AutoDesigner, a De Novo Design Algorithm for Rapidly Exploring Large Chemical Space for Lead Optimization: Application to the Design and Synthesis of d-Amino Acid Oxidase Inhibitors.

The lead optimization stage of a drug discovery program generally involves the design, synthesis, and assaying of hundreds to thousands of compounds. The design phase is usually carried out via traditional medicinal chemistry approaches and/or structure-based drug design (SBDD) when suitable structural information is available. Two of the major limitations of this approach are (1) difficulty in rapidly designing potent molecules that adhere to myriad project criteria, or the multiparameter optimization (MPO) problem, and (2) the relatively small number of molecules explored compared to the vast size of chemical space. To address these limitations, we have developed AutoDesigner, a de novo design algorithm. AutoDesigner employs a cloud-native, multistage search algorithm to carry out successive rounds of chemical space exploration and filtering. Millions to billions of virtual molecules are explored and optimized while adhering to a customizable set of project criteria such as physicochemical properties and potency. Additionally, the algorithm only requires a single ligand with measurable affinity and a putative binding model as a starting point, making it amenable to the early stages of an SBDD project where limited data are available. To assess the effectiveness of AutoDesigner, we applied it to the design of novel inhibitors of d-amino acid oxidase (DAO), a target for the treatment of schizophrenia. AutoDesigner was able to generate and efficiently explore over 1 billion molecules to successfully address a variety of project goals. The compounds generated by AutoDesigner that were synthesized and assayed (1) simultaneously met not only physicochemical criteria, clearance, and central nervous system (CNS) penetration (Kp,uu) cutoffs but also potency thresholds and (2) fully utilize structural data to discover and explore novel interactions and a previously unexplored subpocket in the DAO active site. The reported data demonstrate that AutoDesigner can play a key role in accelerating the discovery of novel, potent chemical matter within the constraints of a given drug discovery lead optimization campaign.

Potency- and Selectivity-Enhancing Mutations of Conotoxins for Nicotinic Acetylcholine Receptors Can Be Predicted Using Accurate Free-Energy Calculations.

Nicotinic acetylcholine receptor (nAChR) subtypes are key drug targets, but it is challenging to pharmacologically differentiate between them because of their highly similar sequence identities. Furthermore, α-conotoxins (α-CTXs) are naturally selective and competitive antagonists for nAChRs and hold great potential for treating nAChR disorders. Identifying selectivity-enhancing mutations is the chief aim of most α-CTX mutagenesis studies, although doing so with traditional docking methods is difficult due to the lack of α-CTX/nAChR crystal structures. Here, we use homology modeling to predict the structures of α-CTXs bound to two nearly identical nAChR subtypes, α3ß2 and α3ß4, and use free-energy perturbation (FEP) to re-predict the relative potency and selectivity of α-CTX mutants at these subtypes. First, we use three available crystal structures of the nAChR homologue, acetylcholine-binding protein (AChBP), and re-predict the relative affinities of twenty point mutations made to the α-CTXs LvIA, LsIA, and GIC, with an overall root mean square error (RMSE) of 1.08 ± 0.15 kcal/mol and an R2 of 0.62, equivalent to experimental uncertainty. We then use AChBP as a template for α3ß2 and α3ß4 nAChR homology models bound to the α-CTX LvIA and re-predict the potencies of eleven point mutations at both subtypes, with an overall RMSE of 0.85 ± 0.08 kcal/mol and an R2 of 0.49. This is significantly better than the widely used molecular mechanics-generalized born/surface area (MM-GB/SA) method, which gives an RMSE of 1.96 ± 0.24 kcal/mol and an R2 of 0.06 on the same test set. Next, we demonstrate that FEP accurately classifies α3ß2 nAChR selective LvIA mutants while MM-GB/SA does not. Finally, we use FEP to perform an exhaustive amino acid mutational scan of LvIA and predict fifty-two mutations of LvIA to have greater than 100X selectivity for the α3ß2 nAChR. Our results demonstrate the FEP is well-suited to accurately predict potency- and selectivity-enhancing mutations of α-CTXs for nAChRs and to identify alternative strategies for developing selective α-CTXs.

Exposure to music and noise-induced hearing loss (NIHL) among professional pop/rock/jazz musicians.

