Reducing overprediction of molecular crystal structures via threshold clustering.

Crystal structure prediction is becoming an increasingly valuable tool for assessing polymorphism of crystalline molecular compounds, yet invariably, it overpredicts the number of polymorphs. One of the causes for this overprediction is in neglecting the coalescence of potential energy minima, separated by relatively small energy barriers, into a single basin at finite temperature. Considering this, we demonstrate a method underpinned by the threshold algorithm for clustering potential energy minima into basins, thereby identifying kinetically stable polymorphs and reducing overprediction.

[177Lu]Lu-PSMA-617 plus enzalutamide in patients with metastatic castration-resistant prostate cancer (ENZA-p): an open-label, multicentre, randomised, phase 2 trial.

BACKGROUND: Enzalutamide and lutetium-177 [177Lu]Lu-prostate-specific membrane antigen (PSMA)-617 both improve overall survival in patients with metastatic castration-resistant prostate cancer. Androgen and PSMA receptors have a close intracellular relationship, with data suggesting complementary benefit if targeted concurrently. In this study, we assessed the activity and safety of enzalutamide plus adaptive-dosed [177Lu]Lu-PSMA-617 versus enzalutamide alone as first-line treatment for metastatic castration-resistant prostate cancer. METHODS: ENZA-p was an open-label, randomised, controlled phase 2 trial done at 15 hospitals in Australia. Participants were men aged 18 years or older with metastatic castration-resistant prostate cancer not previously treated with docetaxel or androgen receptor pathway inhibitors for metastatic castration-resistant prostate cancer, gallium-68 [68Ga]Ga-PSMA-PET-CT (PSMA-PET-CT) positive disease, Eastern Cooperative Oncology Group performance status of 0-2, and at least two risk factors for early progression on enzalutamide. Participants were randomly assigned (1:1) by a centralised, web-based system using minimisation with a random component to stratify for study site, disease burden, use of early docetaxel, and previous treatment with abiraterone acetate. Patients were either given oral enzalutamide 160 mg daily alone or with adaptive-dosed (two or four doses) intravenous 7·5 GBq [177Lu]Lu-PSMA-617 every 6-8 weeks dependent on an interim PSMA-PET-CT (week 12). The primary endpoint was prostate-specific antigen (PSA) progression-free survival, defined as the interval from the date of randomisation to the date of first evidence of PSA progression, commencement of non-protocol anticancer therapy, or death. The analysis was done in the intention-to-treat population, using stratified Cox proportional hazards regression. This trial is registered with ClinicalTrials.gov, NCT04419402, and participant follow-up is ongoing. FINDINGS: 162 participants were randomly assigned between Aug 17, 2020, and July 26, 2022. 83 men were assigned to the enzalutamide plus [177Lu]Lu-PSMA-617 group, and 79 were assigned to the enzalutamide group. Median follow-up in this interim analysis was 20 months (IQR 18-21), with 32 (39%) of 83 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 16 (20%) of 79 patients in the enzalutamide group remaining on treatment at the data cutoff date. Median age was 71 years (IQR 64-76). Median PSA progression-free survival was 13·0 months (95% CI 11·0-17·0) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 7·8 months (95% CI 4·3-11·0) in the enzalutamide group (hazard ratio 0·43, 95% CI 0·29-0·63, p<0·0001). The most common adverse events (all grades) were fatigue (61 [75%] of 81 patients), nausea (38 [47%]), and dry mouth (32 [40%]) in the enzalutamide plus [177Lu]Lu-PSMA-617 group and fatigue (55 [70%] of 79), nausea (21 [27%]), and constipation (18 [23%]) in the enzalutamide group. Grade 3-5 adverse events occurred in 32 (40%) of 81 patients in the enzalutamide plus [177Lu]Lu-PSMA-617 group and 32 (41%) of 79 patients in the enzalutamide group. Grade 3 events that occurred only in the enzalutamide plus [177Lu]Lu-PSMA-617 group included anaemia (three [4%] of 81 participants) and decreased platelet count (one [1%] participant). No grade 4 or 5 events were attributed to treatment on central review in either group. INTERPRETATION: The addition of [177Lu]Lu-PSMA-617 to enzalutamide improved PSA progression-free survival providing evidence of enhanced anticancer activity in patients with metastatic castration-resistant prostate cancer with risk factors for early progression on enzalutamide and warrants further evaluation of the combination more broadly in metastatic prostate cancer. FUNDING: Prostate Cancer Research Alliance (Movember and Australian Federal Government), St Vincent's Clinic Foundation, GenesisCare, Roy Morgan Research, and Endocyte (a Novartis company).

