A General Strategy for N-(Hetero)arylpiperidine Synthesis Using Zincke Imine Intermediates.

Methods to synthesize diverse collections of substituted piperidines are valuable due to the prevalence of this heterocycle in pharmaceutical compounds. Here, we present a general strategy to access N-(hetero)arylpiperidines using a pyridine ring-opening and ring-closing approach via Zincke imine intermediates. This process generates pyridinium salts from a wide variety of substituted pyridines and (heteroaryl)anilines; hydrogenation reactions and nucleophilic additions then access the N-(hetero)arylpiperidine derivatives. We successfully applied high-throughput experimentation (HTE) using pharmaceutically relevant pyridines and (heteroaryl)anilines as inputs and developed a one-pot process using anilines as nucleophiles in the pyridinium salt-forming processes. This strategy is viable for generating piperidine libraries and applications such as the convergent coupling of complex fragments.

Causal effects of point-of-sale cigarette promotions and subjective social status on cigarette craving: a randomised within-person experiment.

BACKGROUND: Cigarette smoking continues to be a leading cause of preventable deaths in the USA, in part because the USA has not adopted the WHO Framework Convention on Tobacco Control. One way the tobacco industry counteracts tobacco control policies is by heavily advertising cigarettes at the point of sale in retailers (eg, at the cash register) and by offering discounts on cigarettes. DESIGN: A within-subject experimental design with adults who smoke cigarettes daily (n=281) investigated whether: (1) exposure to images of cigarette promotions in an online experiment is associated with greater cigarette craving relative to viewing images of non-smoking cues, and (2) if exposure to images of point-of-sale cigarette promotions with a discount (vs without) increases cigarette craving. The study also examined how participants' subjective social status (compared with others in the USA) relates to cigarette craving after exposure to images of cigarette promotions with and without a discount. RESULTS: In an online experiment, exposure to images of smoking cues, including point-of-sale cigarette promotions, elicited greater craving relative to non-smoking cues (all p<0.001). In addition, images of promotions with a discount elicited higher levels of craving compared with those without a discount (b=0.09, p=0.001). Although participants with a higher (vs lower) subjective social status craved cigarettes less overall (b=-0.12, p=0.012), there was no difference in their craving between images of promotions with and without a discount, while craving was higher for images of promotions with a discount than without for participants with higher subjective social status (b=0.06, p=0.021). CONCLUSION: Viewing images of point-of-sale cigarette promotions can causally increase cravings to smoke, which may also apply to real-world retail settings that display cigarette promotions. Restricting point-of-sale promotions generally, and discounts specifically, could help reduce cigarette smoking and address tobacco use disparities in the USA.

Improved Real-Time Quaking Induced Conversion for Early Diagnostics of Creutzfeldt-Jakob Disease in Denmark.

Cerebrospinal fluid-based real-time quaking-induced conversion (CSF RT-QuIC) is currently the most prominent method for early detection of sporadic Creutzfeldt-Jakob disease (sCJD), the most common prion disease. CSF RT-QuIC delivers high sensitivity (>90%) and specificity (100%), which has been demonstrated by large ring-trial studies testing probable and definitive sCJD cohorts. Following the inclusion of CSF RT-QuIC in the revised European CJD Surveillance Network diagnostic criteria for sCJD, it has become a standard diagnostic procedure in many prion disease reference or surveillance centers around the world. In this study, we present the implementation of the second-generation CSF RT-QuIC (commonly known as Improved QuIC or IQ) at the Danish Reference Center for Prion Diseases (DRCPD). The method's sensitivity and specificity were evaluated and validated by analyzing 63 CSF samples. These 63 samples were also analyzed at the National CJD Research and Surveillance Unit (NCJDRSU), based at the University of Edinburgh, UK; analysis was carried out using the first generation or previous CSF RT-QuIC method (PQ). The sensitivity and specificity of PQ during tests at the NCJDRSU were 92% and 100%, respectively. Using these 63 CSF samples, the agreement between the two RT-QuIC generations at DRCPD and NCJDRSU prion laboratories was 100%.