Noise-induced hearing loss (NIHL) has been extensively studied in industrial work environments. With the advent of new technologies, loud music has been increasingly affecting listeners outside of the industrial setting. Most research on the effects of music and hearing loss has focused on classical musicians. The purpose of the current study was to examine the relationship between the amount of experience a professional pop/rock/jazz musician has and objective and subjective variables of the musician's hearing loss. This study also examined professional pop/rock/jazz musicians' use of hearing protection devices in relation to the extent of their exposure to amplified music. Forty-four pop/rock/jazz musicians were interviewed using the Pop/Rock/Jazz Musician's Questionnaire (PRJMQ) in order to obtain self-reported symptoms of tinnitus and hyperacusis. Forty-two of the subjects were also tested for air-conduction hearing thresholds in the frequency range of 1-8 kHz. Results show that the extent of professional pop/rock/jazz musicians' exposure to amplified music was related to both objective and subjective variables of hearing loss: Greater musical experience was positively linked to higher hearing thresholds in the frequency range of 3-6 kHz and to the subjective symptom of tinnitus. Weekly hours playing were found to have a greater effect on hearing loss in comparison to years playing. Use of hearing protection was not linked to the extent of exposure to amplified music. It is recommended that further research be conducted with a larger sample, in order to gain a greater understanding of the detrimental effects of hours playing versus years playing.

How much gaming is too much? An analysis based on psychological distress.

Background: While there are calls to restrict the time spent on gaming because it is seen as problematic and potentially leading to gaming disorder (GD), there is conflicting evidence about this issue. We explored the association between the average weekly time spent gaming and reported GD symptoms. Additionally, Latent Profile Analysis was employed to investigate how time spent gaming relates to variables representing psychological distress (PD), such as satisfaction with life, symptoms of depression, and perceived stress. Methods: Data were collected using surveys with a large sample of highly engaged gamers (N = 14,740; Mage = 24.14 years, SDage = 7.0, 89.3% males). Results: We observed a positive, close to linear association between time spent gaming and GD symptoms. Groups at risk of GD played for about 42 h (SD = 19) on average, according to the American Psychiatric Association and World Health Organization frameworks. Furthermore, we identified four profiles representing varying levels of PD. Gamers reporting very high levels of PD (4.2% of the sample) played for 33 h per week on average. Remarkably, a substantial percentage of the sample (41.9%) showed no PD despite playing for 26 h per week. Conclusion: The association between gaming time and PD is complex as even prolonged time spent gaming can be unproblematic for many gamers.

A POCUS-first pathway to streamline care for children with suspected ileocolic intussusception.

OBJECTIVES: As point-of-care ultrasound (POCUS) has emerged as a valuable tool for intussusception screening, this quality improvement study aimed to implement a "POCUS-first" pathway in a Pediatric Emergency Department (ED) to streamline workflow and expedite care for children with suspected intussusception. METHODS: This was a prospective analysis of children diagnosed with ileocolic intussusception in a Pediatric ED between June 2022 and June 2023. The study compared the "POCUS-first" cohort with the group receiving only radiology-performed ultrasound. Key outcomes included physician initial assessment to radiology-performed US time and physician initial assessment to reduction time. Continuous improvement efforts incorporated pediatric emergency medicine physician training, education, and pathway dissemination through plan-do-study-act cycles. RESULTS: The study included 29 patients in the "POCUS-first" pathway group and 70 patients in the non-POCUS group. The "POCUS-first" pathway demonstrated a significantly shorter physician initial assessment to reduction time compared to the non-POCUS group (170.7 min vs. 240.6 min, p = 0.02). Among non-transferred patients, the "POCUS-first" group also had a significantly shorter emergency department length of stay (386 min vs. 544 min, p = 0.047). CONCLUSIONS: Implementation of a "POCUS-first" pathway for managing ileocolic intussusception led to notable improvements in process efficiency. The shorter physician initial assessment to reduction time highlights the potential for expedited decision-making and intervention. These study findings support the potential of this pathway to optimize the management and outcomes of children with ileocolic intussusception.

