Effectiveness of Nirmatrelvir-Ritonavir for the Prevention of COVID-19-Related Hospitalization and Mortality: A Systematic Literature Review.

BACKGROUND: Nirmatrelvir/ritonavir (NMV/r) is an oral antiviral drug used to treat mild-to-moderate coronavirus disease 2019 (COVID-19) in patients aged 12 years or older at high risk of progression to severe disease (eg, hospitalization and death). Despite being the preferred option for outpatient treatment in the majority of countries worldwide, NMV/r is currently underutilized in real-world clinical practice. AREAS OF UNCERTAINTY: As numerous real-world studies have described patient outcomes following treatment with NMV/r, this systematic literature review provides a comprehensive summary of evidence on NMV/r effectiveness against hospitalization and mortality further organized by clinically meaningful categories, such as acute versus longer-term follow-up, age, underlying health conditions, and vaccination status, to help inform health care decision making. DATA SOURCES: We searched Embase and PubMed (December 22, 2021-March 31, 2023) and congress abstracts (December 1, 2021-December 31, 2022) for reports describing NMV/r effectiveness. THERAPEUTIC ADVANCES: In total, 18 real-world studies met final selection criteria. The evidence showed that NMV/r significantly reduced postinfection risk of all-cause and COVID-19-related hospitalization and mortality in both acute (≤30 days) (21%-92%) and longer-term (>30 days) (1%-61%) follow-up. The reduction in postinfection risk was higher when treatment was received within 5 days of symptom onset. Real-world effectiveness of NMV/r treatment was observed regardless of age, underlying high-risk conditions, and vaccination status. CONCLUSION: The systematic literature review findings demonstrated the effectiveness of NMV/r against hospitalization and mortality during the Omicron period among individuals at high risk of progression to severe COVID-19 disease.

Normality Analysis of Numeric Rating Scale Scores in Patients with Chronic Axial Spine Pain Before and After Medial Branch Blocks: a Multicenter Study.

OBJECTIVE: The statistical analysis typically employed to compare pain both before and after interventions assumes scores are normally distributed. The present study evaluates whether Numeric Rating Scale (NRS), specifically the NRS-11, scores are indeed normally distributed in a clinically-relevant cohort of adults with chronic axial spine pain pre- and post-analgesic intervention. METHODS: Retrospective review from four academic medical centers of prospectively collected data from a uniform pain diary administered to consecutive patients after undergoing medial branch blocks. The pain diary assessed NRS-11 scores immediately pre-injection and at 12 different time points post-injection up to 48 hours. D'Agostino-Pearson tests were used to test normality at all time points. RESULTS: One hundred fifty pain diaries were reviewed and despite normally distributed pre-injection NRS-11 scores (K2 = 0.655, p = 0.72), all post-injection NRS-11 data was not normally distributed (K2 = 9.70- 17.62, p = 0.0001-0.008). CONCLUSIONS: Although the results of parametric analyses of NRS-11 scores are commonly reported in pain research, some properties of NRS-11 do not satisfy the assumptions required for these analyses. The data demonstrate non-normal distributions in post-intervention NRS-11 scores, thereby violating a key requisite for parametric analysis. We urge pain researchers to consider appropriate statistical analysis and reporting for non-normally distributed NRS-11 scores to ensure accurate interpretation and communication of these data. Practicing pain physicians should similarly recognize that parametric post-intervention pain score statistics may not accurately describe the data and should expect manuscripts to utilize measures of normality to justify the selected statistical methods.

RNA language models predict mutations that improve RNA function.

Structured RNA lies at the heart of many central biological processes, from gene expression to catalysis. While advances in deep learning enable the prediction of accurate protein structural models, RNA structure prediction is not possible at present due to a lack of abundant high-quality reference data. Furthermore, available sequence data are generally not associated with organismal phenotypes that could inform RNA function. We created GARNET (Gtdb Acquired RNa with Environmental Temperatures), a new database for RNA structural and functional analysis anchored to the Genome Taxonomy Database (GTDB). GARNET links RNA sequences derived from GTDB genomes to experimental and predicted optimal growth temperatures of GTDB reference organisms. This enables construction of deep and diverse RNA sequence alignments to be used for machine learning. Using GARNET, we define the minimal requirements for a sequence- and structure-aware RNA generative model. We also develop a GPT-like language model for RNA in which triplet tokenization provides optimal encoding. Leveraging hyperthermophilic RNAs in GARNET and these RNA generative models, we identified mutations in ribosomal RNA that confer increased thermostability to the Escherichia coli ribosome. The GTDB-derived data and deep learning models presented here provide a foundation for understanding the connections between RNA sequence, structure, and function.

