[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.

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.

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.

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.

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.

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.

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.

Evaluating transgender youth and parent interest and preferences regarding support groups.

The purpose of this cross-sectional survey study is to explore transgender teens' and their parents' interest in and preferences regarding support groups in an effort to optimally serve the entire family's needs. The aims of the study were to: (1) describe transgender teens interest level and preferences regarding support groups; (2) describe parents of transgender teens interest level and preferences regarding support groups; and (3) compare responses based on demographics including teens versus parent, natal sex, and gender identity. De-identified surveys were collected from a convenience sample of transgender patients (N = 26), ages 13-18 years, and their parents (N = 20). Overall level of interest in support groups was 7.20/10 for youth and 7.95/10 for parents where 0 is not interested and 10 is very interested. Both groups endorsed benefits of a support group, including help with managing school issues, learning about local resources for transgender teens, and providing peer support. Both groups indicated "no time" as the most common potential barrier to attendance. Both groups expressed moderate interest in support groups, with minor differences between youths and parents noted in preferred support group structure. Further examination is warranted to determine optimal support group characteristics aimed specifically at parents and, separately, for youth. Additional support services might complement groups for a more comprehensive approach to support resources for this community.

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.

Self-assembly of M4L4 tetrahedral cages incorporating pendant P[double bond, length as m-dash]S and P[double bond, length as m-dash]Se functionalised ligands.

Herein, the synthesis of metal-organic tetrahedral cages featuring flexible thio- and selenophosphate-based ligands is described. The cages were prepared by sub-component self-assembly of A[double bond, length as m-dash]P(OC6H4NH2-4)3 (A = S, Se) or S[double bond, length as m-dash]P(SC6H4NH2-4)3, 2-pyridinecarboxaldehyde, and either Fe[BF4]2 or Co[BF4]2. Preliminary host-guest studies into the ability of the pendant P[double bond, length as m-dash]S and P[double bond, length as m-dash]Se groups to interact with suitable substrates will be discussed.

Impacts of "supermoon" events on the physiology of a wild bird.

The position of the Moon in relation to the Earth and the Sun gives rise to several predictable cycles, and natural changes in nighttime light intensity are known to cause alterations to physiological processes and behaviors in many animals. The limited research undertaken to date on the physiological responses of animals to the lunar illumination has exclusively focused on the synodic lunar cycle (full moon to full moon, or moon phase) but the moon's orbit-its distance from the Earth-may also be relevant. Every month, the moon moves from apogee, its most distant point from Earth-and then to perigee, its closest point to Earth. Here, we studied wild barnacle geese (Branta leucopsis) to investigate the influence of multiple interacting lunar cycles on the physiology of diurnally active animals. Our study, which uses biologging technology to continually monitor body temperature and heart rate for an entire annual cycle, asks whether there is evidence for a physiological response to natural cycles in lunar brightness in wild birds, particularly "supermoon" phenomena, where perigee coincides with a full moon. There was a three-way interaction between lunar phase, lunar distance, and cloud cover as predictors of nighttime mean body temperature, such that body temperature was highest on clear nights when the full moon coincided with perigee moon. Our study is the first to report the physiological responses of wild birds to "supermoon" events; the wild geese responded to the combination of two independent lunar cycles, by significantly increasing their body temperature at night. That wild birds respond to natural fluctuations in nighttime ambient light levels support the documented responses of many species to anthropogenic sources of artificial light, that birds seem unable to override. As most biological systems are arguably organized foremost by light, this suggests that any interactions between lunar cycles and local weather conditions could have significant impacts on the energy budgets of birds.

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.

Growing tiny eyes: How juvenile jumping spiders retain high visual performance in the face of size limitations and developmental constraints.

Adult jumping spiders are known for their extraordinary eyesight and complex, visually guided behaviors, including elaborate communicatory displays, navigational abilities, and prey-specific predatory strategies. Juvenile spiders also exhibit many of these behaviors, yet their visual systems are many times smaller. How do juveniles retain high visually guided performance despite severe size constraints on their visual systems? We investigated developmental changes in eye morphology and visual function in the jumping spider Phidippus audax using morphology, histology, ophthalmoscopy, and optical measurements. We find that juvenile spiders have proportionally larger lenses in relation to their body size than adults. This should alleviate some of the costs of small body size on visual function. However, photoreceptor number in the anterior lateral eyes (ALE) remains constant from early development onward, consistent with a developmental constraint on photoreceptor differentiation. To accommodate these photoreceptors within the diminutive volume of the spiderling cephalothorax, ALE rhabdoms in early life stages are more tightly packed and significantly smaller in diameter and length, properties that expand across development. Lens focal lengths increase as eyes and retinas grow, resulting in a remarkable maintenance of ALE spatial acuity and field-of-view across life stages. However, this maintenance of acuity comes at a sensitivity cost given the small rhabdomal volumes required by space constraints early in life. Taken together, our results indicate that young jumping spiders have eyes already equipped for high acuity vision, but these young spiders may struggle to perform visually demanding behaviors in low-light environments, a notion that warrants further testing.

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.

Protecting Adolescent Confidentiality: A Response to One State's "Parents' Bill of Rights".

PURPOSE: In November, 2014, the State of Oklahoma enacted legislation potentially eliminating the provision of conditional confidential pediatric care. A consent form for treatment specific to adolescent confidential care was developed in response. This study examines parent/guardian response to the consent form. METHODS: The consent to treatment form describes the clinical and developmental benefits of conditional confidential treatment of adolescent minors and asks parent/guardians to waive the right to: (1) access confidential portions of the medical record, (2) be present for the physical exam, (3) be present for risk behavior discussions, and (4) consent for hormonal contraception, if indicated. RESULTS: Of 269parent/guardian respondents to the consent form, over 95% waived their rights for each of the four provisions. CONCLUSIONS: When provided with information on the rationale for provision of conditional confidential care, a diverse group of parent/guardians in a conservative state overwhelmingly agree to this standard of care.

Do Bar-Headed Geese Train for High Altitude Flights?

SYNOPSIS: Exercise at high altitude is extremely challenging, largely due to hypobaric hypoxia (low oxygen levels brought about by low air pressure). In humans, the maximal rate of oxygen consumption decreases with increasing altitude, supporting progressively poorer performance. Bar-headed geese (Anser indicus) are renowned high altitude migrants and, although they appear to minimize altitude during migration where possible, they must fly over the Tibetan Plateau (mean altitude 4800 m) for much of their annual migration. This requires considerable cardiovascular effort, but no study has assessed the extent to which bar-headed geese may train prior to migration for long distances, or for high altitudes. Using implanted loggers that recorded heart rate, acceleration, pressure, and temperature, we found no evidence of training for migration in bar-headed geese. Geese showed no significant change in summed activity per day or maximal activity per day. There was also no significant change in maximum heart rate per day or minimum resting heart rate, which may be evidence of an increase in cardiac stroke volume if all other variables were to remain the same. We discuss the strategies used by bar-headed geese in the context of training undertaken by human mountaineers when preparing for high altitude, noting the differences between their respective cardiovascular physiology.