Tailoring Reaction Selectivity by Modulating a Catalytic Diad on a Foldamer Scaffold.

Use of a tunable molecular scaffold to align a reactive diad for bifunctional catalysis can reveal relationships between functional group identity and reactivity that might otherwise be impossible to identify. Here we use an α/ß-peptide helix to show that an aligned pair of primary amine groups is uniquely competent to catalyze crossed aldol condensations with an aryl aldehyde as the electrophile. Geometrically similar diads in which one amine group is secondary, or both are secondary, are good catalysts for other types of aldol condensations but not those involving an aryl aldehyde. Catalytic efficacy requires ß-amino acid residues that are preorganized for helix formation via cyclic constraint. Conventional peptides (exclusively α-amino acid residues) that display the primary amine diad are poor catalysts, which highlights the critical role of the foldamer scaffold.

Concordance of cerebrospinal fluid real-time quaking-induced conversion across the European Creutzfeldt-Jakob Disease Surveillance Network.

BACKGROUND AND PURPOSE: Cerebrospinal fluid (CSF) real-time quaking-induced conversion (RT-QuIC) has a high degree of sensitivity and specificity for the diagnosis of sporadic Creutzfeldt-Jakob disease (sCJD) and this has led to its being included in revised European CJD Surveillance Network diagnostic criteria for sCJD. As CSF RT-QuIC becomes more widely established, it is crucial that the analytical performance of individual laboratories is consistent. The aim of this ring-trial was to ascertain the degree of concordance between European countries undertaking CSF RT-QuIC. METHODS: Ten identical CSF samples, seven from probable or neuropathologically confirmed sCJD and three from non-CJD cases, were sent to 13 laboratories from 11 countries for RT-QuIC analysis. A range of instrumentation and different recombinant prion protein substrates were used. Each laboratory analysed the CSF samples blinded to the diagnosis and reported the results as positive or negative. RESULTS: All 13 laboratories correctly identified five of the seven sCJD cases and the remaining two sCJD cases were identified by 92% of laboratories. Of the two sCJD cases that were not identified by all laboratories, one had a disease duration >26 months with a negative 14-3-3, whilst the remaining case had a 4-month disease duration and a positive 14-3-3. A single false positive CSF RT-QuIC result was observed in this study. CONCLUSIONS: This study shows that CSF RT-QuIC demonstrates an excellent concordance between centres, even when using a variety of instrumentation, recombinant prion protein substrates and CSF volumes. The adoption of CSF RT-QuIC by all CJD surveillance centres is recommended.

Adoption of Tobacco- and Smoke-Free Policies in a US National Sample of Postsecondary Educational Institutions.

OBJECTIVES: To examine the institutional characteristics associated with the adoption of tobacco- and smoke-free policies among US postsecondary educational institutions. METHODS: In 2017, we collected information on tobacco policy types and institutional characteristics of a national sample of US postsecondary educational institutions (n = 605) attended by the participants of the NEXT Generation Health Study. We used logistic regression to examine the relationships between these variables. RESULTS: Overall, 35.2% of these institutions adopted tobacco-free policies (i.e., prohibit all tobacco product use on campus), 10.1% had smoke-free policies (i.e., prohibit smoking but not other tobacco product use on campus), and 53.7% did not have tobacco- or smoke-free policies. Proprietary (privately owned, for-profit) institutions (vs public institutions) were the least likely to have tobacco- or smoke-free policies (P < .05), which were disproportionately attended by racial/ethnic minority students. Adoption of these policies also varied by census region (P < .05). CONCLUSIONS: Prevalence of tobacco- and smoke-free policies among US postsecondary educational institutions is low. Public Health Implications. Wide dissemination of evidence-based interventions to accelerate adoption of tobacco-free policies in all postsecondary educational institutions is warranted.

Physical Effects of Anabolic-androgenic Steroids in Healthy Exercising Adults: A Systematic Review and Meta-analysis.

