Structures of the Staphylococcus aureus ribosome inhibited by fusidic acid and fusidic acid cyclopentane.

The antibiotic fusidic acid (FA) is used to treat Staphylococcus aureus infections. It inhibits protein synthesis by binding to elongation factor G (EF-G) and preventing its release from the ribosome after translocation. While FA, due to permeability issues, is only effective against gram-positive bacteria, the available structures of FA-inhibited complexes are from gram-negative model organisms. To fill this knowledge gap, we solved cryo-EM structures of the S. aureus ribosome in complex with mRNA, tRNA, EF-G and FA to 2.5 Å resolution and the corresponding complex structures with the recently developed FA derivative FA-cyclopentane (FA-CP) to 2.0 Å resolution. With both FA variants, the majority of the ribosomal particles are observed in chimeric state and only a minor population in post-translocational state. As expected, FA binds in a pocket between domains I, II and III of EF-G and the sarcin-ricin loop of 23S rRNA. FA-CP binds in an identical position, but its cyclopentane moiety provides additional contacts to EF-G and 23S rRNA, suggesting that its improved resistance profile towards mutations in EF-G is due to higher-affinity binding. These high-resolution structures reveal new details about the S. aureus ribosome, including confirmation of many rRNA modifications, and provide an optimal starting point for future structure-based drug discovery on an important clinical drug target.

Harnessing the open access version of ChatGPT for enhanced clinical opinions.

With the advent of Large Language Models (LLMs) like ChatGPT, the integration of Generative Artificial Intelligence (GAI) into clinical medicine is becoming increasingly feasible. This study aimed to evaluate the ability of the freely available ChatGPT-3.5 to generate complex differential diagnoses, comparing its output to case records of the Massachusetts General Hospital published in the New England Journal of Medicine (NEJM). Forty case records were presented to ChatGPT-3.5, prompting it to provide a differential diagnosis and then narrow it down to the most likely diagnosis. The results indicated that the final diagnosis was included in ChatGPT-3.5's original differential list in 42.5% of the cases. After narrowing, ChatGPT correctly determined the final diagnosis in 27.5% of the cases, demonstrating a decrease in accuracy compared to previous studies using common chief complaints. These findings emphasize the necessity for further investigation into the capabilities and limitations of LLMs in clinical scenarios while highlighting the potential role of GAI as an augmented clinical opinion. Anticipating the growth and enhancement of GAI tools like ChatGPT, physicians and other healthcare workers will likely find increasing support in generating differential diagnoses. However, continued exploration and regulation are essential to ensure the safe and effective integration of GAI into healthcare practice. Future studies may seek to compare newer versions of ChatGPT or investigate patient outcomes with physicians integrating this GAI technology. Understanding and expanding GAI's capabilities, particularly in differential diagnosis, may foster innovation and provide additional resources, especially in underserved areas in the medical field.

Discovery of KRB-456, a KRAS G12D Switch-I/II Allosteric Pocket Binder That Inhibits the Growth of Pancreatic Cancer Patient-derived Tumors.

Currently, there are no clinically approved drugs that directly thwart mutant KRAS G12D, a major driver of human cancer. Here, we report on the discovery of a small molecule, KRB-456, that binds KRAS G12D and inhibits the growth of pancreatic cancer patient-derived tumors. Protein nuclear magnetic resonance studies revealed that KRB-456 binds the GDP-bound and GCP-bound conformation of KRAS G12D by forming interactions with a dynamic allosteric binding pocket within the switch-I/II region. Isothermal titration calorimetry demonstrated that KRB-456 binds potently to KRAS G12D with 1.5-, 2-, and 6-fold higher affinity than to KRAS G12V, KRAS wild-type, and KRAS G12C, respectively. KRB-456 potently inhibits the binding of KRAS G12D to the RAS-binding domain (RBD) of RAF1 as demonstrated by GST-RBD pulldown and AlphaScreen assays. Treatment of KRAS G12D-harboring human pancreatic cancer cells with KRB-456 suppresses the cellular levels of KRAS bound to GTP and inhibits the binding of KRAS to RAF1. Importantly, KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer whose tumors harbor KRAS G12D and KRAS G12V and who relapsed after chemotherapy and radiotherapy. These results warrant further development of KRB-456 for pancreatic cancer. SIGNIFICANCE: There are no clinically approved drugs directly abrogating mutant KRAS G12D. Here, we discovered a small molecule, KRB-456, that binds a dynamic allosteric binding pocket within the switch-I/II region of KRAS G12D. KRB-456 inhibits P-MEK, P-AKT, and P-S6 levels in vivo and inhibits the growth of subcutaneous and orthotopic xenografts derived from patients with pancreatic cancer. This discovery warrants further advanced preclinical and clinical studies in pancreatic cancer.

