Gut bacteria convert glucocorticoids into progestins in the presence of hydrogen gas.

Recent studies suggest that human-associated bacteria interact with host-produced steroids, but the mechanisms and physiological impact of such interactions remain unclear. Here, we show that the human gut bacteria Gordonibacter pamelaeae and Eggerthella lenta convert abundant biliary corticoids into progestins through 21-dehydroxylation, thereby transforming a class of immuno- and metabo-regulatory steroids into a class of sex hormones and neurosteroids. Using comparative genomics, homologous expression, and heterologous expression, we identify a bacterial gene cluster that performs 21-dehydroxylation. We also uncover an unexpected role for hydrogen gas production by gut commensals in promoting 21-dehydroxylation, suggesting that hydrogen modulates secondary metabolism in the gut. Levels of certain bacterial progestins, including allopregnanolone, better known as brexanolone, an FDA-approved drug for postpartum depression, are substantially increased in feces from pregnant humans. Thus, bacterial conversion of corticoids into progestins may affect host physiology, particularly in the context of pregnancy and women's health.

Genetic testing in prostate cancer management: Considerations informing primary care.

Inherited genetic mutations can significantly increase the risk for prostate cancer (PC), may be associated with aggressive disease and poorer outcomes, and can have hereditary cancer implications for men and their families. Germline genetic testing (hereditary cancer genetic testing) is now strongly recommended for patients with advanced/metastatic PC, particularly given the impact on targeted therapy selection or clinical trial options, with expanded National Comprehensive Cancer Network guidelines and endorsement from multiple professional societies. Furthermore, National Comprehensive Cancer Network guidelines recommend genetic testing for men with PC across the stage and risk spectrum and for unaffected men at high risk for PC based on family history to identify hereditary cancer risk. Primary care is a critical field in which providers evaluate men at an elevated risk for PC, men living with PC, and PC survivors for whom germline testing may be indicated. Therefore, there is a critical need to engage and educate primary care providers regarding the role of genetic testing and the impact of results on PC screening, treatment, and cascade testing for family members of affected men. This review highlights key aspects of genetic testing in PC, the role of clinicians, with a focus on primary care, the importance of obtaining a comprehensive family history, current germline testing guidelines, and the impact on precision PC care. With emerging evidence and guidelines, clinical pathways are needed to facilitate integrated genetic education, testing, and counseling services in appropriately selected patients. There is also a need for providers to understand the field of genetic counseling and how best to collaborate to enhance multidisciplinary patient care.

Rucaparib or Physician's Choice in Metastatic Prostate Cancer.

BACKGROUND: In a phase 2 study, rucaparib, an inhibitor of poly(ADP-ribose) polymerase (PARP), showed a high level of activity in patients who had metastatic, castration-resistant prostate cancer associated with a deleterious BRCA alteration. Data are needed to confirm and expand on the findings of the phase 2 study. METHODS: In this randomized, controlled, phase 3 trial, we enrolled patients who had metastatic, castration-resistant prostate cancer with a BRCA1, BRCA2, or ATM alteration and who had disease progression after treatment with a second-generation androgen-receptor pathway inhibitor (ARPI). We randomly assigned the patients in a 2:1 ratio to receive oral rucaparib (600 mg twice daily) or a physician's choice control (docetaxel or a second-generation ARPI [abiraterone acetate or enzalutamide]). The primary outcome was the median duration of imaging-based progression-free survival according to independent review. RESULTS: Of the 4855 patients who had undergone prescreening or screening, 270 were assigned to receive rucaparib and 135 to receive a control medication (intention-to-treat population); in the two groups, 201 patients and 101 patients, respectively, had a BRCA alteration. At 62 months, the duration of imaging-based progression-free survival was significantly longer in the rucaparib group than in the control group, both in the BRCA subgroup (median, 11.2 months and 6.4 months, respectively; hazard ratio, 0.50; 95% confidence interval [CI], 0.36 to 0.69) and in the intention-to-treat group (median, 10.2 months and 6.4 months, respectively; hazard ratio, 0.61; 95% CI, 0.47 to 0.80; P<0.001 for both comparisons). In an exploratory analysis in the ATM subgroup, the median duration of imaging-based progression-free survival was 8.1 months in the rucaparib group and 6.8 months in the control group (hazard ratio, 0.95; 95% CI, 0.59 to 1.52). The most frequent adverse events with rucaparib were fatigue and nausea. CONCLUSIONS: The duration of imaging-based progression-free survival was significantly longer with rucaparib than with a control medication among patients who had metastatic, castration-resistant prostate cancer with a BRCA alteration. (Funded by Clovis Oncology; TRITON3 ClinicalTrials.gov number, NCT02975934.).