Facial Selectivity in Mechanical Bond Formation: Axially Chiral Enantiomers and Geometric Isomers from a Simple Prochiral Macrocycle.

In 1971, Schill recognized that a prochiral macrocycle encircling an oriented axle led to geometric isomerism in rotaxanes. More recently, we identified an overlooked chiral stereogenic unit in rotaxanes that arises when a prochiral macrocycle encircles a prochiral axle. Here, we show that both stereogenic units can be accessed using equivalent strategies, with a single weak stereodifferentiating interaction sufficient for moderate to excellent stereoselectivity. Using this understanding, we demonstrated the first direct enantioselective (70% ee) synthesis of a mechanically axially chiral rotaxane.

Machine-Learned Potentials by Active Learning from Organic Crystal Structure Prediction Landscapes.

A primary challenge in organic molecular crystal structure prediction (CSP) is accurately ranking the energies of potential structures. While high-level solid-state density functional theory (DFT) methods allow for mostly reliable discrimination of the low-energy structures, their high computational cost is problematic because of the need to evaluate tens to hundreds of thousands of trial crystal structures to fully explore typical crystal energy landscapes. Consequently, lower-cost but less accurate empirical force fields are often used, sometimes as the first stage of a hierarchical scheme involving multiple stages of increasingly accurate energy calculations. Machine-learned interatomic potentials (MLIPs), trained to reproduce the results of ab initio methods with computational costs close to those of force fields, can improve the efficiency of the CSP by reducing or eliminating the need for costly DFT calculations. Here, we investigate active learning methods for training MLIPs with CSP datasets. The combination of active learning with the well-developed sampling methods from CSP yields potentials in a highly automated workflow that are relevant over a wide range of the crystal packing space. To demonstrate these potentials, we illustrate efficiently reranking large, diverse crystal structure landscapes to near-DFT accuracy from force field-based CSP, improving the reliability of the final energy ranking. Furthermore, we demonstrate how these potentials can be extended to more accurately model structures far from lattice energy minima through additional on-the-fly training within Monte Carlo simulations.

A Co-conformationally "Topologically" Chiral Catenane.

Catenanes composed of two achiral rings that are oriented (Cnh symmetry) because of the sequence of atoms they contain are referred to as topologically chiral. Here, we present the synthesis of a highly enantioenriched catenane containing a related but overlooked "co-conformationally 'topologically' chiral" stereogenic unit, which arises when a bilaterally symmetric Cnv ring is desymmetrized by the position of an oriented macrocycle.

Tackling the Tibetan Plateau in a down suit: insights into thermoregulation by bar-headed geese during migration.

Birds migrating through extreme environments can experience a range of challenges while meeting the demands of flight, including highly variable ambient temperatures, humidity and oxygen levels. However, there has been limited research into avian thermoregulation during migration in extreme environments. This study aimed to investigate the effect of flight performance and high altitude on body temperature (Tb) of free-flying bar-headed geese (Anser indicus), a species that completes a high-altitude trans-Himalayan migration through very cold, hypoxic environments. We measured abdominal Tb, along with altitude (via changes in barometric pressure), heart rate and body acceleration of bar-headed geese during their migration across the Tibetan Plateau. Bar-headed geese vary the circadian rhythm of Tb in response to migration, with peak daily Tb during daytime hours outside of migration but early in the morning or overnight during migration, reflecting changes in body acceleration. However, during flight, changes in Tb were not consistent with changes in flight performance (as measured by heart rate or rate of ascent) or altitude. Overall, our results suggest that bar-headed geese are able to thermoregulate during high-altitude migration, maintaining Tb within a relatively narrow range despite appreciable variation in flight intensity and environmental conditions.

Safety and outcomes of 177 Lu-DOTATATE for neuroendocrine tumours: experience in New South Wales, Australia.