Reciprocal antagonism of PIN1-APC/CCDH1 governs mitotic protein stability and cell cycle entry.

Induced oncoproteins degradation provides an attractive anti-cancer modality. Activation of anaphase-promoting complex (APC/CCDH1) prevents cell-cycle entry by targeting crucial mitotic proteins for degradation. Phosphorylation of its co-activator CDH1 modulates the E3 ligase activity, but little is known about its regulation after phosphorylation and how to effectively harness APC/CCDH1 activity to treat cancer. Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1)-catalyzed phosphorylation-dependent cis-trans prolyl isomerization drives tumor malignancy. However, the mechanisms controlling its protein turnover remain elusive. Through proteomic screens and structural characterizations, we identify a reciprocal antagonism of PIN1-APC/CCDH1 mediated by domain-oriented phosphorylation-dependent dual interactions as a fundamental mechanism governing mitotic protein stability and cell-cycle entry. Remarkably, combined PIN1 and cyclin-dependent protein kinases (CDKs) inhibition creates a positive feedback loop of PIN1 inhibition and APC/CCDH1 activation to irreversibly degrade PIN1 and other crucial mitotic proteins, which force permanent cell-cycle exit and trigger anti-tumor immunity, translating into synergistic efficacy against triple-negative breast cancer.

Differences in Pertussis Incidence by Race and Ethnicity in the United States, 2010-2017.

Background: An increased pertussis burden has been demonstrated among Hispanic or Latino and American Indian or Alaska Native (AI/AN) infants. However, data on potential disparities among other age and racial groups are limited. Methods: We analyzed pertussis cases reported through Enhanced Pertussis Surveillance from 2010 to 2017. Pertussis and severe pertussis incidence were calculated by race (White, Black or African American, AI/AN, and Asian or Pacific Islanders), ethnicity (Hispanic or Latino and non-Hispanic or non-Latino), and age. Results: Compared with White persons, overall incidence was lower among Black or African American (incidence rate ratio [IRR], .57; 95% confidence interval [CI], .53-.61), AI/AN (IRR, 0.65; 95% CI, .58-.72), and Asian or Pacific Islander persons (IRR, 0.39; 95% CI, .35-.43). Overall incidence of pertussis was higher (1.5-fold; 95% CI, 1.37-1.60) among Hispanic or Latino compared with non-Hispanic or non-Latino adults, potentially related to household size or lower pertussis vaccine uptake among adult Hispanic or Latino cases. Severe pertussis incidence was similar among Black or African American and AI/AN persons compared with White persons. Among infants, severe pertussis incidence was 1.4-fold higher (95% CI, 1.03-1.82) among Black or African American infants than among White infants, and 2.1-fold higher (95% CI, 1.67-2.57) among Hispanic or Latino infants than non-Hispanic or non-Latino infants. Conclusions: The contrast between lower reported incidence but similar or higher severe pertussis incidence among Black or African American and AI/AN persons compared with White persons warrants further investigation and may reflect underdiagnosis or underreporting of mild disease.

CasPEDIA Database: a functional classification system for class 2 CRISPR-Cas enzymes.