Actinide 2-metallabiphenylenes that satisfy Hückel's rule.

Aromaticity and antiaromaticity, as defined by Hückel's rule, are key ideas in organic chemistry, and are both exemplified in biphenylene1-3-a molecule that consists of two benzene rings joined by a four-membered ring at its core. Biphenylene analogues in which one of the benzene rings has been replaced by a different (4n + 2) π-electron system have so far been associated only with organic compounds4,5. In addition, efforts to prepare a zirconabiphenylene compound resulted in the isolation of a bis(alkyne) zirconocene complex instead6. Here we report the synthesis and characterization of, to our knowledge, the first 2-metallabiphenylene compounds. Single-crystal X-ray diffraction studies reveal that these complexes have nearly planar, 11-membered metallatricycles with metrical parameters that compare well with those reported for biphenylene. Nuclear magnetic resonance spectroscopy, in addition to nucleus-independent chemical shift calculations, provides evidence that these complexes contain an antiaromatic cyclobutadiene ring and an aromatic benzene ring. Furthermore, spectroscopic evidence, Kohn-Sham molecular orbital compositions and natural bond orbital calculations suggest covalency and delocalization of the uranium f2 electrons with the carbon-containing ligand.

Complement genes contribute sex-biased vulnerability in diverse disorders.

Many common illnesses, for reasons that have not been identified, differentially affect men and women. For instance, the autoimmune diseases systemic lupus erythematosus (SLE) and Sjögren's syndrome affect nine times more women than men1, whereas schizophrenia affects men with greater frequency and severity relative to women2. All three illnesses have their strongest common genetic associations in the major histocompatibility complex (MHC) locus, an association that in SLE and Sjögren's syndrome has long been thought to arise from alleles of the human leukocyte antigen (HLA) genes at that locus3-6. Here we show that variation of the complement component 4 (C4) genes C4A and C4B, which are also at the MHC locus and have been linked to increased risk for schizophrenia7, generates 7-fold variation in risk for SLE and 16-fold variation in risk for Sjögren's syndrome among individuals with common C4 genotypes, with C4A protecting more strongly than C4B in both illnesses. The same alleles that increase risk for schizophrenia greatly reduce risk for SLE and Sjögren's syndrome. In all three illnesses, C4 alleles act more strongly in men than in women: common combinations of C4A and C4B generated 14-fold variation in risk for SLE, 31-fold variation in risk for Sjögren's syndrome, and 1.7-fold variation in schizophrenia risk among men (versus 6-fold, 15-fold and 1.26-fold variation in risk among women, respectively). At a protein level, both C4 and its effector C3 were present at higher levels in cerebrospinal fluid and plasma8,9 in men than in women among adults aged between 20 and 50 years, corresponding to the ages of differential disease vulnerability. Sex differences in complement protein levels may help to explain the more potent effects of C4 alleles in men, women's greater risk of SLE and Sjögren's syndrome and men's greater vulnerability to schizophrenia. These results implicate the complement system as a source of sexual dimorphism in vulnerability to diverse illnesses.

COVID-19 and systemic lupus erythematosus genetics: A balance between autoimmune disease risk and protection against infection.