BACKGROUND: Peptide receptor radionuclide therapy with 177 Lu-DOTATATE is a promising treatment for inoperable or metastatic neuroendocrine tumours (NET). In 2015, the NSW Ministry of Health provided funding for 177 Lu-DOTATATE treatment of NET under an evaluation framework. AIMS: To examine the safety and outcomes of NET patients treated with 177 Lu-DOTATATE under the evaluation framework and assess the statewide implementation of the NSW Lutate therapy referral and protocol for neuroendocrine cancer patients. METHODS: A quality of care clinical audit was conducted on all NET patients treated with 177 Lu-DOTATATE from October 2010 to October 2015 at St George Hospital, and from August 2013 to March 2017 at Royal North Shore Hospital. Percentage of patients who met protocol selection criteria was calculated. Survival was estimated using the Kaplan-Meier method. Adjusted regression analyses assessed associations between key clinical factors and outcomes. RESULTS: A total of 279 patients was treated. Statewide protocol implementation led to an increase from 60.5 to 83.8% in patients meeting selection criteria. Estimated median overall survival was significantly longer for patients who met selection criteria compared with those who did not (50.7 vs 34.2 months) (P = 0.018). This was driven by the significantly worse overall survival in patients who failed exclusion criteria (P < 0.001). 177 Lu-DOTATATE was well tolerated with haematological, renal and hepatic treatment-related serious adverse events experienced by 9.7, 0.4 and 0.4% of patients respectively. CONCLUSIONS: 177 Lu-DOTATATE is a promising treatment for advanced NET. Superior survival in patients who met selection criteria emphasise the importance of protocol adherence.

Flight feather moult drives minimum daily heart rate in wild geese.

Waterfowl undergo an annual simultaneous flight-feather moult that renders them flightless for the duration of the regrowth of the flight feathers. In the wild, this period of flightlessness could restrict the capacity of moulting birds to forage and escape predation. Selection might therefore favour a short moult, but feather growth is constrained and presumably energetically demanding. We therefore tested the hypothesis that for birds that undergo a simultaneous flight-feather moult, this would be the period in the annual cycle with the highest minimum daily heart rates, reflecting these increased energetic demands. Implantable heart rate data loggers were used to record year-round heart rate in six wild barnacle geese (Branta leucopsis), a species that undergoes a simultaneous flight-feather moult. The mean minimum daily heart rate was calculated for each individual bird over an 11-month period, and the annual cycle was divided into seasons based on the life-history of the birds. Mean minimum daily heart rate varied significantly between seasons and was significantly elevated during wing moult, to 200 ± 32 beats min-1, compared to all other seasons of the annual cycle, including both the spring and autumn migrations. The increase in minimum daily heart rate during moult is likely due to feather synthesis, thermoregulation and the reallocation of minerals and protein.

How bar-headed geese fly over the Himalayas.

Bar-headed geese cross the Himalayas on one of the most iconic high-altitude migrations in the world. Heart rates and metabolic costs of flight increase with elevation and can be near maximal during steep climbs. Their ability to sustain the high oxygen demands of flight in air that is exceedingly oxygen-thin depends on the unique cardiorespiratory physiology of birds in general along with several evolved specializations across the O2 transport cascade.

Stable Isotopes Suggest Low Site Fidelity in Bar-headed Geese (Anser indicus) in Mongolia: Implications for Disease Transmission.

Population connectivity is an important consideration in studies of disease transmission and biological conservation, especially with regard to migratory species. Determining how and when different subpopulations intermingle during different phases of the annual cycle can help identify important geographical regions or features as targets for conservation efforts and can help inform our understanding of continental-scale disease transmission. In this study, stable isotopes of hydrogen and carbon in contour feathers were used to assess the degree of molt-site fidelity among Bar-headed Geese (Anser indicus) captured in north-central Mongolia. Samples were collected from actively molting Bar-headed Geese (n = 61), and some individual samples included both a newly grown feather (still in sheath) and an old, worn feather from the bird's previous molt (n = 21). Although there was no difference in mean hydrogen isotope ratios for the old and new feathers, the isotopic variance in old feathers was approximately three times higher than that of the new feathers, which suggests that these birds use different and geographically distant molting locations from year to year. To further test this conclusion, online data and modeling tools from the isoMAP website were used to generate probability landscapes for the origin of each feather. Likely molting locations were much more widespread for old feathers than for new feathers, which supports the prospect of low molt-site fidelity. This finding indicates that population connectivity would be greater than expected based on data from a single annual cycle, and that disease spread can be rapid even in areas like Mongolia where Bar-headed Geese generally breed in small isolated groups.

The trans-Himalayan flights of bar-headed geese (Anser indicus).

Birds that fly over mountain barriers must be capable of meeting the increased energetic cost of climbing in low-density air, even though less oxygen may be available to support their metabolism. This challenge is magnified by the reduction in maximum sustained climbing rates in large birds. Bar-headed geese (Anser indicus) make one of the highest and most iconic transmountain migrations in the world. We show that those populations of geese that winter at sea level in India are capable of passing over the Himalayas in 1 d, typically climbing between 4,000 and 6,000 m in 7-8 h. Surprisingly, these birds do not rely on the assistance of upslope tailwinds that usually occur during the day and can support minimum climb rates of 0.8-2.2 km·h(-1), even in the relative stillness of the night. They appear to strategically avoid higher speed winds during the afternoon, thus maximizing safety and control during flight. It would seem, therefore, that bar-headed geese are capable of sustained climbing flight over the passes of the Himalaya under their own aerobic power.