CRISPR-Cas enzymes enable RNA-guided bacterial immunity and are widely used for biotechnological applications including genome editing. In particular, the Class 2 CRISPR-associated enzymes (Cas9, Cas12 and Cas13 families), have been deployed for numerous research, clinical and agricultural applications. However, the immense genetic and biochemical diversity of these proteins in the public domain poses a barrier for researchers seeking to leverage their activities. We present CasPEDIA (http://caspedia.org), the Cas Protein Effector Database of Information and Assessment, a curated encyclopedia that integrates enzymatic classification for hundreds of different Cas enzymes across 27 phylogenetic groups spanning the Cas9, Cas12 and Cas13 families, as well as evolutionarily related IscB and TnpB proteins. All enzymes in CasPEDIA were annotated with a standard workflow based on their primary nuclease activity, target requirements and guide-RNA design constraints. Our functional classification scheme, CasID, is described alongside current phylogenetic classification, allowing users to search related orthologs by enzymatic function and sequence similarity. CasPEDIA is a comprehensive data portal that summarizes and contextualizes enzymatic properties of widely used Cas enzymes, equipping users with valuable resources to foster biotechnological development. CasPEDIA complements phylogenetic Cas nomenclature and enables researchers to leverage the multi-faceted nucleic-acid targeting rules of diverse Class 2 Cas enzymes.

Quality by Design Approach for Optimization of Microbial and pH-Triggered Colon-Targeted Tablet Formulation Using Carboxymethyl Tamarind Gum.

ABSTRACT The purpose of this study was to apply the quality by design (QbD) approach in the development of a microbial and pH-triggered colon-targeted budesonide tablet. A retrospective research strategy was used to select various polysaccharide-based natural gums such as tamarind gum, gellan gum, karaya gum, gum ghutti, and khaya gum, which were then evaluated for their effectiveness in microbial degradation and targeting the colon. Viscosity profiles were generated in the presence of a prebiotic culture medium prepared by using the Velgut capsule that mimicked the impact of 4% rat cecal content and helpful in screening of natural polymer. Based on the cumulative drug release data of preliminary batches, carboxymethyl (CM) tamarind gum was identified as a superior and an excellent polymer over the tamarind gum for formulation development. The presence of water as a bridging agent in wet granulation also played an important role in the retardation of drug release. Tablets were supercoated with the enteric polymer, Eudragit S100. The Box-Behnken design was utilized, where the selected independent variables were the proportion of CM tamarind gum, % water proportion, and % weight gain of Eudragit S 100 to optimize the formulation. The optimized design space was generated with the criteria that a drug release should be of less than 5% within the first 2 h, less than 10% within the first 5 h, and more than 70% within the first 8 h, to achieve colon targeting. The optimized batch F3 was found stable as per International Council for Harmonisation guidelines. The roentgenography study for optimized formulation demonstrated that it remained intact for 5 h and, at 7 h, was disseminated completely. CM tamarind gum is efficient for colon targeting, and its proportion in 100 mg along with an enteric coating of 6% led to the optimized formulation.

Development of Delayed Release Oral Formulation Comprising Esomeprazole Spray Dried Dispersion Utilizing Design of Experiment As An Optimization Strategy.

Solid dispersion (SD) technology is one of the most widely preferred solubility enhancement methods, especially for Biopharmaceutics classification system class II and IV drugs. Since the last decade, its application for the dual purpose of solubility hike and modified release using novel carriers has been in demand for its added advantages. Spray drying is a commercially accepted technique with high aspects of scalability and product characteristics. The current study used spray-dried dispersion to design delayed release capsule for the proton pump inhibitor esomeprazole. The SD carrier hydroxypropyl methylcellulose acetate succinate-medium grade (HPMCAS-MF) enhanced solubility, inhibited precipitation of saturated drug solutions, and allowed enteric release owing to its solubility above pH 6. The proposed approach avoided compression, coating with enteric polymers, and the development of multi-particulate pellet-based formulations, improving manufacturing feasibility. The formulation was optimized using Box-Behnken design, considering significant formulation variables like HPMCAS-MF proportion and critical process parameters like feed flow rate and inlet temperature. The optimized spray-dried dispersion were characterized based on Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry (DSC), powder X-ray diffraction (PXRD), and scanning electron microscopy (SEM) and also evaluated for solubility, in vitro drug release, residual solvent content, and stability testing. Response surface methodology optimization anticipated that formulation variables affected solubility and release profile, whereas CPPs affected yield. The design space was developed via overlay plot based on constraints specified to attain the desired response and validated using three checkpoint batches with desirability 1. FTIR showed active pharmaceutical ingredient-polymer compatibility. Particle size and SEM studies showed spherical particles with an average Z-value of 1.8 µ. DSC and PXRD confirmed SD's amorphous nature. The drug release investigation and release kinetics prediction utilizing DD-solver software showed a 2-h lag time with > 90% cumulative drug release up to 4 h for the DR formulation. ESM SDD were prepared by spray drying technique using the novel solid dispersion carrier HPMCAS-MF to serve the dual purpose of solubility enhancement and delayed release. The ratio of API:carrier and process variables like feed flow rate and inlet temperature were varied using the Box-Behnken Design to determine the design space of optimized product to procure the desired characteristics of solubility improvement compared to crystalline API and delayed release of PPI to avoid the degradation in the gastric environment. The developed formulation represents several benefits over the already existing marketed products.