Genome wide association studies show there is a genetic component to severe COVID-19. We find evidence that the genome-wide genetic association signal with severe COVID-19 is correlated with that of systemic lupus erythematosus (SLE), having formally tested this using genetic correlation analysis by LD score regression. To identify the shared associated loci and gain insight into the shared genetic effects, using summary level data we performed meta-analyses, a local genetic correlation analysis and fine-mapping using stepwise regression and functional annotation. This identified multiple loci shared between the two traits, some of which exert opposing effects. The locus with most evidence of shared association is TYK2, a gene critical to the type I interferon pathway, where the local genetic correlation is negative. Another shared locus is CLEC1A, where the direction of effects is aligned, that encodes a lectin involved in cell signaling, and the anti-fungal immune response. Our analyses suggest that several loci with reciprocal effects between the two traits have a role in the defense response pathway, adding to the evidence that SLE risk alleles are protective against infection.

Extended Safety and Tolerability of Darolutamide for Nonmetastatic Castration-Resistant Prostate Cancer and Adverse Event Time Course in ARAMIS.

BACKGROUND: Patients with nonmetastatic castration-resistant prostate cancer (nmCRPC) are usually asymptomatic and seek treatments that improve survival but have a low risk of adverse events. Darolutamide, a structurally distinct androgen receptor inhibitor (ARi), significantly reduced the risk of metastasis and death versus placebo in ARAMIS. We assessed the extended safety and tolerability of darolutamide and the time-course profile of treatment-emergent adverse events (TEAEs) related to ARis and androgen-suppressive treatment. PATIENTS AND METHODS: Patients with nmCRPC were randomized 2:1 to darolutamide (n = 955) or placebo (n = 554). After trial unblinding, patients could receive open-label darolutamide. Tolerability and TEAEs were assessed every 16 weeks. Time interval-specific new and cumulative event rates were determined during the first 24 months of the double-blind period. RESULTS: Darolutamide remained well tolerated during the double-blind and open-label periods, with 98.8% of patients receiving the full planned dose. The incidence of TEAEs of interest in the darolutamide group was low and ≤2% different from that in the placebo group, except for fatigue. When incidences were adjusted for exposure time, there were minimal differences between the darolutamide double-blind and double-blind plus open-label periods. The rate of initial onset and cumulative incidence of grade 3/4 TEAEs and serious TEAEs were similar for darolutamide and placebo groups over 24 months. CONCLUSION: Extended treatment with darolutamide was well tolerated and no new safety signals were observed. Most ARi-associated and androgen-suppressive treatment-related TEAEs occurred at low incidences with darolutamide, were similar to placebo, and showed minimal increase over time with continued treatment. TRIAL NUMBER: ClinicalTrials.gov identifier NCT02200614.

Haematopoietic stem cell-derived immune cells have reduced X chromosome inactivation skewing in systemic lupus erythematosus.

OBJECTIVES: Systemic lupus erythematosus (SLE) shows a marked female bias in prevalence. X chromosome inactivation (XCI) is the mechanism which randomly silences one X chromosome to equalise gene expression between 46, XX females and 46, XY males. Though XCI is expected to result in a random pattern of mosaicism across tissues, some females display a significantly skewed ratio in immune cells, termed XCI-skew. We tested whether XCI was abnormal in females with SLE and hence contributes to sexual dimorphism. METHODS: We assayed XCI in whole blood DNA in 181 female SLE cases, 796 female healthy controls and 10 twin pairs discordant for SLE. Using regression modelling and intra-twin comparisons, we assessed the effect of SLE on XCI and combined clinical, cellular and genetic data via a polygenic score to explore underlying mechanisms. RESULTS: Accommodating the powerful confounder of age, XCI-skew was reduced in females with SLE compared with controls (p=1.3×10-5), with the greatest effect seen in those with more severe disease. Applying an XCI threshold of >80%, we observed XCI-skew in 6.6% of SLE cases compared with 22% of controls. This difference was not explained by differential white cell counts, medication or genetic susceptibility to SLE. Instead, XCI-skew correlated with a biomarker for type I interferon-regulated gene expression. CONCLUSIONS: These results refute current views on XCI-skew in autoimmunity and suggest, in lupus, XCI patterns of immune cells reflect the impact of disease state, specifically interferon signalling, on the haematopoietic stem cells from which they derive.

