigate the potential domains and dimensions of family life, school culture and environment, and neighbourhood factors that may operate as protective health assets. RESULTS: The results indicated that while peer support did not appear to operate as a protective health asset in the context of self-harm, key dimensions of adolescent/parent interaction and adolescent experience of the school culture and their neighbourhood were associated with reduced likelihood of self-harming behaviours during adolescence. CONCLUSIONS: The Findings highlight the significance of belonging and connectedness as important constituent elements of protective health assets for young people. Interventions that address the multiple environments of the young person, may offer an effective means to reduce the levels of self-harm.

Reversible photocapture of a [2]rotaxane harnessing a barbiturate template.

Photoirradiation of a hydrogen-bonded molecular complex comprising acyclic components, namely, a stoppered thread (1) with a central barbiturate motif and an optimized doubly anthracene-terminated acyclic Hamilton-like receptor (2b), leads to an interlocked architecture, which was isolated and fully characterized. The sole isolated interlocked photoproduct (Φ = 0.06) is a [2]rotaxane, with the dimerized anthracenes assuming a head-to-tail geometry, as evidenced by NMR spectroscopy and consistent with molecular modeling (PM6). A different behavior was observed on irradiating homologous molecular complexes 1⊂2a, 1⊂2b, and 1⊂2c, where the spacers of 2a, 2b, and 2c incorporated 3, 6, and 9 methylene units, respectively. While no evidence of interlocked structure formation was observed following irradiation of 1⊂2a, a kinetically labile rotaxane was obtained on irradiating the complex 1⊂2c, and ring slippage was revealed. A more stable [2]rotaxane was formed on irradiating 1⊂2b, whose capture is found to be fully reversible upon heating, thereby resetting the system, with some fatigue (38%) after four irradiation­thermal reversion cycles.

Diastereotopic group selectivity and chemoselectivity of alkylidene carbene reactions on 8-oxabicyclo[3.2.1]- oct-6-ene ring systems.

α-Hydroxyalkylidene carbenes, generated from thermolysis of α,ß-epoxy-N-aziridinylimines, undergo diastereotopic group selective 1,5 C­H insertion reactions on 2,4-dimethyl-8-oxabicyclo[3.2.1]oct-6-ene ring systems. Protection of a tertiary alcohol at C-3 of the bridged oxabicycle as a trimethylsilyl ether reverses the sense of diastereoselectivity. 1,5 C­H insertion into a methine adjacent to an OBn group, 1,5 O­R insertion into a tertiary alcohol (R = H) or silylether (R = TMS) at C-3 to form spirocyclic dihydrofurans, 1,2-rearrangement to an alkyne and fragmentation to a ketone are competing major pathways for 2-benzyloxy-substituted 8-oxabicyclo[3.2.1]oct-6-ene systems. Dihydrofuran formation is shown to be a result of substitution on the oxabicyclic ring system through comparison with other methods of alkylidene carbene formation.

Multielement NMR studies of the liquid-liquid phase separation and the metal-to-nonmetal transition in fluid lithium- and sodium-ammonia solutions.

(1)H, (7)Li, (14)N, and (23)Na high resolution nuclear magnetic resonance (NMR) measurements are reported for fluid solutions of lithium and sodium in anhydrous liquid ammonia across the metal-to-nonmetal transition (MNM transition), paying particular attention to the phenomenon of liquid-liquid phase separation which occurs in the composition/temperature region close to the MNM transition. Our results are discussed in terms of the electronic structure of fluid metal-ammonia solutions at low temperatures (ca. 240 K). We find that the electronic phase transition to the metallic state in these solutions, especially at temperatures close to the liquid-liquid critical consolute temperature, occurs from a nonmetallic, electrolytic solution containing a predominance of electron spin-paired, (diamagnetic) charged bosonic states. The possible implications of these observations to the nature of the liquid-liquid phase separation are discussed, both from the views of N. F. Mott, regarding the MNM transition in sodium-ammonia solutions, and those of R. A. Ogg, regarding the possibility of high-temperature superconductivity in these solutions. Similarities between the electronic structure of metal-ammonia solutions and the high-temperature cuprate superconductors are also briefly emphasized.