Many athletes use anabolic-androgenic steroids (AAS) for physical enhancement but the magnitude of these gains and associated adverse effects has not been rigorously quantified. MEDLINE, EMBASE, Cochrane, SPORTDiscus, and PsycINFO were searched to identify randomized placebo-controlled trials of AAS in healthy exercising adults that reported one of the following outcomes: muscular strength, body composition, cardiovascular endurance, or power. Two authors appraised abstracts to identify studies for full-text retrieval; these were reviewed in duplicate to identify included studies. Study quality was assessed using the Cochrane method. Data were extracted in duplicate and pooled using the DerSimonian and Laird random effects model and to calculate the ratio of mean outcome improvement where possible. Pooled standardized mean difference (SMD) in muscle strength between AAS and placebo was 0.27 (95% confidence interval, 0.07-0.47; I = 12.7%; 21 studies). Change in strength was 52% greater in the AAS group compared to placebo. The SMD for change in lean mass between AAS and placebo was 0.62 (95% confidence interval, 0.35-0.89; I = 26%; 14 studies). Due to missing data, fat mass, cardiovascular endurance, power, and adverse effects were summarized qualitatively. Only 13 of 25 studies reported adverse effects including increased low density lipoprotein (LDL), decreased high density lipoprotein (HDL), irritability, and acne. In healthy exercising adults, AAS use is associated with a small absolute increase in muscle strength and moderate increase in lean mass. However, the transparency and completeness of adverse effect reporting varied, most studies were of short duration, and doses studied may not reflect actual use by athletes.

Nurses who work in rural and remote communities in Canada: a national survey.

BACKGROUND: In Canada, as in other parts of the world, there is geographic maldistribution of the nursing workforce, and insufficient attention is paid to the strengths and needs of those providing care in rural and remote settings. In order to inform workforce planning, a national study, Nursing Practice in Rural and Remote Canada II, was conducted with the rural and remote regulated nursing workforce (registered nurses, nurse practitioners, licensed or registered practical nurses, and registered psychiatric nurses) with the intent of informing policy and planning about improving nursing services and access to care. In this article, the study methods are described along with an examination of the characteristics of the rural and remote nursing workforce with a focus on important variations among nurse types and regions. METHODS: A cross-sectional survey used a mailed questionnaire with persistent follow-up to achieve a stratified systematic sample of 3822 regulated nurses from all provinces and territories, living outside of the commuting zones of large urban centers and in the north of Canada. RESULTS: Rural workforce characteristics reported here suggest the persistence of key characteristics noted in a previous Canada-wide survey of rural registered nurses (2001-2002), namely the aging of the rural nursing workforce, the growth in baccalaureate education for registered nurses, and increasing casualization. Two thirds of the nurses grew up in a community of under 10 000 people. While nurses' levels of satisfaction with their nursing practice and community are generally high, significant variations were noted by nurse type. Nurses reported coming to rural communities to work for reasons of location, interest in the practice setting, and income, and staying for similar reasons. Important variations were noted by nurse type and region. CONCLUSIONS: The proportion of the rural nursing workforce in Canada is continuing to decline in relation to the proportion of the Canadian population in rural and remote settings. Survey results about the characteristics and practice of the various types of nurses can support workforce planning to improve nursing services and access to care.

Asymptomatic Malaria and Other Infections in Children Adopted from Ethiopia, United States, 2006-2011.

We screened 52 children adopted from Ethiopia for malaria because they had previously lived in a disease-endemic region or had past or current hepatomegaly or splenomegaly. Seven (13.5%) children had asymptomatic malaria parasitemia by microscopy (n = 2) or PCR (n = 5). Our findings suggest that adoptees at risk for asymptomatic malaria should be screened, preferably by PCR.

Dietary factors and luteal phase deficiency in healthy eumenorrheic women.