Poliovirus type 1 systemic humoral and intestinal mucosal immunity induced by monovalent oral poliovirus vaccine, fractional inactivated poliovirus vaccine, and bivalent oral poliovirus vaccine: A randomized controlled trial.

BACKGROUND: To inform response strategies, we examined type 1 humoral and intestinal immunity induced by 1) one fractional inactivated poliovirus vaccine (fIPV) dose given with monovalent oral poliovirus vaccine (mOPV1), and 2) mOPV1 versus bivalent OPV (bOPV). METHODS: We conducted a randomized, controlled, open-label trial in Dhaka, Bangladesh. Healthy infants aged 5 weeks were block randomized to one of four arms: mOPV1 at age 6-10-14 weeks/fIPV at 6 weeks (A); mOPV1 at 6-10-14 weeks/fIPV at 10 weeks (B); mOPV1 at 6-10-14 weeks (C); and bOPV at 6-10-14 weeks (D). Immune response at 10 weeks and cumulative response at 14 weeks was assessed among the modified intention-to-treat population, defined as seroconversion from seronegative (<1:8 titers) to seropositive (≥1:8) or a four-fold titer rise among seropositive participants sustained to age 18 weeks. We examined virus shedding after two doses of mOPV1 with and without fIPV, and after the first mOPV1 or bOPV dose. The trial is registered at ClinicalTrials.gov (NCT03722004). FINDINGS: During 18 December 2018 - 23 November 2019, 1,192 infants were enrolled (arms A:301; B:295; C:298; D:298). Immune responses at 14 weeks did not differ after two mOPV1 doses alone (94% [95% CI: 91-97%]) versus two mOPV1 doses with fIPV at 6 weeks (96% [93-98%]) or 10 weeks (96% [93-98%]). Participants who received mOPV1 and fIPV at 10 weeks had significantly lower shedding (p < 0·001) one- and two-weeks later compared with mOPV1 alone. Response to one mOPV1 dose was significantly higher than one bOPV dose (79% versus 67%; p < 0·001) and shedding two-weeks later was significantly higher after mOPV1 (76% versus 56%; p < 0·001) indicating improved vaccine replication. Ninety-nine adverse events were reported, 29 serious including two deaths; none were attributed to study vaccines. INTERPRETATION: Given with the second mOPV1 dose, fIPV improved intestinal immunity but not humoral immunity. One mOPV1 dose induced higher humoral and intestinal immunity than bOPV. FUNDING: U.S. Centers for Disease Control and Prevention.

Status of New Vaccine Introduction - Worldwide, 2016-2021.

This report describes the status of introductions globally for eight World Health Organization (WHO)-recommended new and underutilized vaccines, comprising 10 individual vaccine antigens. By 2021, among 194 countries worldwide, 33 (17%) provided all of these 10 WHO-recommended antigens as part of their routine immunization schedules; only one low-income country had introduced all of these recommended vaccines. Universal hepatitis B birth dose; human papillomavirus vaccine; rotavirus vaccine; and diphtheria, tetanus, and pertussis-containing vaccine first booster dose have been introduced by 57%, 59%, 60%, and 72% of all countries worldwide, respectively. Pneumococcal conjugate vaccine, rubella-containing vaccine, measles-containing vaccine second dose, and Haemophilus influenzae type b vaccine have been introduced by 78%, 89%, 94%, and 99% of all countries, respectively. The annual rate of new vaccine introductions declined precipitously when the COVID-19 pandemic started, from 48 in 2019 to 15 in 2020 before rising to 26 in 2021. Increased efforts to accelerate new and underutilized vaccine introductions are urgently needed to improve universal equitable access to all recommended vaccines to achieve the global Immunization Agenda 2021-2030 (IA2030) targets.

