A preparative small-molecule mimic of liver CYP450 enzymes in the aliphatic C-H oxidation of carbocyclic N-heterocycles.

An emerging trend in small-molecule pharmaceuticals, generally composed of nitrogen heterocycles (N-heterocycles), is the incorporation of aliphatic fragments. Derivatization of the aliphatic fragments to improve drug properties or identify metabolites often requires lengthy de novo syntheses. Cytochrome P450 (CYP450) enzymes are capable of direct site- and chemo-selective oxidation of a broad range of substrates but are not preparative. A chemoinformatic analysis underscored limited structural diversity of N-heterocyclic substrates oxidized using chemical methods relative to pharmaceutical chemical space. Here, we describe a preparative chemical method for direct aliphatic oxidation that tolerates a wide range of nitrogen functionality (chemoselective) and matches the site of oxidation (site-selective) of liver CYP450 enzymes. Commercial small-molecule catalyst Mn(CF3-PDP) selectively effects direct methylene oxidation in compounds bearing 25 distinct heterocycles including 14 out of 27 of the most frequent N-heterocycles found in U.S. Food and Drug Administration (FDA)-approved drugs. Mn(CF3-PDP) oxidations of carbocyclic bioisostere drug candidates (for example, HCV NS5B and COX-2 inhibitors including valdecoxib and celecoxib derivatives) and precursors of antipsychotic drugs blonanserin, buspirone, and tiospirone and the fungicide penconazole are demonstrated to match the major site of aliphatic metabolism obtained with liver microsomes. Oxidations are demonstrated at low Mn(CF3-PDP) loadings (2.5 to 5 mol%) on gram scales of substrate to furnish preparative amounts of oxidized products. A chemoinformatic analysis supports that Mn(CF3-PDP) significantly expands the pharmaceutical chemical space accessible to small-molecule C-H oxidation catalysis.

Fungal abscess of the parotid gland - the value of microbiological assessment.

SUMMARY: Fungal parotitis is rare and the sequela parotid abscess exceedingly so. We report our experience with Candida glabrata and Candida albicans parotid gland abscesses in critically ill HIV-positive patients and highlight the value of microbiological assessment to tailor management.

Exploring views of members of the public and policymakers on the acceptability of population level dietary and active-travel policies: a qualitative study.

BACKGROUND: There is limited evidence on what shapes the acceptability of population level dietary and active-travel policies in England. This information would be useful in the decision-making process about which policies should be implemented and how to increase their effectiveness and sustainability. To fill this gap, we explored public and policymakers' views about factors that influence public acceptability of dietary and active-travel policies and how to increase public acceptability for these policies. METHODS: We conducted online, semi-structured interviews with 20 members of the public and 20 policymakers in England. A purposive sampling frame was used to recruit members of the public via a recruitment agency, based on age, sex, socioeconomic status and ethnicity. Policymakers were recruited from existing contacts within our research collaborations and via snowball sampling. We explored different dietary and active-travel policies that varied in their scope and focus. Interviews were transcribed verbatim and analysed using thematic reflexive analysis with both inductive and deductive coding. RESULTS: We identified four themes that informed public acceptability of dietary and active-travel policies: (1) perceived policy effectiveness, i.e., policies that included believable mechanisms of action, addressed valued co-benefits and barriers to engage in the behaviour; (2) perceived policy fairness, i.e., policies that provided everyone with an opportunity to benefit (mentioned only by the public), equally considered the needs of various population subgroups and rewarded 'healthy' behaviours rather than only penalising 'unhealthy' behaviours; (3) communication of policies, i.e., policies that were visible and had consistent and positive messages from the media (mentioned only by policymakers) and (4) how to improve policy support, with the main suggestion being an integrated strategy addressing multiple aspects of these behaviours, inclusive policies that consider everyone's needs and use of appropriate channels and messages in policy communication. CONCLUSIONS: Our findings highlight that members' of the public and policymakers' support for dietary and active-travel policies can be shaped by the perceived effectiveness, fairness and communication of policies and provide suggestions on how to improve policy support. This information can inform the design of acceptable policies but can also be used to help communicate existing and future policies to maximise their adoption and sustainability.

The association of new-onset diabetes with subsequent diagnosis of pancreatic cancer-novel use of a large administrative database.