Confidentiality and Contraception: Protecting Adolescent Care in Response to One State's "Parents' Bill of Rights".

PURPOSE: This study aims to analyze parent responses to current strict Oklahoma confidentiality and consent laws in an outpatient subspecialty setting. METHODS: A consent for treatment form including an explanation of the benefits of qualified confidential care for adolescents was given to parents of patients under 18 years of age. The form asked parents to waive the right to access confidential portions of the medical record, be present for the physical exam, be present for risk behavior discussions, and consent for hormonal contraception including a subdermal implant. Demographic information was collected using patient medical records. Data were analyzed using frequencies, chi-square, and t tests. RESULTS: Of the 507 parent forms, 95% of total parents gave permission for providers to have confidential conversations with the patients, 86% allowed providers to examine the patient alone, 84% of parents allowed providers to prescribe contraception, and 66% gave permission for subdermal implant. New patient status, race, ethnicity, assigned sex at birth, and insurance type did not correlate with parents' willingness to provide permissions. There was a statistically significant difference between patient gender identity and percentage of parents who granted permission for a confidential physical exam. Groups more likely to discuss questions about confidential care with the health care provider included parents of new patients, Native American and Black patients, and cisgender female patients. DISCUSSION: Despite laws that limit adolescent ability to access confidential care in Oklahoma, the majority of parents who were provided an explanatory document allowed their children the right to access this care.

Evaluation of a novel platform for placement confirmation of enteral feeding tubes in adults.

OBJECTIVE: The aim of this study was to validate the ability of a novel, impedance-based platform for nasogastric feeding tube (FT) insertion to correctly predict intragastric FT placement in healthy individuals with and without acid suppression medication. METHODS: Ten patients underwent successive placement of 8, 10, and 12 French FTs with the final intragastric position predicted using an impedance-based algorithm and verified with an abdominal x-ray. Study procedures were repeated after patients received a proton pump inhibitor (PPI) for 3 d. RESULTS: Nasogastric FTs with embedded electrodes spaced along the distal 31 cm of the tubes were placed with the final insertion depth determined by an algorithm integrating impedance and other physiologic parameters. Sixty FT (30 pre-PPI and 30 post-PPI) insertions were performed. The algorithm-predicted location was confirmed as intragastric in all insertions by post-placement abdominal x-ray. For all tube sizes and those with and without PPIs, the impedance at electrodes within the esophagus was significantly higher than at electrodes in the stomach (P < 0.01). As a secondary objective to assess the use of gastric aspirate pH to determine location, gastric aspirate could only be obtained in 30% of insertions. The mean gastric pH was 6.9 (SD 0.6) in patients taking PPIs. CONCLUSIONS: A novel platform for real-time assistance with nasogastric FT placement confirmation correctly determined intragastric FT location as confirmed by abdominal x-ray (standard of care) in all 60 insertions. Gastric pH measurements were difficult to obtain and unreliable for intragastric FT placement confirmation in patients taking acid suppression medication.

Seasonal variation in energy expenditure is not related to activity level or water temperature in a large diving bird.

There is considerable interest in understanding how the energy budget of an endotherm is modulated from a physiological and ecological point of view. In this paper, we used daily (24 h) heart rate (f(H24)), as a proxy of daily energy expenditure (DEE) across seasons, to test the effect of locomotion activity and water temperature on the energy budget of a large diving bird. f(H24) was monitored continuously in common eiders (Somateria mollissima) during 7 months together with measures of time spent flying and time spent feeding. f(H24) varied substantially during the recording period, with numerous increases and decreases that occurred across seasons, although we did not find any relationship between f(H24) and the time spent active (feeding and flying). However, inactive heart rate (f(H,inactive)) decreased as locomotion activity increased, suggesting that common eiders were using some form of compensation when under a high work load. We were also unable to detect a negative relationship between water temperature and resting heart rate, a proxy of resting metabolic rate. This was unexpected, based on the assumption that high thermoregulation costs would be associated with cold waters. We showed instead that a high level of energy expenditure coincided with feather moult and warm waters, which suggests that the observed variable pattern of seasonal DEE was driven by these two factors. Nevertheless, our results indicate that compensation and possibly the timing of moult may be used as mechanisms to reduce seasonal variation in energy expenditure.

Wild geese do not increase flight behaviour prior to migration.