Simultaneous isolation of hormone receptor-positive breast cancer organoids and fibroblasts reveals stroma-mediated resistance mechanisms.

Recurrent hormone receptor-positive (HR+) breast cancer kills more than 600,000 women annually. Although HR+ breast cancers typically respond well to therapies, approximately 30% of patients relapse. At this stage, the tumors are usually metastatic and incurable. Resistance to therapy, particularly endocrine therapy is typically thought to be tumor intrinsic (e.g., estrogen receptor mutations). However, tumor-extrinsic factors also contribute to resistance. For example, stromal cells, such as cancer-associated fibroblasts (CAFs), residing in the tumor microenvironment, are known to stimulate resistance and disease recurrence. Recurrence in HR+ disease has been difficult to study due to the prolonged clinical course, complex nature of resistance, and lack of appropriate model systems. Existing HR+ models are limited to HR+ cell lines, a few HR+ organoid models, and xenograft models that all lack components of the human stroma. Therefore, there is an urgent need for more clinically relevant models to study the complex nature of recurrent HR+ breast cancer, and the factors contributing to treatment relapse. Here, we present an optimized protocol that allows a high take-rate, and simultaneous propagation of patient-derived organoids (PDOs) and matching CAFs, from primary and metastatic HR+ breast cancers. Our protocol allows for long-term culturing of HR+ PDOs that retain estrogen receptor expression and show responsiveness to hormone therapy. We further show the functional utility of this system by identifying CAF-secreted cytokines, such as growth-regulated oncogene α , as stroma-derived resistance drivers to endocrine therapy in HR+ PDOs.

Goiter and Abdominal Mass: A Rare Presentation of Riedel's Thyroiditis.

Riedel's thyroiditis (RT) is a rare inflammatory autoimmune disease, often associated with various forms of systemic fibrosis such as sclerosing mesenteritis (SM). A woman in her late 30s presented with a diffusely enlarged firm goiter and a mesenteric mass complicated by biliary obstruction and hydronephrosis. Labs and thyroid ultrasound were consistent with autoimmune thyroiditis. Abdominal imaging demonstrated a mesenteric mass that encased mesenteric vessels and ureter. Flow cytometry and infectious workup were negative. Both thyroid and mesenteric biopsies revealed dense fibrosis with patchy lymphoplasmacytic aggregates, no evidence of carcinoma, lymphoma, or IgG4-related disease, which confirmed diagnoses of RT and SM. She improved clinically with steroids. The coincidental timing of thyroid enlargement and the mesenteric mass, and the similarity in histology suggest an association between RT and SM. Overall, the case highlights the challenges in diagnosing RT given its rarity and emphasises the importance of early treatment to prevent systemic involvement.

Elevated APE1 Dysregulates Homologous Recombination and Cell Cycle Driving Genomic Evolution, Tumorigenesis, and Chemoresistance in Esophageal Adenocarcinoma.

BACKGROUND & AIMS: The purpose of this study was to identify drivers of genomic evolution in esophageal adenocarcinoma (EAC) and other solid tumors. METHODS: An integrated genomics strategy was used to identify deoxyribonucleases correlating with genomic instability (as assessed from total copy number events in each patient) in 6 cancers. Apurinic/apyrimidinic nuclease 1 (APE1), identified as the top gene in functional screens, was either suppressed in cancer cell lines or overexpressed in normal esophageal cells and the impact on genome stability and growth was monitored in vitro and in vivo. The impact on DNA and chromosomal instability was monitored using multiple approaches, including investigation of micronuclei, acquisition of single nucleotide polymorphisms, whole genome sequencing, and/or multicolor fluorescence in situ hybridization. RESULTS: Expression of 4 deoxyribonucleases correlated with genomic instability in 6 human cancers. Functional screens of these genes identified APE1 as the top candidate for further evaluation. APE1 suppression in EAC, breast, lung, and prostate cancer cell lines caused cell cycle arrest; impaired growth and increased cytotoxicity of cisplatin in all cell lines and types and in a mouse model of EAC; and inhibition of homologous recombination and spontaneous and chemotherapy-induced genomic instability. APE1 overexpression in normal cells caused a massive chromosomal instability, leading to their oncogenic transformation. Evaluation of these cells by means of whole genome sequencing demonstrated the acquisition of changes throughout the genome and identified homologous recombination as the top mutational process. CONCLUSIONS: Elevated APE1 dysregulates homologous recombination and cell cycle, contributing to genomic instability, tumorigenesis, and chemoresistance, and its inhibitors have the potential to target these processes in EAC and possibly other cancers.