BACKGROUND: Screening options for pancreatic ductal adenocarcinoma (PDAC) are limited. New-onset type 2 diabetes (NoD) is associated with subsequent diagnosis of PDAC in observational studies and may afford an opportunity for PDAC screening. We evaluated this association using a large administrative database. METHODS: Patients were identified using claims data from the OptumLabs® Data Warehouse. Adult patients with NoD diagnosis were matched 1:3 with patients without NoD using age, sex and chronic obstructive pulmonary disease (COPD) status. The event of PDAC diagnosis was compared between cohorts using the Kaplan-Meier method. Factors associated with PDAC diagnosis were evaluated with Cox's proportional hazards modeling. RESULTS: We identified 640 421 patients with NoD and included 1 921 263 controls. At 3 years, significantly more PDAC events were identified in the NoD group vs control group (579 vs 505; P < 0.001). When controlling for patient factors, NoD was significantly associated with elevated risk of PDAC (HR 3.474, 95% CI 3.082-3.920, P < 0.001). Other factors significantly associated with PDAC diagnosis were increasing age, increasing age among Black patients, and COPD diagnosis (P ≤ 0.05). CONCLUSIONS: NoD was independently associated with subsequent diagnosis of PDAC within 3 years. Future studies should evaluate the feasibility and benefit of PDAC screening in patients with NoD.

Making integration foundational in population health intervention research: why we need 'Work Package Zero'.

OBJECTIVES: We aimed to identify when and how integration should take place within evaluations of complex population health interventions (PHIs). STUDY DESIGN: Descriptive analytical approach. METHODS: We draw on conceptual insights that emerged through (1) a working group on integration and (2) a diverse range of literature on case studies, small-n evaluations and mixed methods evaluation studies. RESULTS: We initially sought techniques to integrate analyses at the end of a complex PHI evaluation. However, this conceptualization of integration proved limiting. Instead, we found value in conceptualizing integration as a process that commences at the beginning of an evaluation and continues throughout. Many methods can be used for this type of integration, including process tracing, realist evaluation, congruence analysis, general elimination methodology/modus operandi, pattern matching and contribution analysis. Clearly signposting when integrative methods should commence within an evaluation should be of value to the PHI evaluation community, as well as to funders and related stakeholders. CONCLUSIONS: Rather than being a tool used at the end of an evaluation, we propose that integration is more usefully conceived as a process that commences at the start of an evaluation and continues throughout. To emphasize the importance of this timing, integration can be described as comprising 'Work Package Zero' within evaluations of complex PHIs.

Food-related parenting practices and styles in households with sibling children: A scoping review.

Interventions that promote responsive feeding in early childhood have been shown to reduce obesity risks. However, interventions mostly target parent-child dyads without considering the complexities of implementing responsive feeding across multiple children within a family unit. This scoping review aims to assess the extent and nature of current literature examining feeding in the context of siblings. Six electronic databases were searched (APA PsycINFO, CINAHL, Embase, Medline, ProQuest Dissertations & Theses Global, and Scopus) for articles published up until November 25, 2021. Studies were included if they compared the use of parent feeding practices and/or styles for two or more siblings aged ≤18 years. Data were extracted from relevant studies and analysed using basic descriptive statistics. A total of 18 studies from North America (n = 12) and Europe (n = 6) were included, with the majority targeting children between 6 and 18 years of age (n = 12). All studies were cross-sectional, with most designed to test differences in parent-reported feeding practices for siblings, primarily restriction and/or pressure to eat, in relation to differences in their characteristics (n = 12). The studies provide some evidence that parents may modify certain feeding practices or styles for siblings in response to differences in their characteristics, such as weight status and eating behaviours. Future research should examine processes that underlie feeding decisions in the context of siblings, including the contexts and consequences of differential feeding, with particular focus on early childhood when feeding interventions may be most effective.

Allylic C-H amination cross-coupling furnishes tertiary amines by electrophilic metal catalysis.

Intermolecular cross-coupling of terminal olefins with secondary amines to form complex tertiary amines-a common motif in pharmaceuticals-remains a major challenge in chemical synthesis. Basic amine nucleophiles in nondirected, electrophilic metal-catalyzed aminations tend to bind to and thereby inhibit metal catalysts. We reasoned that an autoregulatory mechanism coupling the release of amine nucleophiles with catalyst turnover could enable functionalization without inhibiting metal-mediated heterolytic carbon-hydrogen cleavage. Here, we report a palladium(II)-catalyzed allylic carbon-hydrogen amination cross-coupling using this strategy, featuring 48 cyclic and acyclic secondary amines (10 pharmaceutically relevant cores) and 34 terminal olefins (bearing electrophilic functionality) to furnish 81 tertiary allylic amines, including 12 drug compounds and 10 complex drug derivatives, with excellent regio- and stereoselectivity (>20:1 linear:branched, >20:1 E:Z).