Obstetric-Focused POCUS Training for Medical Students.

Point of care ultrasound (POCUS) is rapidly expanding throughout the United States. Due to its ability to quickly and accurately diagnose and guide therapy for critical conditions, POCUS is becoming routine in many specialties, with established guidelines in fields such as emergency medicine and critical care 1, 2, 3. For example, a study entitled "Ultrasound Integration in Undergraduate Medical Education: Comparison of Ultrasound Proficiency Between Trained and Untrained Medical Students" initiated an Emergency Medicine POCUS curriculum for first-year medical students that showed an increase in ultrasound capability 4. In short, as POCUS becomes more common practice, medical schools are beginning to implement POCUS training into their undergraduate medical education; studies from these institutions demonstrate that implementing a formal ultrasound curriculum into preclinical medical education significantly increases medical students' POCUS capabilities4, 5 and assisted in their understanding and learning of anatomy 6, 7.

Porin-independent accumulation in Pseudomonas enables antibiotic discovery.

Gram-negative antibiotic development has been hindered by a poor understanding of the types of compounds that can accumulate within these bacteria1,2. The presence of efflux pumps and substrate-specific outer-membrane porins in Pseudomonas aeruginosa renders this pathogen particularly challenging3. As a result, there are few antibiotic options for P. aeruginosa infections4 and its many porins have made the prospect of discovering general accumulation guidelines seem unlikely5. Here we assess the whole-cell accumulation of 345 diverse compounds in P. aeruginosa and Escherichia coli. Although certain positively charged compounds permeate both bacterial species, P. aeruginosa is more restrictive compared to E. coli. Computational analysis identified distinct physicochemical properties of small molecules that specifically correlate with P. aeruginosa accumulation, such as formal charge, positive polar surface area and hydrogen bond donor surface area. Mode of uptake studies revealed that most small molecules permeate P. aeruginosa using a porin-independent pathway, thus enabling discovery of general P. aeruginosa accumulation trends with important implications for future antibiotic development. Retrospective antibiotic examples confirmed these trends and these discoveries were then applied to expand the spectrum of activity of a gram-positive-only antibiotic, fusidic acid, into a version that demonstrates a dramatic improvement in antibacterial activity against P. aeruginosa. We anticipate that these discoveries will facilitate the design and development of high-permeating antipseudomonals.

Prenatal diagnosis of bilateral anophthalmia: Identifying de novo SOX2 variant.

A 26 year old nulligravida presented at 24 weeks gestation for the second opinion of abnormal fetal profile and mid-face views on ultrasound at another institution. A detailed fetal anatomic ultrasound at our facility revealed the absence of fetal lens and globes bilaterally consistent with bilateral anophthalmia (HP: 0000528) without other anomalies. Karyotype and chromosomal microarray analysis were completed from amniocentesis sample. After these results, duo exome testing with paternal sequencing was completed from proband amniotic fluid sample and parental blood samples. A pathogenic variant in SOX2 (NM_003106.3: c.513C>G p.(Tyr171*Ter)) with heterozygous autosomal dominant inheritance resulted. On duo exome testing with paternal segregation analysis, the variant was found to be consistent with likely sporadic de novo inheritance. The SOX2 variant reported is consistent with the fetal phenotype in this case. While germline mosaicism could exist, this identified variant provided the family with a likely explanation for this proband's finding. This ultrasound and genetic testing allowed the family to make decisions related to planning in current and future pregnancies.