STUDY QUESTION: Are prospectively assessed dietary factors, including overall diet quality, macronutrients and micronutrients, associated with luteal phase deficiency (LPD) in healthy reproductive aged women with regular menstrual cycles? SUMMARY ANSWER: Mediterranean Diet Score (MDS), fiber and isoflavone intake were positively associated with LPD while selenium was negatively associated with LPD after adjusting for age, percentage body fat and total energy intake. WHAT IS KNOWN ALREADY: LPD may increase the risk of infertility and early miscarriage. Prior research has shown positive associations between LPD and low energy availability, either through high dietary restraint alone or in conjunction with high energy expenditure via exercise, but few studies with adequate sample sizes have been conducted investigating dietary factors and LPD among healthy, eumenorrheic women. STUDY DESIGN, SIZE, DURATION: The BioCycle Study (2005-2007) prospectively enrolled 259 women from Western New York state, USA, and followed them for one (n = 9) or two (n = 250) menstrual cycles. PARTICIPANTS/MATERIALS, SETTING, METHODS: Women aged 18-44 years, with self-reported BMI between 18 and 35 kg/m(2) and cycle lengths between 21 and 35 days, were included in the study. Participants completed baseline questionnaires, four 24-h dietary recalls per cycle and daily diaries capturing vigorous exercise, perceived stress and sleep; they also provided up to eight fasting serum samples during clinic visits timed to specific phases of the menstrual cycle using a fertility monitor. Cycles were included for this analysis if the peak serum luteal progesterone was >1 ng/ml and a urine or serum LH surge was detected. Associations between prospectively assessed diet quality, macronutrients and micronutrients and LPD (defined as luteal duration <10 days) were evaluated using generalized linear models adjusting for age, percentage body fat and total energy intake. MAIN RESULTS AND THE ROLE OF CHANCE: LPD occurred in 41 (8.9%) of the 463 cycles from 246 women in the final analysis. After adjusting for age, percentage body fat and total energy intake, LPD was positively associated with MDS, adjusted odds ratio (aOR): 1.70 (95% confidence interval [CI]: 1.17, 2.48), P = 0.01. In separate macro- and micronutrient adjusted models, increased fiber and isoflavone intake showed modest positive associations with LPD: fiber (per g), aOR: 1.10 (95% CI: 0.99, 1.23), P = 0.07; and isoflavones (per 10 mg), aOR: 1.38 (95% CI: 0.99, 1.92), P = 0.06. In contrast, selenium (per 10 mcg) was inversely associated with LPD, aOR: 0.80 (95% CI: 0.65, 0.97), P = 0.03. Additional adjustments for relevant lifestyle factors including vigorous exercise, perceived stress and sleep did not appreciably alter estimates. LIMITATIONS, REASONS FOR CAUTION: The number of LPD cycles was limited, and thus these findings are exploratory. We relied on participant self-report of their medical history to apply exclusion criteria; it is possible that we admitted to the study women with a gynecologic or medical disease who were unaware of their diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our study suggests that diet quality may be associated with LPD among healthy eumenorrheic women. As LPD may contribute to infertility and early miscarriage, further research is warranted to elucidate how dietary factors, such as MDS, may influence LPD. The inverse association we found with selenium is supported by previous research and deserves further investigation to determine whether this finding has pathophysiologic and therapeutic implications. STUDY FUNDING/COMPETING INTERESTS: This work was supported by the Intramural Research Program, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health. No competing interests declared.

Characterisation of RT-QuIC negative cases from the UK National CJD Research and Surveillance programme.