Extraocular Muscle Enlargement in Growth Hormone-Secreting Pituitary Adenomas.

BACKGROUND AND PURPOSE: While Graves disease is the most common cause of extraocular muscle enlargement, case reports have also associated growth hormone-secretory pituitary adenomas with this same phenomenon. We investigated the prevalence and response to treatment of extraocular muscle enlargement in patients with growth hormone-secretory pituitary adenomas. MATERIALS AND METHODS: We retrospectively reviewed extraocular muscle sizes using MR imaging in patients with growth hormone-secretory pituitary adenomas who underwent a transsphenoidal surgical resection compared with a matched control group with nonsecretory pituitary adenomas. Descriptive and comparative statistics were used to evaluate patient characteristics and extraocular muscle sizes between the 2 groups. RESULTS: We identified 16 patients who presented with growth hormone-secreting pituitary adenomas and underwent transsphenoidal surgical resection from 2010 to 2019. The average diameter of the extraocular muscle at the time of diagnosis for the group with growth hormone-secretory pituitary adenomas was larger than that in the control group (4.7 versus 3.8 mm, P < .001). Nine patients achieved insulin-like growth factor 1 level normalization at a median of 11.5 months before their most recent MR imaging evaluation. The average size of the extraocular muscles of patients who achieved a normalized insulin-like growth factor 1 was smaller compared with those that did not (difference, 0.7 mm; 95% CI, 0.3-1.2 mm; P < .001), approaching the size of extraocular muscle in the control group. CONCLUSIONS: We describe a high prevalence of extraocular muscle enlargement in patients with growth hormone-secreting pituitary adenomas. Additionally, we note that the size of extraocular muscles decreased with associated improvement in the biochemical control of acromegaly.

Use of cytology for canine mammary masses and perceived diagnostic utility in four European countries.

OBJECTIVES: To investigate the use of cytology of canine mammary masses and its perceived diagnostic utility in four European countries. MATERIALS AND METHODS: The link to a web-based questionnaire was sent to veterinarians of Italy, UK, Greece and Spain. The questionnaire contained basic questions regarding the respondents' background, their general use of cytology as a diagnostic tool, the incidence of canine mammary tumours within their clinics and their use of cytology for canine mammary masses. Multiple binary and ordinal logistics models were used to evaluate associations between variables. RESULTS: Four hundred and sixty-five veterinarians completed the survey (Italy: 114; UK: 66; Greece: 55; Spain: 230). Most veterinarians working in each country used cytology as a diagnostic tool, although only 43.0%, 54.6%, 43.6% and 36.5% used cytology for the investigation of CMMs in Italy, UK, Greece and Spain respectively. Supposing the cytology were able to correctly differentiate benign versus malignant canine mammary masses, the percentage of veterinarians using this test would increase in Italy, UK and Greece (Italy: 91.2%; UK: 93.9%; Greece: 96.4%); however, this was not reflected by veterinarians working in Spain (51.7%). CLINICAL SIGNIFICANCE: If cytology of canine mammary masses were able to differentiate between benign and malignant, most veterinarians in Italy, UK and Greece would utilise the technique, justifying further research into the diagnostic accuracy of this test. Spanish veterinarians were significantly different and further research into why these individuals would not value the ability of cytology to differentiate between benign and malignant may be of value.

Fate of thiamethoxam from treated seeds in mesocosms and response of aquatic invertebrate communities.

Thiamethoxam is a neonicotinoid insecticide widely applied in the Canadian Prairies. It has been detected in surface waters of agro-ecosystems, including wetlands, but the potential effects on non-target invertebrate communities in these wetlands have not been well characterized. In an effort to understand better the fate of thiamethoxam in wetlands and the response of invertebrates (zooplankton and emergent insects), model systems were used to mimic wetland flooding into planted fields. Outdoor mesocosms were treated with a single application of thiamethoxam-treated canola seeds at three treatment levels based on a recommended seeding rate (i.e., 6 kg/ha; 1×, 10×, and 100× seeding rate) and monitored over ten weeks. The mean half-life of thiamethoxam in the water column was 6.2 d. There was no ecologically meaningful impact on zooplankton abundances or community structure among treatments. Statistically significant differences were observed in aquatic insect abundance between control mesocosms and the two greatest thiamethoxam treatments (10× and 100× seeding rate). The observed results indicate exposure to thiamethoxam at environmentally relevant concentrations likely does not represent a significant ecological risk to abundance and community structure of wetland zooplankton and emergent insects.