ChatGPT: a pioneering approach to complex prenatal differential diagnosis.

This commentary examines how ChatGPT can assist healthcare teams in the prenatal diagnosis of rare and complex cases by creating a differential diagnoses based on deidentified clinical findings, while also acknowledging its limitations.

Chat Generative Pre-trained Transformer: why we should embrace this technology.

With the advent of artificial intelligence that not only can learn from us but also can communicate with us in plain language, humans are embarking on a brave new future. The interaction between humans and artificial intelligence has never been so widespread. Chat Generative Pre-trained Transformer is an artificial intelligence resource that has potential uses in the practice of medicine. As clinicians, we have the opportunity to help guide and develop new ways to use this powerful tool. Optimal use of any tool requires a certain level of comfort. This is best achieved by appreciating its power and limitations. Being part of the process is crucial in maximizing its use in our field. This clinical opinion demonstrates the potential uses of Chat Generative Pre-trained Transformer for obstetrician-gynecologists and encourages readers to serve as the driving force behind this resource.

Remote patient monitoring for management of diabetes mellitus in pregnancy is associated with improved maternal and neonatal outcomes.

BACKGROUND: Diabetes mellitus is a common medical complication of pregnancy, and its treatment is complex. Recent years have seen an increase in the application of mobile health tools and advanced technologies, such as remote patient monitoring, with the aim of improving care for diabetes mellitus in pregnancy. Previous studies of these technologies for the treatment of diabetes in pregnancy have been small and have not clearly shown clinical benefit with implementation. OBJECTIVE: Remote patient monitoring allows clinicians to monitor patients' health data (such as glucose values) in near real-time, between office visits, to make timely adjustments to care. Our objective was to determine if using remote patient monitoring for the management of diabetes in pregnancy leads to an improvement in maternal and neonatal outcomes. STUDY DESIGN: This was a retrospective cohort study of pregnant patients with diabetes mellitus managed by the maternal-fetal medicine practice at one academic institution between October 2019 and April 2021. This practice transitioned from paper-based blood glucose logs to remote patient monitoring in February 2020. Remote patient monitoring options included (1) device integration with Bluetooth glucometers that automatically uploaded measured glucose values to the patient's Epic MyChart application or (2) manual entry in which patients manually logged their glucose readings into their MyChart application. Values in the MyChart application directly transferred to the patient's electronic health record for review and management by clinicians. In total, 533 patients were studied. We compared 173 patients managed with paper logs to 360 patients managed with remote patient monitoring (176 device integration and 184 manual entry). Our primary outcomes were composite maternal morbidity (which included third- and fourth-degree lacerations, chorioamnionitis, postpartum hemorrhage requiring transfusion, postpartum hysterectomy, wound infection or separation, venous thromboembolism, and maternal admission to the intensive care unit) and composite neonatal morbidity (which included umbilical cord pH <7.00, 5 minute Apgar score <7, respiratory morbidity, hyperbilirubinemia, meconium aspiration, intraventricular hemorrhage, necrotizing enterocolitis, sepsis, pneumonia, seizures, hypoxic ischemic encephalopathy, shoulder dystocia, trauma, brain or body cooling, and neonatal intensive care unit admission). Secondary outcomes were measures of glycemic control and the individual components of the primary composite outcomes. We also performed a secondary analysis in which the patients who used the two different remote patient monitoring options (device integration vs manual entry) were compared. Chi-square, Fisher's exact, 2-sample t, and Mann-Whitney tests were used to compare the groups. A result was considered statistically significant at P<.05. RESULTS: Maternal baseline characteristics were not significantly different between the remote patient monitoring and paper groups aside from a slightly higher baseline rate of chronic hypertension in the remote patient monitoring group (6.1% vs 1.2%; P=.011). The primary outcomes of composite maternal and composite neonatal morbidity were not significantly different between the groups. However, remote patient monitoring patients submitted more glucose values (177 vs 146; P=.008), were more likely to achieve glycemic control in target range (79.2% vs 52.0%; P<.0001), and achieved the target range sooner (median, 3.3 vs 4.1 weeks; P=.025) than patients managed with paper logs. This was achieved without increasing in-person visits. Remote patient monitoring patients had lower rates of preeclampsia (5.8% vs 15.0%; P=.0006) and their infants had lower rates of neonatal hypoglycemia in the first 24 hours of life (29.8% vs 51.7%; P<.0001). CONCLUSION: Remote patient monitoring for the management of diabetes mellitus in pregnancy is superior to a traditional paper-based approach in achieving glycemic control and is associated with improved maternal and neonatal outcomes.