HoloLens in Breast Reconstruction: What Is the Future?

SUMMARY: Autologous breast reconstruction using the deep inferior epigastric perforator flap has been established as the standard for perforator-based free-flap breast reconstruction. This technique relies on the surgeon's ability to identify the patient's relevant abdominal vasculature to facilitate accurate dissection, optimize surgical outcomes, and minimize morbidity. A technique is described in which the authors incorporate augmented reality using HoloLens technology in their surgical planning to identify epigastric arteries and perforators. This technology allows the surgeon to superimpose computed tomography angiography images directly onto the patient, facilitating an in vivo appreciation of underlying anatomy before incision and dissection. This allows real-time surgical planning, increasing the value and tangibility of preoperative computed tomography angiography with the potential to enhance the accuracy and efficiency of the operative technique. Although the authors did not use the HoloLens technology to make clinical decisions, they provide evidence of its accuracy and ease of use, offering a proof of concept. The potential of this technology is demonstrated, and the authors encourage future application in free-flap breast reconstruction and beyond.

Prescribing patterns of SGLT-2 inhibitors for patients with heart failure: A two-center analysis.

Background: Sodium glucose co-transporter 2 inhibitors (SGLT2i) have been proven to reduce the combined risk of cardiovascular death and hospitalizations in patients with heart failure (HF), irrespective of the presence or absence of diabetes. Despite class 1 and class 2A recommendations for their usage in HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF) respectively by the American College of Cardiology, their prescription rate has remained low. Objective: The aim of this study is to analyze SGLT2i prescription patterns at two academic institutions, with the goal of identifying barriers to implementation. Design: A two-center retrospective analysis was conducted on patients ≥18 years old with a diagnosis of heart failure who were admitted to one of two hospital systems between 5/1/21 and 5/31/22. Patients with an eGFR ≥20 mL/min/1.73m2 and BNP ≥ 100 pg/mL were included. Results: SGLT2i was prescribed in only 19 out of 1081 HFpEF patients (1.8 %) and 51 out of 1596 HFrEF patients (3.2 %). A majority of SGLT2i prescriptions for the HFpEF population came from general medicine services (57.9 %) after obtaining approval from a cardiologist, which was required at our institutions. Adverse effects such as hypoglycemia and urinary tract infections were not significantly associated with SGLT2i use. Conclusions: Despite proven benefits of this class of medications as witnessed in large-scale clinical trials, the implementation of this drug class continues to be low.

CDC's COVID-19 International Vaccine Implementation and Evaluation Program and Lessons from Earlier Vaccine Introductions.

The US Centers for Disease Control and Prevention (CDC) supports international partners in introducing vaccines, including those against SARS-CoV-2 virus. CDC contributes to the development of global technical tools, guidance, and policy for COVID-19 vaccination and has established its COVID-19 International Vaccine Implementation and Evaluation (CIVIE) program. CIVIE supports ministries of health and their partner organizations in developing or strengthening their national capacities for the planning, implementation, and evaluation of COVID-19 vaccination programs. CIVIE's 7 priority areas for country-specific technical assistance are vaccine policy development, program planning, vaccine confidence and demand, data management and use, workforce development, vaccine safety, and evaluation. We discuss CDC's work on global COVID-19 vaccine implementation, including priorities, challenges, opportunities, and applicable lessons learned from prior experiences with Ebola, influenza, and meningococcal serogroup A conjugate vaccine introductions.