Salty water and salty leaf litter alters riparian detrital processes: Evidence from sodium-addition laboratory mesocosm experiments.

Terrestrial and freshwater secondary salinization is a global phenomenon arising partially from anthropogenic activities. How low-level direct (e.g., sodium exposure through irrigation runoff) or indirect (e.g., sodium exposure through sodium-enriched leaves as riparian plants uptake sodium that via senescence enters detrital systems) impacts detrital processes in riparia have received little attention. Based on the sodium ecosystem respiration hypothesis, we predicted low-level salinization of an inland mesic riparia would result in increased detrital processing and increased leachate dissolved organic carbon (DOC) and conductivity. Two riparian soil mesocosm experiments tested how low-level salinization affects leachate chemistry and conductivity and riparian decomposition rates and detritivore community structure: 1) direct low-level NaCl deposition in water (weekly additions of 300 ml of 0.05% NaCl or just H2O (controls)), and 2) indirect low-level NaCl deposition through Na-enriched artificial litter (0.05% NaCl or just H2O (controls)). After three months, leachate Na+ concentrations were 12-fold and 1.5-fold higher in Na-addition than control mesocosms for direct and indirect Na-addition experiments, respectively. Contrary to predictions, decomposition rate was 1.3-fold lower in indirect Na-addition than control mesocosms but invertebrate communities were similar. Decomposition rate did not differ in direct Na-addition experiments, and although invertebrate abundance was lower, diversity was 1.4-fold higher in Na-addition than control mesocosms. Leachate DOC did not differ between Na-addition and control mesocosms for either direct or indirect Na-addition experiments. This study adds to the growing evidence that even low-level Na addition can stress inland mesic terrestrial systems and demonstrates that even Na-enriched detritus alone can induce salt-stress in riparian soil systems. These results suggest that even low-level salinization of riparia can impact riparian ecosystem function and leachate chemistry through direct exposure and indirectly through Na-enriched detritus, a previously overlooked pathway.

Generalized Electrical Substitution Methods and Detectors for Absolute Optical Power Measurements.

We have developed generalized methods for electrical substitution optical measurements, as well as cryogenic detectors which can be used to implement them. The new methods detailed here enable measurement of arbitrary periodic waveforms by an electrical substitution radiometer (ESR), which means that spectral and dynamic optical power can be absolutely calibrated directly by a primary standard detector. Cryogenic ESRs are not often used directly by researchers for optical calibrations due to their slow response times and cumbersome operation. We describe two types of ESRs with fast response times, including newly developed cryogenic bolometers with carbon nanotube absorbers, which are manufacturable by standard microfabrication techniques. These detectors have response times near 10 ms, spectral coverage from the ultraviolet to far-infrared, and are ideal for use with generalized electrical substitution. In our first tests of the generalized electrical substitution method with FTS, we have achieved uncertainty in detector response of 0.13 % (k=1) and total measurement uncertainty of 1.1 % (k=1) in the mid-infrared for spectral detector responsivity calibrations. The generalized method and fast detectors greatly expand the range of optical power calibrations which can be made using a wideband primary standard detector, which can shorten calibration chains and improve uncertainties.

Substantial oxygen consumption by aerobic nitrite oxidation in oceanic oxygen minimum zones.

Oceanic oxygen minimum zones (OMZs) are globally significant sites of biogeochemical cycling where microorganisms deplete dissolved oxygen (DO) to concentrations <20 µM. Amid intense competition for DO in these metabolically challenging environments, aerobic nitrite oxidation may consume significant amounts of DO and help maintain low DO concentrations, but this remains unquantified. Using parallel measurements of oxygen consumption rates and 15N-nitrite oxidation rates applied to both water column profiles and oxygen manipulation experiments, we show that the contribution of nitrite oxidation to overall DO consumption systematically increases as DO declines below 2 µM. Nitrite oxidation can account for all DO consumption only under DO concentrations <393 nM found in and below the secondary chlorophyll maximum. These patterns are consistent across sampling stations and experiments, reflecting coupling between nitrate reduction and nitrite-oxidizing Nitrospina with high oxygen affinity (based on isotopic and omic data). Collectively our results demonstrate that nitrite oxidation plays a pivotal role in the maintenance and biogeochemical dynamics of OMZs.