RéSUMé: OBJECTIFS: Comme l'échographie au point de soin (POCUS) est devenue un outil précieux pour le dépistage de l'intussusception, cette étude d'amélioration de la qualité visait à mettre en œuvre une voie "POCUS-first" dans un service d'urgence pédiatrique (ED) rationaliser le flux de travail et accélérer les soins aux enfants présentant une intussusception suspectée. MéTHODES: Il s'agissait d'une analyse prospective des enfants diagnostiqués avec une intussusception iléo-colique dans un DE pédiatrique entre juin 2022 et juin 2023. L'étude a comparé la cohorte "POCUS-first" avec le groupe recevant uniquement des ultrasons radiologiques. Les principaux résultats comprenaient l'évaluation initiale par le médecin du temps de radiologie effectué aux États-Unis et l'évaluation initiale par le médecin du temps de réduction. Les efforts d'amélioration continue ont incorporé la formation, l'éducation et la diffusion des parcours des médecins en médecine d'urgence pédiatrique par le biais de cycles de plan-do-study-act. RéSULTATS: L'étude a inclus 29 patients dans le groupe "POCUS-first" et 70 patients dans le groupe non-POCUS. La voie "POCUS-first" a démontré une évaluation initiale significativement plus courte du temps de réduction par rapport au groupe non POCUS (170,7 minutes vs. 240,6 minutes, p = 0,02). Parmi les patients non transférés, le groupe "POCUS-first" a également eu une durée de séjour à l'urgence significativement plus courte (386 minutes vs. 544 minutes, p = 0,047). CONCLUSIONS: La mise en œuvre d'une voie "POCUS-first" pour gérer l'intussusception iléo-colique a conduit à des améliorations notables de l'efficacité des processus. L'évaluation initiale plus courte du médecin pour réduire le temps met en évidence la possibilité d'une prise de décision et d'une intervention accélérée. Les résultats de cette étude confirment le potentiel de cette voie pour optimiser la prise en charge et les résultats des enfants atteints d'intussusception iléo-colique.

The concept of recovery in gaming disorder: A scoping review.

Background: Recovery from mental health and behavioral disorders is classically defined as a reduction in symptoms. More recent definitions see it as a process in which individuals improve their health, wellness and other life domains. The inclusion of gaming disorder (GD) in the 11th International Classification of Diseases in 2019 prompted growing interest in GD. However, relatively little is known about recovery from GD, and there is scant literature describing or assessing its course. Objectives: This scoping review was designed to explore the state of the art on recovery from GD (e.g., terminology and measures used to assess recovery, main topics in studies about recovery from GD). Methods: PubMed, Web of Science, and Scopus databases were searched and critically reviewed according to PRISMA guidelines. We included empirical studies in English covering individuals across all age groups who met the diagnostic criteria of GD/internet gaming disorder (IGD) according to valid scales that relate to recovery or any change, and were published before February 2022. Results: A total of 47 out of 966 studies met the inclusion criteria. Recovery as a concept is not explicitly mentioned in GD studies. Rather, changes in subjects' disorders are described in terms of decreases/reductions in symptom severity, or improvement/increases. These changes are primarily measured by scales that evaluate symptom reduction and/or improvement in GD and other psychopathologies. Conclusions: The concept of recovery is included in the GD field but is not clearly mentioned or used. Therapists and researchers should aim to promote and integrate the notion of recovery in GD.

Basic Residues at Position 11 of α-Conotoxin LvIA Influence Subtype Selectivity between α3ß2 and α3ß4 Nicotinic Receptors via an Electrostatic Mechanism.

Understanding the determinants of α-conotoxin (α-CTX) selectivity for different nicotinic acetylcholine receptor (nAChR) subtypes is a prerequisite for the design of tool compounds to study nAChRs. However, selectivity optimization of these small, disulfide-rich peptides is difficult not only because of an absence of α-CTX/nAChR co-structures but also because it is challenging to predict how a mutation to an α-CTX will alter its potency and selectivity. As a prototypical system to investigate selectivity, we employed the α-CTX LvIA that is 25-fold selective for the α3ß2 nAChR over the related α3ß4 nAChR subtype, which is a target for nicotine addiction. Using two-electrode voltage clamp electrophysiology, we identified LvIA[D11R] that is 2-fold selective for the α3ß4 nAChR, reversing the subtype preference. This effect is specifically due to the change in charge and not shape of LvIA[D11R], as substitution of D11 with citrulline retains selectivity for the α3ß2 nAChR. Furthermore, LvIA[D11K] shows a stronger reversal, with 4-fold selectivity for the α3ß4 nAChR. Motivated by these findings, using site-directed mutagenesis, we found that ß2[K79A] (I79 on ß4), but not ß2[K78A] (N78 on ß4), largely restores the potency of basic mutants at position 11. Finally, to understand the structural basis of this effect, we used AlphaFold2 to generate models of LvIA in complex with both nAChR subtypes. Both models confirm the plausibility of an electrostatic mechanism to explain the data and also reproduce a broad range of potency and selectivity structure-activity relationships for LvIA mutants, as measured using free energy perturbation simulations. Our work highlights how electrostatic interactions can drive α-CTX selectivity and may serve as a strategy for optimizing the selectivity of LvIA and other α-CTXs.