Development and Optimization of a Subtraction-Normalized Immunocyte Profiling Signature for Prostate Cancer Active Surveillance Risk Stratification.

PURPOSE: Less invasive decision support tools are desperately needed to identify occult high-risk disease in men with prostate cancer (PCa) on active surveillance (AS). For a variety of reasons, many men on AS with low- or intermediate-risk disease forgo the necessary repeat surveillance biopsies needed to identify potentially higher-risk PCa. Here, we describe the development of a blood-based immunocyte transcriptomic signature to identify men harboring occult aggressive PCa. We then validate it on a biopsy-positive population with the goal of identifying men who should not be on AS and confirm those men with indolent disease who can safely remain on AS. This model uses subtraction-normalized immunocyte transcriptomic profiles to risk-stratify men with PCa who could be candidates for AS. MATERIALS AND METHODS: Men were eligible for enrollment in the study if they were determined by their physician to have a risk profile that warranted prostate biopsy. Both training (n = 1017) and validation cohort (n = 1198) populations had blood samples drawn coincident to their prostate biopsy. Purified CD2+ and CD14+ immune cells were obtained from peripheral blood mononuclear cells, and RNA was extracted and sequenced. To avoid overfitting and unnecessary complexity, a regularized regression model was built on the training cohort to predict PCa aggressiveness based on the National Comprehensive Cancer Network PCa guidelines. This model was then validated on an independent cohort of biopsy-positive men only, using National Comprehensive Cancer Network unfavorable intermediate risk and worse as an aggressiveness outcome, identifying patients who were not appropriate for AS. RESULTS: The best final model for the AS setting was obtained by combining an immunocyte transcriptomic profile based on 2 cell types with PSA density and age, reaching an AUC of 0.73 (95% CI: 0.69-0.77). The model significantly outperforms (P < .001) PSA density as a biomarker, which has an AUC of 0.69 (95% CI: 0.65-0.73). This model yields an individualized patient risk score with 90% negative predictive value and 50% positive predictive value. CONCLUSIONS: While further validation in an intended-use cohort is needed, the immunocyte transcriptomic model offers a promising tool for risk stratification of individual patients who are being considered for AS.

Enhancing the Efficacy of HIPEC Through Bromelain: A Preclinical Investigation in Appendiceal Cancer.

INTRODUCTION: Appendiceal cancer (AC) excessive mucin production is a barrier to heated intraperitoneal chemotherapy (HIPEC) drug delivery. Bromelain is a pineapple stem extract with mucolytic properties. We explored bromelain treatment effects against mucinous AC in a patient-derived tumor organoid (PTO) model and an AC cell line. PATIENTS AND METHODS: PTOs were fabricated from tumor specimens obtained from patients with AC undergoing cytoreductive surgery with HIPEC. PTOs underwent HIPEC treatment with bromelain, cisplatin, and mitomycin C (MMC) at 37 °C and 42 °C with and without bromelain pretreatment. RESULTS: From October 2020 to May 2023, 16 specimens were collected from 13 patients with low-grade (12/16, 75%) and high-grade AC (4/16, 25%). The mucin-depleting effects of bromelain were most significant in combination with N-acetylcysteine (NAC) compared with bromelain (47% versus 10%, p = 0.0009) or NAC alone (47% versus 12.8%, p = 0.0027). Bromelain demonstrated > 31% organoid viability reduction at 60 min (p < 0.001) and > 66% in 48 h (p < 0.0001). Pretreatment with bromelain increased cytotoxicity of both cisplatin and MMC HIPEC conditions by 31.6% (p = 0.0001) and 35.5% (p = 0.0001), respectively. Ki67, CK20, and MUC2 expression decreased after bromelain treatment; while increased caspase 3/7 activity and decreased Bcl-2 (p = 0.009) and Bcl-xL (p = 0.01) suggest induction of apoptosis pathways. Furthermore, autophagy proteins LC3A/B I (p < 0.03) and II (p < 0.031) were increased; while ATG7 (p < 0.01), ATG 12 (p < 0.04), and Becline 1(p < 0.03), expression decreased in bromelain-treated PTOs. CONCLUSIONS: Bromelain demonstrates cytotoxicity and mucolytic activity against appendiceal cancer organoids. As a pretreatment agent, it potentiates the cytotoxicity of multiple HIPEC regimens, potentially mediated through programmed cell death and autophagy.