Synthesis of azetidines and pyrrolidines via iodocyclisation of homoallyl amines and exploration of activity in a zebrafish embryo assay.

Room temperature iodocyclisation of homoallylamines stereoselectively delivers functionalised 2-(iodomethyl)azetidine derivatives in high yield. Increasing reaction temperature from 20 °C to 50 °C switches the reaction outcome to realise the stereoselective formation of functionalised 3-iodopyrrolidine derivatives. It was shown that these pyrrolidines are formed via thermal isomerisation of the aforementioned azetidines. Primary and secondary amines could be reacted with iodomethyl azetidine derivatives to deliver stable methylamino azetidine derivatives. With subtle changes to the reaction sequences homoallyl amines could be stereoselectively converted to either cis- or trans-substituted 3-amino pyrrolidine derivatives at will. The stereochemical divergent synthesis of cis and trans substituted pyrrolidines supports an ion part, aziridinium, isomerisation pathway for azetidine to pyrrolidine isomerisation. Six azetidine derivatives were probed in a zebrafish embryo developmental assay to detect potential biological effects through the analysis of morphology and motility behaviour phenotypes. The range of effects across the probed molecules demonstrates the suitability of this assay for screening azetidine derivatives. One of the probed molecules, rac-(((cis)-1-benzyl-4-phenylazetidin-2-yl)methyl)piperidine, exhibited particularly interesting effects in the developmental assay presenting with hypopigmentation and reduced circulation amongst others. This shows that the zebrafish embryo provides a fast, sensitive and effective way to screen new compounds and in the future in combination with existing in vivo and in vitro assays it will become an integral part in drug discovery and development.

Total synthesis of kottamide E.

The first synthesis of kottamide E, a marine natural product containing a 5,6-dibromoindole linked via a (Z)-enamide to an unusual 1,2-dithiolane-containing amino acid, is reported.

Conformational Study of an Artificial Metal-Dependent Regulation Site for Use in Designer Proteins.

This report describes the dimerisation of glutathione, and by extension, other cysteine-containing peptides or protein fragments, with a 5, 5'-disubstituted-2, 2'-bipyridine or 6, 6"-disubstituted-2, 2':6',2"-terpyridine unit. The resulting bipy-GS2 and terpy-GS2 were investigated as potential metal ion dependent switches in aqueous solution, and were found to predominantly adopt the transoïd conformation at physiological pH. Metal complexation with CuII and ZnII at this pH has been studied by UV/Vis, CD, NMR and ion-mobility mass spectrometry. ZnII titrations are consistent with the formation of a 1:1 ZnII:terpy-GS2 complex at pH 7.4, but bipy-GS2 was shown to form both 1:1 and 1:2 complexes with the former being predominant under dilute micromolar conditions. Formation constants for the resulting 1:1 complexes were determined to be log KM 6.86 (bipy-GS2 ) and 6.22 (terpy-GS2 ), consistent with a higher affinity for the unconstrained bipyridine, compared to the strained terpyridine. CuII coordination involves the initial formation of 1:1 complexes, followed by 1.5Cu:1bipy-GS2 and 2Cu:1terpy-GS2 complexes at micromolar concentrations. Binding constants for formation of the 1:1 complexes (log KM 12.5 (bipy-GS2 ); 8.04 and 7.14 (terpy-GS2 )) indicate a higher affinity for CuII than ZnII. Finally, ion-mobility MS studies detected the free ligands in their protonated form, and were consistent with the formation of two different Cu adducts with different conformations in the gas-phase. We illustrate that the bipyridine and terpyridine dimerisation units can behave like conformational switches in response to Cu/Zn complexation, and propose that in future these can be employed in synthetic biology with larger peptide or protein fragments, to control large scale folding and related biological function.

Synthesis of the trans-hydrindane core of dictyoxetane.

A concise, stereoselective synthesis of the trans-hydrindane core of the marine natural product dictyoxetane is reported, starting from a Robinson annelation derived bicyclic enone. A phosphorane-mediated, pinacol-like rearrangement of a cis-diol, via a formal 1,2-hydride shift, is used to establish the requisite trans ring junction. (31)P NMR supports the formation of the intermediate phosphorane, generated in situ from the reaction of a diol with Ph(3)PCl(2).