Vasa previa: avoiding incising the membranes at cesarean delivery.

We present our technique for cesarean delivery of prenatally diagnosed vasa previa in which we avoid incising the membranes and fetal vessels. This technique allows direct visualization of the fetal blood vessels and may prevent blood loss from the baby at the time of birth.

Performance of a Multianalyte 'Rule-Out' Assay in Pregnant Individuals With Suspected Preeclampsia.

BACKGROUND: The ability to diagnose preeclampsia clinically is suboptimal. Our objective was to validate a novel multianalyte assay and characterize its performance, when intended for use as an aid to rule-out preeclampsia. METHODS: Prospective, multicenter cohort study of pregnant individuals presenting between 280/7 and 366/7 weeks' with preeclampsia-associated signs and symptoms. Individuals not diagnosed with preeclampsia after baseline evaluation were enrolled in the study cohort, with those who later developed preeclampsia, classified as cases and compared with a negative control group who did not develop preeclampsia. Individuals with assay values at time of enrollment ≥0.0325, determined using a previously developed algorithm, considered at risk. The primary analysis was the time to develop preeclampsia assessed using a multivariate Cox regression model. RESULTS: One thousand thirty-six pregnant individuals were enrolled in the study cohort with an incidence of preeclampsia of 30.3% (27.6%-33.2%). The time to develop preeclampsia was shorter for those with an at-risk compared with negative assay result (log-rank P<0.0001; adjusted hazard ratio of 4.81 [3.69-6.27, P<0.0001]). The performance metrics for the assay to rule-out preeclampsia within 7 days of enrollment showed a sensitivity 76.4% (67.5%-83.5%), negative predictive value 95.0% (92.8%-96.6%), and negative likelihood ratio 0.46 (0.32-0.65). Assay performance improved if delivery occurred <37 weeks and for individuals enrolled between 28 and 35 weeks. CONCLUSIONS: We confirmed that a novel multianalyte assay was associated with the time to develop preeclampsia and has a moderate sensitivity and negative likelihood ratio but high negative predictive value when assessed as an aid to rule out preeclampsia within 7 days of enrollment. REGISTRATION: The study was registered on Clinicaltrials.gov (Identifier NCT02780414).

Combined Medical and Minimally Invasive Robotic Surgical Approach to the Treatment and Repair of Cesarean Scar Pregnancies.