Improvements in Between-Vendor MRI Harmonization of Renal T2 Mapping using Stimulated Echo Compensation.

BACKGROUND: T2 mapping is valuable to evaluate pathophysiology in kidney disease. However, variations in T2 relaxation time measurements across MR scanners and vendors may occur requiring additional correction. PURPOSE: To harmonize renal T2 measurements between MR vendor platforms, and use an extended-phase-graph-based fitting method ("StimFit") to correct stimulated echoes and reduce between-vendor variations. STUDY TYPE: Prospective. SUBJECTS: 8 healthy "travelling" volunteers (37.5% female, 32 ± 6 years) imaged on four MRI systems across three vendors at four sites, 10 healthy volunteers (50% female, 32 ± 8 years) scanned multiple times on a given MR scanner for repeatability evaluation. ISMRM/NIST system phantom scanned for evaluation of T2 accuracy. FIELD STRENGTH/SEQUENCE: 3T, multiecho spin-echo sequence. ASSESSMENT: T2 images fit using conventional monoexponential fitting and "StimFit." Mean absolute percentage error (MAPE) of phantom measurements with reference T2 values. Average cortex and medulla T2 values compared between MR vendors, with masks obtained from T2 -weighted images and T1 maps. Full-width-at-half-maximum (FWHM) T2 distributions to evaluate local homogeneity of measurements. STATISTICAL TESTS: Coefficient of variation (CV), linear mixed-effects model, analysis of variance, student's t-tests, Bland-Altman plots, P-value <0.05 considered statistically significant. RESULTS: In the ISMRM/NIST phantom, "StimFit" reduced the MAPE from 4.9%, 9.1%, 24.4%, and 18.1% for the four sites (three vendors) to 3.3%, 3.0%, 6.6%, and 4.1%, respectively. In vivo, there was a significant difference in kidney T2 measurements between vendors using a monoexponential fit, but not with "StimFit" (P = 0.86 and 0.92, cortex and medulla, respectively). The intervendor CVs of T2 measures were reduced from 8.0% to 2.6% (cortex) and 7.1% to 2.8% (medulla) with StimFit, resulting in no significant differences for the CVs of intravendor repeat acquisitions (P = 0.13 and 0.05). "StimFit" significantly reduced the FWHM of T2 distributions in the cortex and whole kidney. DATA CONCLUSION: Stimulated-echo correction reduces renal T2 variation across MR vendor platforms. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 1.

A semi-structured interview to capture manual wheelchair use for mobility activities among individuals with spinal cord injury in real-life situations: development and content validity of the Wheelchair Mobility Activity Log (WC-MAL).