Late-Stage Intermolecular Allylic C-H Amination.

Allylic amination enables late-stage functionalization of natural products where allylic C-H bonds are abundant and introduction of nitrogen may alter biological profiles. Despite advances, intermolecular allylic amination remains a challenging problem due to reactivity and selectivity issues that often mandate excess substrate, furnish product mixtures, and render important classes of olefins (for example, functionalized cyclic) not viable substrates. Here we report that a sustainable manganese perchlorophthalocyanine catalyst, [MnIII(ClPc)], achieves selective, preparative intermolecular allylic C-H amination of 32 cyclic and linear compounds, including ones housing basic amines and competing sites for allylic, ethereal, and benzylic amination. Mechanistic studies support that the high selectivity of [MnIII(ClPc)] may be attributed to its electrophilic, bulky nature and stepwise amination mechanism. Late-stage amination is demonstrated on five distinct classes of natural products, generally with >20:1 site-, regio-, and diastereoselectivity.

Surface oil is the primary driver of macroinvertebrate impacts following spills of diluted bitumen in freshwater.

The response of freshwater invertebrates following accidental releases of oil is not well understood. This knowledge gap is more substantial for unconventional oils such as diluted bitumen (dilbit). We evaluated the effects of dilbit on insect emergence and benthic invertebrates by conducting experimental spills in limnocorrals (10-m diameter; ~100-m3) deployed in a boreal lake at the IISD-Experimental Lakes Area, Canada. The study included seven dilbit treatments (spill volumes ranged from 1.5 L [1:66,000, oil:water, v/v] to 180 L [1:590, oil:water, v/v]), two controls, and additional lake reference sites, monitored for 11 weeks. Invertebrate emergence declined at the community level following oil addition in a significantly volume-dependent manner, and by 93-100 % over the 11 weeks following the spill in the highest treatment. Dilbit altered community structure of benthic invertebrates, but not abundance. One-year post-spill and following oil removal using traditional skimming and absorption techniques, benthic richness and abundance were greater among all treatments than the previous year. These results indicate that recovery in community composition is possible following oil removal from a lake ecosystem. Research is needed concerning the mechanisms by which surface oil directly affect adult invertebrates, whether through limiting oviposition, limiting emergence, or both. The response of benthic communities to sediment tar mats is also warranted.

Two Consecutive Invasive Surgeries Utilizing Zymogen Protein C (ZPC) That Enhanced Patient Safety and Reduced Costs.

This case report describes a major surgical procedure for a protein C-deficient, hypercoagulable patient who underwent two back-to-back invasive surgeries, hip replacement, and spinal stenosis correction. The patient, an 84-year-old male with a history of deep vein thromboses (DVT) and pulmonary emboli (PE), was treated pre-, peri-, and postoperatively with zymogen protein C (ZPC-Baxter, International) and recovered without clotting or increased bleeding. During the procedure, the patient was not administered any other anticoagulants. There have now been several case reports on different patients with unrelated teams in various locations worldwide using zymogen protein C during surgical procedures. Thus, this procedure is becoming a viable choice for patients with a high probability of clotting during and after invasive surgery. This case focuses on accomplishing safer surgery and reducing costs, by using less ZPC while accomplishing two surgeries in one procedure. As a result, this procedure might be useful for many medical situations where acquired protein C deficiency could be a problem (e.g., sepsis, pregnancy, etc.). This approach may have greater application to medical conditions other than protein C deficiency, where clotting and inflammation can become issues.

Room temperature laser power standard using a microfabricated, electrical substitution bolometer.

The design and performance of a room temperature electrical substitution radiometer for use as an absolute standard for measuring continuous-wave laser power over a wide range of wavelengths, beam diameters, and powers are described. The standard achieves an accuracy of 0.46% (k = 2) for powers from 10 mW to 100 mW and 0.83% (k = 2) for powers from 1 mW to 10 mW and can accommodate laser beam diameters (1/e2) up to 11 mm and wavelengths from 300 nm to 2 µm. At low power levels, the uncertainty is dominated by sensitivity to fluctuations in the thermal environment. The core of the instrument is a planar, silicon microfabricated bolometer with vertically aligned carbon nanotube absorbers, commercial surface mount thermistors, and an integrated heater. Where possible, commercial electronics and components were used. The performance was validated by comparing it to a National Institute of Standards and Technology primary standard through a transfer standard silicon trap detector and by comparing it to the legacy "C-series" standards in operation at the U.S. Air Force Metrology and Calibration Division (AFMETCAL).