INTRODUCTION: Incorporation of the real-time quaking-induced conversion (RT-QuIC) assays for diagnosis of sporadic Creutzfeldt-Jakob disease (CJD) has transformed diagnosis largely related to its extremely high specificity. However, the test has a c.10% false-negative result and we aim to characterize the clinical features, investigation profile, and molecular subtype in this cohort of patients. METHODS: 250 individuals diagnosed with definite sporadic CJD were identified from the UK National CJD Research and Surveillance Unit from 2012 to 2023. We compared the clinical features and investigation profile in those with a negative CSF RT-QuIC to those with a positive RT-QuIC. RESULTS: 27 individuals (10.8%) were CSF RT-QuIC negative. Median age of onset was younger (62 years vs 68 years, p = 0.002), median disease duration was longer (4.4 months vs 10.5 months, p < 0.001), and these individuals were less likely to present with gait difficulties (73% vs 93%, p = 0.003) or motor symptoms (62% vs 80%, p = 0.04). The sensitivity of electroencephalography and diffusion-weighted MRI were similar in both groups. In those who were RT-QuIC negative, there was an overrepresentation of the VV1 (32% vs 1%) and MM2 molecular subtypes (21% vs 3%). Co-occurring neurodegenerative disease was found in 33% (9/27) of those who were RT-QuIC negative. CONCLUSIONS: Individuals with sporadic CJD and a negative CSF RT-QuIC present with younger age of onset, different clinical features and are over-represented with the VV1 and MM2 subtypes of sporadic CJD. Further work is required to better understand the biochemical properties contributing to RT-QuIC negative results in these cases.

Contingent interactions among biofilm-forming bacteria determine preservation or decay in the first steps toward fossilization of marine embryos.

Fossils of soft tissues provide important records of early animals and embryos, and there is substantial evidence for a role for microbes in soft tissue fossilization. We are investigating the initial events in interactions of bacteria with freshly dead tissue, using marine embryos as a model system. We previously found that microbial invasion can stabilize embryo tissue that would otherwise disintegrate in hours or days by generating a bacterial pseudomorph, a three dimensional biofilm that both replaces the tissue and replicates its morphology. In this study, we sampled seawater at different times and places near Sydney, Australia, and determined the range and frequency of different taphonomic outcomes. Although destruction was most common, bacteria in 35% of seawater samples yielded morphology­preserving biofilms. We could replicate the taphonomic pathways seen with seawater bacterial communities using single cultured strains of marine gammaproteobacteria. Each given species reproducibly generated a consistent taphonomic outcome and we identified species that yielded each of the distinct pathways produced by seawater bacterial communities. Once formed,bacterial pseudomorphs are stable for over a year and resist attack by other bacteria and destruction by proteases and other lytic enzymes. Competition studies showed that the initial action of a pseudomorphing strain can be blocked by a strain that destroys tissues. Thus embryo preservation in nature may depend on contingent interactions among bacterial species that determine if pseudomorphing occurs.We used Artemia nauplius larvae to show that bacterial biofilm replacement of tissue is not restricted to embryos, but is relevant for preservation of small multicellular organisms. We present a model for bacterial self­assembly of large­scale three­dimensional tissue pseudomorphs, based on smallscaleinteractions among individual bacterial cells to form local biofilms at structural boundaries within the tissue. Localbiofilms then conjoin to generate the pseudomorph.

Real time quaking-induced conversion analysis of cerebrospinal fluid in sporadic Creutzfeldt-Jakob disease.

OBJECTIVE: Current cerebrospinal fluid (CSF) tests for sporadic Creutzfeldt-Jakob disease (sCJD) are based on the detection of surrogate markers of neuronal damage such as CSF 14-3-3, which are not specific for sCJD. A number of prion protein conversion assays have been developed, including real time quaking-induced conversion (RT-QuIC). The objective of this study is to investigate whether CSF RT-QuIC analysis could be used as a diagnostic test in sCJD. METHODS: An exploratory study was undertaken that analyzed 108 CSF samples from patients with neuropathologically confirmed sCJD or from control patients. Of the 108 CSF samples, 56 were from sCJD patients (30 female, 26 male; aged 31-84 years; mean age, 62.3 ± 13.5 years), and 52 were from control patients (26 female, 26 male; aged 43-84 years; mean age, 67.8 ± 10.4 years). A confirmatory group of 118 patients was subsequently examined that consisted of 67 cases of neuropathologically confirmed sCJD (33 female, 34 male; aged 39-82 years; mean age, 67.5 ± 9.0 years) and 51 control cases (26 female, 25 male; aged 36-87 years; mean age, 63.5 ± 11.6 years). RESULTS: The exploratory study showed that RT-QuIC analysis had a sensitivity of 91% and a specificity of 98% for the diagnosis of sCJD. These results were confirmed in the confirmatory study, which showed that CSF RT-QuIC analysis had a sensitivity and specificity of 87% and 100%, respectively. INTERPRETATION: This study shows that CSF RT-QuIC analysis has the potential to be a more specific diagnostic test for sCJD than current CSF tests.