STUDY DESIGN: Mixed-method approach. OBJECTIVES: To develop and assess the content validity of a semi-structured interview that captures the lived experience of using a manual wheelchair among individuals with SCI in the real world, the Wheelchair Mobility Activity Log (WC-MAL). SETTING: SCIR-Group (UDESC)/Brazil. METHODS: Developing the WC-MAL comprised five steps: (1) defining the construct-based on the International Classification of Functioning, Disability and Health (ICF); (2) identifying relevant activities from other assessment instruments and interviews with the end-users (14 Individuals with SCI and 13 rehabilitation professionals); (3) Selecting the items - activities were linked to ICF codes and grouped into sets; (4) developing the scoring scales based on interviews with the end-users; and, (5) evaluating content validity in accordance with the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN). The content validity ratio (CVR) for each item and scale and the overall instrument content validity index (CVI) were calculated. RESULTS: From an initial draft of 295 activities identified, a set of 222 activities was linked to the ICF domain of "Mobility (d4)" and further refined to generate the 23 items in the WC-MAL. Three scales were developed to assess Frequency (how often), Performance (how well), and Assistance (assistance needed) levels. The items and scales showed a CVR superior to the critical value established (≥0.64). The general CVI value was 0.96. CONCLUSION: The WC-MAL is a promising clinical instrument with adequate content validity to assess the spontaneous use of the manual wheelchair in the real world among individuals with SCI.

Repeat cytoreductive surgery with HIPEC for colorectal peritoneal metastases: a systematic review.

BACKGROUND: Colorectal peritoneal metastases (CRPM) are present in 10-20% of patients at the time of their initial cancer diagnosis, and affects over 20% of those who develop colorectal cancer recurrence. Cytoreductive surgery (CRS) with HIPEC is firmly established as the optimal surgical treatment, but there is very little known about the benefit of repeat or iterative CRS. The aim of this review is to provide a systematic evaluation of the perioperative complications, survival outcomes and quality of life in patients undergoing repeat CRS with HIPEC for CRPM. METHODS: A systematic review of PubMed, Ovid MEDLINE, EMBASE, Scopus and Cochrane databases was performed to identify all studies that reported outcomes for repeat CRS with or without HIPEC for CRPM. RESULTS: Four hundred and ninety-three manuscripts were screened, and 15 retrospective studies were suitable for inclusion. Sample sizes ranged from 2 to 30 participants and comprised a total of 229 patients. HIPEC was used in all studies, but exact rates were not consistently stated. Perioperative morbidity was reported in four studies, between 16.7% and 37.5%. Nine studies reported mortality rate which was consistently 0%. The median overall survival after repeat CRS ranged from 20 to 62.6 months. No studies provided quality of life metrics. CONCLUSION: Repeat CRS for CRPM has perioperative morbidity and mortality rates comparable to initial CRS, and offers a potential survival benefit in selected patients. There is however limited high-quality data in the literature.

Neoadjuvant chemotherapy does not improve survival for patients with high volume colorectal peritoneal metastases undergoing cytoreductive surgery.

BACKGROUND: Colorectal peritoneal metastases (CRPM) affects 15% of patients at initial colorectal cancer diagnosis. Neoadjuvant chemotherapy (NAC) prior to cytoreductive surgery (CRS) has been demonstrated to be a safe and feasible option, however there is limited data describing its efficacy in advanced peritoneal disease. This study evaluated the effect of NAC on survival in patients with high volume CRPM undergoing CRS with or without HIPEC. METHODS: A retrospective review of all patients who underwent CRS with or without HIPEC for CRPM from 2004 to 2019 at our institution was performed. The cohort was divided based on peritoneal carcinomatosis index (PCI) at surgery: Low Volume (PCI ≤ 16) and High Volume (PCI > 16). RESULTS: A total of 326 patients underwent CRS with HIPEC for CRPM. There were 39 patients (12%) with High Volume disease, and 15 of these (38%) received NAC. Patients with High Volume disease had significantly longer operating time, lower likelihood of complete macroscopic cytoreduction (CC-0 score), longer intensive care unit length of stay and longer hospital stay compared to Low Volume disease. In High Volume disease, the NAC group had a significantly shorter median survival of 14.4 months compared to 23.8 months in the non-NAC group (p = 0.046). CONCLUSION: Patients with High Volume CRPM achieved good median survival following CRS with HIPEC, which challenges the current PCI threshold for offering CRS. The use of NAC in this cohort did not increase perioperative morbidity but was associated with significantly shorter median survival compared to upfront surgery.