Estrogen Receptor Alpha and ESR1 Mutations in Breast Cancer.

The estrogen receptor alpha (ERα) is a nuclear transcription factor that is expressed in more than 70% of all breast cancers. Key genes involved in proliferation and tumor progression are transcriptionally regulated by ERα making it an important therapeutic target. Indeed, the first class of targeted treatments in cancer are endocrine treatments that target ERα either by competitive inhibition, reduced ligand production or receptor degradation. Despite the efficacy of these drugs, resistance to endocrine treatment remains a key clinical challenge. Only about 50% of patients treated with endocrine treatment in early-stage disease will benefit from adjuvant endocrine treatment and nearly all patients treated in the metastatic setting will develop disease progression while on endocrine treatment. Multiple mechanisms of resistance to endocrine treatment have been identified in pre-clinical models and clinical samples. These include both intrinsic (de novo) mechanisms and adaptive, acquired mechanisms. Over the past few years, gain-of-function missense mutations of ESR1, the gene encoding ERα, have been unveiled and identified as the most common genomic mechanism of acquired resistance to endocrine treatments. These mutations are clustered in a "hot spot" region within the ligand binding domain and engender constitutive, ligand-independent activity. Clinical studies evaluating these ESR1 mutations in metastatic ERα positive breast cancer demonstrate decreased overall survival which also highlights their prognostic role. In this chapter, we will provide a detailed review of structural and biophysical characteristics, functional consequences and clinical implications of the ESR1 mutations. We will also discuss potential therapeutic strategies to overcome treatment resistance in the context of ESR1 mutations and implications for future treatment selection.

3D visualization processes for recreating and studying organismal form.

The study of biological form is a vital goal of evolutionary biology and functional morphology. We review an emerging set of methods that allow scientists to create and study accurate 3D models of living organisms and animate those models for biomechanical and fluid dynamic analyses. The methods for creating such models include 3D photogrammetry, laser and CT scanning, and 3D software. New multi-camera devices can be used to create accurate 3D models of living animals in the wild and captivity. New websites and virtual reality/augmented reality devices now enable the visualization and sharing of these data. We provide examples of these approaches for animals ranging from large whales to lizards and show applications for several areas: Natural history collections; body condition/scaling, bioinspired robotics, computational fluids dynamics (CFD), machine learning, and education. We provide two datasets to demonstrate the efficacy of CFD and machine learning approaches and conclude with a prospectus.

Progress Toward Polio Eradication - Worldwide, January 2020-April 2022.

In 1988, the World Health Assembly established the Global Polio Eradication Initiative (GPEI). Since then, wild poliovirus (WPV) cases have decreased approximately 99.99%, and WPV types 2 and 3 have been declared eradicated. Only Afghanistan and Pakistan have never interrupted WPV type 1 (WPV1) transmission. This report describes global progress toward polio eradication during January 1, 2020-April 30, 2022, and updates previous reports (1,2). This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.* Five WPV1 cases were reported from Afghanistan and Pakistan in 2021, compared with 140 in 2020. In 2022 (as of May 5), three WPV1 cases had been reported: one from Afghanistan and two from Pakistan. WPV1 genetically linked to virus circulating in Pakistan was identified in Malawi in a child with paralysis onset in November 2021. Circulating vaccine-derived polioviruses (cVDPVs), with neurovirulence and transmissibility similar to that of WPV, emerge in populations with low immunity following prolonged circulation of Sabin strain oral poliovirus vaccine (OPV) (3). During January 2020-April 30, 2022, a total of 1,856 paralytic cVDPV cases were reported globally: 1,113 in 2020 and 688 in 2021, including cases in Afghanistan and Pakistan. In 2022 (as of May 5), 55 cVDPV cases had been reported. Intensified programmatic actions leading to more effective outbreak responses are needed to stop cVDPV transmission. The 2022-2026 GPEI Strategic Plan objective of ending WPV1 transmission by the end of 2023 is attainable (4). However, the risk for children being paralyzed by polio remains until all polioviruses, including WPV and cVDPV, are eradicated.

SARS-CoV-2 Breakthrough Infections among US Embassy Staff Members, Uganda, May-June 2021.

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.