Delirium and cerebrospinal fluid S100B in hip fracture patients: a preliminary study.

OBJECTIVES: Delirium is associated with an increased risk of long-term cognitive decline, suggesting the possibility of concurrent central nervous system (CNS) injury. S100B is a putative biomarker of CNS injury and elevated serum levels in delirium have been reported. Here we hypothesize that delirium is associated with raised concentrations of cerebrospinal fluid (CSF) S100B. METHODS: Forty-five patients with hip fracture aged over 60 and awaiting surgery under spinal anesthesia were assessed for delirium pre- and post-operatively. CSF S100B levels were measured in samples collected at the onset of surgery. RESULTS: Participants with pre-operative delirium (N = 8) had elevated Log10 CSF S100B (mean: -0.156; SD: 0.238) compared with those without delirium (mean: -0.306; SD: 0.162), Student's t-test t = 2.18, df = 43, p = 0.035. CONCLUSIONS: This study provides preliminary evidence of elevated CSF S100B in current delirium, consistent with findings in serum and with other studies showing elevated S100B in the presence of diverse forms of CNS injury.

Surveying the Middle Ground: A Thematic Analysis of the Medical School Applications of Standard Performers.

INTRODUCTION: As gatekeepers to the medical profession, admissions committees make important decisions through the analysis of quantitative (e.g. test scores and grade point averages) and qualitative (e.g. letters of recommendation and personal statements) data. One area of the application that deserves additional study is the Work and Activities section, where students describe their extracurricular experiences. Previous research has found different themes that sometimes overlap in the applications of exceptional performing and low performing medical students, but it is unclear if these themes are present in the applications of standard performers. MATERIALS AND METHODS: An exceptional performing medical student is defined as one who was inducted into both the Alpha Omega Alpha Honor Medical Society and the Gold Humanism Honor Society. A low performing medical student is one who was referred to the Student Promotions Committee (SPC) where an administrative action was made. A standard performing medical student is defined as someone who was neither a member of an honor society nor referred to the SPC during medical school. Using a constant comparative method, the applications of standard performers who graduated from the Uniformed Services University between 2017 and 2019 was assessed using exceptional performer themes (success in a practiced activity, altruism, teamwork, entrepreneurship, wisdom, passion, and perseverance) and low performer themes (witnessing teamwork, embellishment of achievement, and description of a future event). The presence of novel themes was also assessed. The absolute number of themes and the diversity of themes were determined. Demographic data were collected (age, gender, number of Medical School Admissions Test [MCAT] attempts, highest MCAT score, and cumulative undergraduate grade point average), and descriptive statistics was performed. RESULTS: A total of 327 standard performers were identified between 2017 and 2019. No novel themes were found after coding 20 applications. All exceptional performer themes were identified in the population of standard performers. The low performing theme of embellishment of achievement was not found. Standard performers had a lower number of total exceptional performer themes and a lower diversity of exceptional performer themes compared to low and exceptional performers, but standard performers also had a lower number and less diversity of low performing themes compared to low performers. CONCLUSIONS: This study suggests that the diversity and frequency of exceptional performing themes in a medical school application may be useful in distinguishing between exceptional performers and other performers, though the small sample size limits quantitative conclusions. Low performing themes may be specific to low performers and thus could be useful to admissions committees. Future studies should include a larger sample size and could assess for predictive validity evidence of these exceptional performing and low performing themes through a blinded protocol.