Potency-Enhancing Mutations of Gating Modifier Toxins for the Voltage-Gated Sodium Channel NaV1.7 Can Be Predicted Using Accurate Free-Energy Calculations.

Gating modifier toxins (GMTs) isolated from venomous organisms such as Protoxin-II (ProTx-II) and Huwentoxin-IV (HwTx-IV) that inhibit the voltage-gated sodium channel NaV1.7 by binding to its voltage-sensing domain II (VSDII) have been extensively investigated as non-opioid analgesics. However, reliably predicting how a mutation to a GMT will affect its potency for NaV1.7 has been challenging. Here, we hypothesize that structure-based computational methods can be used to predict such changes. We employ free-energy perturbation (FEP), a physics-based simulation method for predicting the relative binding free energy (RBFE) between molecules, and the cryo electron microscopy (cryo-EM) structures of ProTx-II and HwTx-IV bound to VSDII of NaV1.7 to re-predict the relative potencies of forty-seven point mutants of these GMTs for NaV1.7. First, FEP predicted these relative potencies with an overall root mean square error (RMSE) of 1.0 ± 0.1 kcal/mol and an R2 value of 0.66, equivalent to experimental uncertainty and an improvement over the widely used molecular-mechanics/generalized born-surface area (MM-GB/SA) RBFE method that had an RMSE of 3.9 ± 0.8 kcal/mol. Second, inclusion of an explicit membrane model was needed for the GMTs to maintain stable binding poses during the FEP simulations. Third, MM-GB/SA and FEP were used to identify fifteen non-standard tryptophan mutants at ProTx-II[W24] predicted in silico to have a at least a 1 kcal/mol gain in potency. These predicted potency gains are likely due to the displacement of high-energy waters as identified by the WaterMap algorithm for calculating the positions and thermodynamic properties of water molecules in protein binding sites. Our results expand the domain of applicability of FEP and set the stage for its prospective use in biologics drug discovery programs involving GMTs and NaV1.7.

Buteyko Breathing Technique for Exertion-Induced Paradoxical Vocal Fold Motion (EI-PVFM).

PURPOSE: The primary purpose of the current study was to determine the usefulness of Buteyko breathing technique (BBT) in reducing dyspnea in patients with one form of Paradoxical Vocal Fold Motion (PVFM), exertion-induced PVFM (EI-PVFM), concomitant with hyperventilation. The secondary purpose was to determine whether BBT had an effect on physiological markers of hyperventilation, as speculated by BBT theory: respiratory tidal minute volume (RTMV), end-tidal carbon dioxide (ETCO2), and resting heart rate (HR). METHODS: Using a within-subjects, repeated measures group design, 12 participants with EI-PVFM and hyperventilation underwent 12 weeks of BBT, following an initial no-treatment control condition. Outcome measures of PVFM-dyspnea frequency and severity-and of hyperventilation-HR, RTMV, and ETCO2-were acquired pre- and post-treatment. RESULTS: Results showed post-treatment decreases in dyspnea severity, HR, and RTMV, as well as increases in ETCO2. Decreases in dyspnea and RTMV measures remained after correction for alpha inflation. CONCLUSIONS: Findings suggest BBT may be useful for some individuals with EI-PVFM and hyperventilation. The high prevalence of hyperventilation in EI-PVFM found in the current study warrants further investigation.

All gifts large and small: toward an understanding of the ethics of pharmaceutical industry gift-giving.