Screw sense and screw sensibility: communicating information by conformational switching in helical oligomers.

Biological systems have evolved a number of different strategies to communicate information on the molecular scale. Among these, the propagation of conformational change is among the most important, being the means by which G-protein coupled receptors (GPCRs) use extracellular signals to modulate intracellular processes, and the way that opsin proteins translate light signals into nerve impulses. The developing field of foldamer chemistry has allowed chemists to employ conformationally well-defined synthetic structures likewise to mediate information transfer, making use of mechanisms that are not found in biological contexts. In this review, we discuss the use of switchable screw-sense preference as a communication mechanism. We discuss the requirements for functional communication devices, and show how dynamic helical foldamers derived from the achiral monomers such as α-aminoisobutyric acid (Aib) and meso-cyclohexane-1,2-diamine fulfil them by communicating information in the form of switchable screw-sense preference. We describe the various stimuli that can be used to switch screw sense, and explore the way that propagation of the resulting conformational preference in a well-defined helical molecule allows screw sense to control chemical events remote from a source of information. We describe the operation of these conformational switches in the membrane phase, and outline the progress that has been made towards using conformational switching to communicate between the exterior and interior of a phospholipid vesicle.

Inshore and offshore marine migration pathways of Atlantic salmon post-smolts from multiple rivers in Scotland, England, Northern Ireland, and Ireland.

The migratory behavior of Atlantic salmon (Salmo salar) post-smolts in coastal waters is poorly understood. In this collaborative study, 1914 smolts, from 25 rivers, in four countries were tagged with acoustic transmitters during a single seasonal migration. In total, 1105 post-smolts entered the marine study areas and 438 (39.6%) were detected on a network of 414 marine acoustic receivers and an autonomous underwater vehicle. Migration pathways (defined as the shortest distance between two detections) of up to 575 km and over 100 days at sea were described for all 25 populations. Post-smolts from different rivers, as well as individuals from the same river, used different pathways in coastal waters. Although difficult to generalize to all rivers, at least during the year of this study, no tagged post-smolts from rivers draining into the Irish Sea were detected entering the areas of sea between the Hebrides and mainland Scotland, which is associated with a high density of finfish aquaculture. An important outcome of this study is that a high proportion of post-smolts crossed through multiple legislative jurisdictions and boundaries during their migration. This study provides the basis for spatially explicit assessment of the impact risk of coastal pressures on salmon during their first migration to sea.

The burden of Finke Desert race-related trauma: A 10-year retrospective descriptive analysis.

INTRODUCTION: The Finke Desert Race is an annual motorsport race (motorbikes, cars and buggies) held in Alice Springs resulting in a significant major trauma burden. This imposes unique challenges in one of the world's most remote healthcare settings. OBJECTIVES: To quantify the volume and characteristics of Finke Desert Race-related trauma presenting to the Alice Springs Hospital. DESIGN: A retrospective descriptive study was undertaken to review all patients presenting to the Alice Springs Hospital with Finke Desert Race-related trauma over a 10-year period. Information collected included demographic data, injury characteristics, patient disposition and required management. FINDINGS: Over the 9 years the event was held, 325 patients were admitted to the Alice Springs Hospital. Patients were almost exclusively male (98.8%), with a mean age of 34.75 and residing outside of Alice Springs (82.2%). There were a total of 460 distinct injuries with the clavicle, spine and ribs the three most commonly injured sites. A total of 129 operations were required, of which 19 required retrieval to an interstate centre. DISCUSSION: Alice Springs is one of the most remote and geographically isolated centres on Earth. This rurality poses unique challenges when trying to coordinate medical and retrieval services, exacerbated for a concentrated, yet highly resource intensive event such as Finke. It has far reaching impacts, placing additional stresses on all aspects of healthcare provision. CONCLUSION: This review has quantified the trauma burden of the event for the first time, enabling local and interstate stakeholders' ability to plan an adequate and sustainable response while also enabling the future effectiveness evaluation of recent safety reforms.