Hypertrophy of the flight muscles is regularly observed in birds prior to long-distance migrations. We tested the hypothesis that a large migratory bird would increase flight behaviour prior to migration, in order to cause hypertrophy of the flight muscles, and upregulate key components of the aerobic metabolic pathways. Implantable data loggers were used to record year-round heart rate in six wild barnacle geese (Branta leucopsis), and the amount of time spent in flight each day was identified. Time in flight per day did not significantly increase prior to either the spring or the autumn migration, both between time periods prior to migration (5, 10 and 15 days), or when compared with a control period of low activity during winter. The lack of significant increase in flight prior to migration suggests that approximately 22 min per day is sufficient to maintain the flight muscles in condition for prolonged long-distance flight. This apparent lack of a requirement for increased flight activity prior to migration may be attributable to pre-migratory mass gains in the geese increasing workload during short flights, potentially prompting hypertrophy of the flight muscles.

Mechanically axially chiral catenanes and noncanonical mechanically axially chiral rotaxanes.

Chirality typically arises in molecules because of a rigidly chiral arrangement of covalently bonded atoms. Less generally appreciated is that chirality can arise when molecules are threaded through one another to create a mechanical bond. For example, when two macrocycles with chemically distinct faces are joined to form a catenane, the structure is chiral, although the rings themselves are not. However, enantiopure mechanically axially chiral catenanes in which the mechanical bond provides the sole source of stereochemistry have not been reported. Here we re-examine the symmetry properties of these molecules and in doing so identify a straightforward route to access them from simple chiral building blocks. Our analysis also led us to identify an analogous but previously unremarked upon rotaxane stereogenic unit, which also yielded to our co-conformational auxiliary approach. With methods to access mechanically axially chiral molecules in hand, their properties and applications can now be explored.

Metabolic rate throughout the annual cycle reveals the demands of an Arctic existence in great cormorants.

Aquatic endotherms living in polar regions are faced with a multitude of challenges, including low air and water temperatures and low illumination, especially in winter. Like other endotherms from cold environments, Great Cormorants (Phalacrocorax carbo) living in Arctic waters were hypothesized to respond to these challenges through a combination of high daily rate of energy expenditure (DEE) and high food requirements, which are met by a high rate of catch per unit effort (CPUE). CPUE has previously been shown in Great Cormorants to be the highest of any diving bird. In the present study, we tested this hypothesis by making the first measurements of DEE and foraging activity of Arctic-dwelling Great Cormorants throughout the annual cycle. We demonstrate that, in fact, Great Cormorants have surprisingly low rates of DEE. This low DEE is attributed primarily to very low levels of foraging activity, particularly during winter, when the cormorants spent only 2% of their day submerged. Such a low level of foraging activity can only be sustained through consistently high foraging performance. We demonstrate that Great Cormorants have one of the highest recorded CPUEs for a diving predator; 18.6 g per minute submerged (95% prediction interval 13.0-24.2 g/min) during winter. Temporal variation in CPUE was investigated, and highest CPUE was associated with long days and shallow diving depths. The effect of day length is attributed to seasonal variation in prey abundance. Shallow diving leads to high CPUE because less time is spent swimming between the surface and the benthic zone where foraging occurs. Our study demonstrates the importance of obtaining accurate measurements of physiology and behavior from free-living animals when attempting to understand their ecology.

Low evidence for implementation of well-documented implants regarding risk of early revision: a systematic review on total hip arthroplasty.

When introducing an implant, surgeons are subjected to steep learning curves, which may lead to a heightened revision rate. Stepwise introduction revolutionized implant introduction but lacks a last step.No guidelines exist for the introduction of a well-documented implant not previously used in a department. This is problematic according to the European Union's legislated tendering process, potentially leading to increased revisions. In this systematic review, the introduction of a well-documented total hip arthroplasty implant to experienced surgeons is explored amid concerns of higher revision rate.Literature search strategies were deployed in the Embase and Medline databases, revealing a total of 14,612 articles. Using the Covidence software (Cochrane, London), two reviewers screened articles for inclusion.No articles were found that fulfilled our eligibility criteria. A post hoc analysis retrieved two national register-based studies only missing information about the surgeon's knowledge of the introduced implant. None of the introduced implants decreased the revision rate and around 30% of the introduced implants were associated with a higher revision rate.The review showed that no data exist about revision rates when introducing well-documented implants. In continuation thereof, the introduction of well-documented implants might also be associated with increased revision rates, as has been shown for total knee arthroplasty. We therefore suggest that special attention should be focused on changes of implants in departments, which can be achieved by way of specific registration in national registers. Cite this article: EFORT Open Rev 2021;6:3-8. DOI: 10.1302/2058-5241.6.200047.