BACKGROUND AND OBJECTIVES: The rise in cesarean deliveries, has led to increase in maternal complications in subsequent pregnancies such as abnormal placental implantation, uterine rupture, hemorrhage and, less commonly, cesarean scar pregnancies (CSP). Our objective was to describe patient characteristics following a combined medical and surgical treatment approach to first trimester cesarean scar pregnancies. METHODS: This was a case series approved by the Institutional Review Board of cesarean scar pregnancies over a two-year period at a single academic institution. The study included five patients with diagnosed cesarean scar pregnancies opting for pregnancy termination with the desire for fertility preservation. Medical treatment involved intra-gestational sac injection of lidocaine followed by systemic injection of methotrexate. At a minimum of two months later, surgical resection of cesarean scar pregnancy and repair of the uterus was performed. RESULTS: Median patient age was 36 (range 34 - 42) years, with 4 (3 - 10) prior pregnancies and 2 (1 - 3) prior cesarean deliveries. 40% (2/5) were Hispanic, 20% (1/5) Caucasian, 20% (1/5) African-American, and 20% (1/5) South Asian. After medical intervention, patients waited on average 4.6 ± 2.3 months before surgery. No post-intervention complications or recurrences occurred. Two patients had a subsequent pregnancy. CONCLUSION: This case series demonstrates an ideal management of cesarean scar pregnancy using combined medical and surgical approach in treating current ectopic pregnancy and repairing the uterine defect successfully without recurrence.

Application of telemedicine video visits in a maternal-fetal medicine practice at the epicenter of the COVID-19 pandemic.

BACKGROUND: Telemedicine in obstetrics has mostly been described in the rural areas that have limited access to subspecialties. During the COVID-19 pandemic, health systems rapidly expanded telemedicine services for urgent and nonurgent healthcare delivery, even in urban settings. The New York University health system implemented a prompt systemwide expansion of video-enabled telemedicine visits, increasing telemedicine to >8000 visits daily within 6 weeks of the beginning of the pandemic. There are limited studies that explore patient and provider satisfaction of telemedicine visits in obstetrical patients during the COVID-19 epidemic, particularly in the United States. OBJECTIVE: This study aimed to evaluate both the patients' and the providers' satisfaction with the administration of maternal-fetal medicine services through telemedicine and to identify the factors that drive the patients' desire for future obstetrical telemedicine services. STUDY DESIGN: A cross-sectional survey was administered to patients who completed a telemedicine video visit with the Division of Maternal-Fetal Medicine at the New York University Langone Hospital-Long Island from March 19, 2020, to May 26, 2020. A 10-question survey assessing the patients' digital experience and desire for future use was either administered by telephone or self-administered by the patients via a link after obtaining verbal consent. The survey responses were scored from 1-strongly disagree to 5-strongly agree. We analyzed the demographics and survey responses of the patients who agreed to vs those who answered neutral or disagree to the question "I would like telehealth to be an option for future obstetric visits." The providers also answered a similar 10-question survey. The median scores were compared using appropriate tests. A P value of <.05 was considered significant. RESULTS: A total of 253 patients participated in 433 telemedicine visits, and 165 patients completed the survey, resulting in a 65% survey response rate. Overall, there were high rates of patient satisfaction in all areas assessed. Those who desired future telemedicine had significantly greater agreeability that they were able to see and hear their provider easily (5 [4.5, 5] vs 5 [4, 5]; P=.014) and that the lack of physical activity was not an issue (5 [4, 5] vs 5 [4, 5]; P=.032). They were also more likely to agree that the telemedicine visits were as good as in-person visits (4 [3, 5] vs 3 [2, 3]; P<.001) and that telehealth made it easier for them to see doctors or specialists (5 [4, 5] vs 3 [2, 3]; P<.001). The patients seeking consults for poor obstetrical history were more likely to desire future telemedicine compared with other visit types (19 (90%) vs 2 (10%); P=.05). Provider survey responses also demonstrated high levels of satisfaction, with 83% agreeing that they would like telemedicine to be an option for future obstetrical visits. CONCLUSION: We demonstrated that maternal-fetal medicine obstetrical patients and providers were highly satisfied with the implementation of telemedicine during the initial wave of the COVID-19 pandemic and a majority of them desire telemedicine as an option for future visits. A patient's desire for future telemedicine visits was significantly affected by their digital experience, the perception of a lack of need for physical contact, perceived time saved on travel, and access to healthcare providers. Health systems need to continue to improve healthcare delivery and invest in innovative solutions to conduct physical examinations remotely.