Revisiting the effect of text complexity on Continuous Discourse Tracking using synthetic speech: Old tricks with new dogs.

Continuous Discourse Tracking (CDT) is a functional test of speech perceptual ability, which has been criticised on account of the procedural variation inherent in the method. This study sought to reduce this variation by using synthetic speech, which was subsequently vocoded to simulate listening with a cochlear implant. We also assessed the complexity of three text excerpts with auditory (n = 10) and written Cloze tests (n = 10). These same passages were used in an auditory-only CDT experiment (n = 12) performed with the synthetic-vocoded material. Mean tracking rates were lower, and the number of blockages was higher for the most difficult text as determined by the Cloze results. We also noted some anomalous realisations from the speech synthesis, but these were unlikely to have contributed to the differences in tracking rates that were observed for text complexity. These results show that Cloze testing is suitable to predict text complexity for CDT performed with synthesised speech. Furthermore, they indicate that the use of text-speech synthesis is viable and may be a useful addition to rehabilitation where functional measures are used to assess communication aptitude.

Compact Rotaxane Superbases.

Challenges for the development of efficacious new superbases include their ease of synthesis, chemical stability, and high basicity, while minimizing nucleophilicity is important for reducing unwanted side reactions. Here, we introduce a new family of organic superbases, compact amine-crown ether rotaxanes, which show desirable characteristics in all these respects. Metal-free active template synthesis provides access to a range of rotaxanes with as little as three atoms between the stoppering groups, locking the location of a small crown ether (21C7 and 24C8 derivatives) over the amine group of the axle. The forced proximity of the interlocked protophilic components results in pKaH+ values as high as 32.2 in acetonitrile, which is up to 13 pKaH+ units greater than the pKaH+ values of the non-interlocked components, and brings the free base rotaxanes into the basicity realm of phosphazene superbases. The rotaxane superbases are generally chemically stable and, in a model reaction for superbases, eliminate HBr from a primary alkyl bromide with complete selectivity for deprotonation over alkylation. Their modest size, ease of synthesis, high basicity, low nucleophilicity, and, in the best cases, rapid substrate deprotonation kinetics and excellent hydrolytic stability make compact amine-crown ether rotaxane superbases intriguing candidates for potential applications in synthesis and supramolecular and materials chemistry.

Dynamic and Persistent Cyclochirality in Hydrogen-Bonded Derivatives of Medium-Ring Triamines.

Cyclic triureas derived from 1,4,7-triazacyclononane (TACN) were synthesized; X-ray crystallography showed a chiral bowl-like conformation with each urea hydrogen-bonded to its neighbor with uniform directionality, forming a "cyclochiral" closed loop of hydrogen bonds. Variable-temperature 1H NMR, 1H-1H exchange spectroscopy, Eyring analysis, computational modeling, and studies in various solvents revealed that cyclochirality is dynamic (ΔG‡25°C = 63-71 kJ mol-1 in noncoordinating solvents), exchanging between enantiomers by two mechanisms: bowl inversion and directionality reversal, with the former subject to a slightly smaller enantiomerization barrier. The enantiomerization rate substantially increased in the presence of hydrogen-bonding solvents. Population of only one of the two cyclochiral hydrogen-bond directionalities could be induced by annulating one ethylene bridge with a trans-cyclohexane. Alternatively, enantiomerization could be inhibited by annulating one ethylene bridge with a cis-cyclohexane (preventing bowl inversion) and replacing one urea function with a formamide (preventing directionality reversal). Combining these structural modifications resulted in an enantiomerization barrier of ΔG‡25°C = 93 kJ mol-1, furnishing a planar-chiral, atropisomeric bowl-shaped structure whose stereochemical stability arises solely from its hydrogen-bonding network.