Much attention has been focused in recent years on the ethical acceptability of physicians receiving gifts from drug companies. Professional guidelines recognize industry gifts as a conflict of interest and establish thresholds prohibiting the exchange of large gifts while expressly allowing for the exchange of small gifts such as pens, note pads, and coffee. Considerable evidence from the social sciences suggests that gifts of negligible value can influence the behavior of the recipient in ways the recipient does not always realize. Policies and guidelines that rely on arbitrary value limits for gift-giving or receipt should be reevaluated.

Correlation of ureteral stone measurements by CT and plain film radiography: utility of the KUB.

BACKGROUND AND PURPOSE: The practice of utilizing helical CT to evaluate patients suspected of renal colic is increasing. Little is known about the accuracy of CT in estimating stone size or the utility of an accompanying plain abdominal radiograph (KUB film). The purpose of our study was to compare ureteral stone size estimation by helical CT and plain film and determine whether a KUB film provides additional information useful in patient management. PATIENTS AND METHODS: Thirty consecutive patients (17 male, 13 female) having both a helical CT and a KUB study for evaluation of renal colic secondary to ureteral calculi comprised the study population. Calculus number, location, and dimensions were determined from these images. Stone dimensions were measured using electronic calipers on a picture archiving and communications system. Information found by KUB and CT was compared, and both sets of stone measurements were correlated with patient outcome. RESULTS: The mean maximal stone transverse diameter and length were similar on CT and plain film: 5.8 mm v 5.8 mm and 9.5 mm v 8.9 mm, respectively (P = 0.57 and 0.29, respectively). The mean anteroposterior stone diameter on CT of 6.8 mm was statistically greater than the transverse diameter as measured by both CT and KUB, which were 5.8 mm and 5.8 mm (P = 0.0002 and 0.0007, respectively). Eleven patients spontaneously passed their stones, while 19 patients required intervention. Patient outcome, as predicted by transverse stone width, was similar for CT and KUB data. CONCLUSIONS: The management of patients with ureteral calculi relies on estimated stone size and the stone's potential for spontaneous passage. Stone dimensions estimated by CT are similar to the size determined by plain film radiography. Although plain film radiography does not provide information on stone dimensions beyond that obtained with CT, it does reveal precise stone location and radiolucency, data helpful in following and treating patients.

All gifts large and small: toward an understanding of the ethics of pharmaceutical industry gift-giving.

Much attention has been focused in recent years on the ethical acceptability of physicians receiving gifts from drug companies. Professional guidelines recognize industry gifts as a conflict of interest and establish thresholds prohibiting the exchange of large gifts while expressly allowing for the exchange of small gifts such as pens, note pads, and coffee. Considerable evidence from the social sciences suggests that gifts of negligible value can influence the behavior of the recipient in ways the recipient does not always realize. Policies and guidelines that rely on arbitrary value limits for gift-giving or receipt should be reevaluated.

Sociodemographic characteristics and health related quality of life in men attending prostate cancer support groups.

PURPOSE: Prostate cancer can be associated with anxiety, depression and fears of recurrence and side effects of treatment. Support groups may help meet the needs of patients with cancer by providing treatment information and emotional support. We describe men in prostate cancer support groups and compare them to a national registry. METHODS AND METHODS: Men attending prostate cancer support groups in the San Francisco Bay area completed a questionnaire including sociodemographic and clinical characteristics, health related quality of life items, satisfaction with treatment, relief of prostate cancer symptoms and bother from perceived side effects of treatment. Patients in support groups were compared to men enrolled in a national prostate cancer registry (Cancer of the Prostate Strategic Urological Research Endeavor). RESULTS: Men attending support groups had higher annual income and education levels, lower median serum prostate specific antigen and higher cancer grades than men in Cancer of the Prostate Strategic Urological Research Endeavor. Clinical stage was comparable for the 2 groups. Men in support groups were satisfied with treatment and alleviation from symptoms. Adjusting for ethnicity, marital status, age and type of treatment, sexual function scores were higher in men who attended support groups (p = 0.001). There was no statistically significant difference in bowel and urinary function between groups, although urinary function approached statistical significance at p = 0.05. Sexual and bowel bother scores indicated less bother for men in support groups (p < or = 0.025). CONCLUSIONS: Men enrolled in support groups have unique sociodemographic characteristics. Their health related quality of life appears to be better than that of other men with prostate cancer. Whether this is related to support group participation is not known. Additional studies are required to determine whether routine support group participation improves outcomes in men with prostate cancer.