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Zeel Vishnubhai Patel,1 Priyadarshi Prajjwal,2 Lakshmi Deepak Bethineedi,3 Divyakshi J Patel,4 Kaarvi Khullar,5 Hinal Patel,6 Kanishka Khatri,2 Mohammed Dheyaa Marsool Marsool,7 Srikanth Gadam,8 Soumya Aleti,9 Omniat Amir10 1Internal Medicine, Medical College Baroda, Baroda, Gujarat, India; 2Internal Medicine, Bharati Vidyapeeth University Medical College, Pune, India; 3Internal Medicine, Andhra Medical College, Visakhapatnam, Andhra Pradesh, India; 4Internal Medicine, Smt. NHL Municipal Medical College, Ahmedabad, India; 5Internal Medicine, Maharashtra University of Health Sciences, Government Medical College, Gondia, India; 6Internal Medicine, GMERS Medical College and Hospital Sola, Ahmedabad, India; 7Internal Medicine, University of Baghdad, Al-Kindy College of Medicine, Baghdad, Iraq; 8Internal Medicine, NYC Health+ Hospitals, New York, NYC, USA; 9Internal Medicine, Berkshire Medical Center, Pittsfield, MA, USA; 10Internal Medicine, Al Manhal Academy of Science, SudanCorrespondence: Omniat Amir, Internal Medicine, Al Manhal Academy of Science, Khartoum, 1442, Sudan, Email omniatamir123@gmail.comAbstract: Sickle cell disease (SCD), the most common autosomal recessive genetic disorder, affects the hemoglobin (Hb) chains in human red blood cells. It is caused by mutations in the β-globin genes, leading to the production of hemoglobin S, which results in the formation of sickle-shaped red blood cells (RBCs). These abnormal cells cause hemolysis, endothelial damage, and small vessel occlusion, leading to both acute and long-term complications. According to the World Health Organization’s 2008 estimates, SCD affects approximately 2.28 per 1000 individuals globally. Despite this high prevalence, therapeutic advancements have been slow. For many years, the only FDA-approved medications for managing SCD complications were hydroxyurea and deferiprone. However, recent years have seen the approval of several new therapies, including L-glutamine (2017), voxelotor and crizanlizumab (2019), as well as exagamglogene autotemcel (Casgevy) and lovotibeglogene autotemcel (Lyfgenia) (2023). These treatments have proven effective in managing both the acute and chronic effects of SCD, including hemolytic anemia, chronic pain, stroke, vaso-occlusive crises, and multiple organ damage syndromes. This review explores the mechanisms of action, practical considerations, and side effects of these emerging therapies, drawing from a comprehensive search of databases such as PubMed, Medline, and Cochrane.Keywords: sickle cell disease, L-Glutamine, Voxelotor, Crizanlizumab, Casgevy, Lyfgenia

Objective: To review the efficacy of intra-aortic balloon counterpulsation (IABCP) in medically refractory ventricular arrhythmia.Design: Retrospective analysis of the outcome of patients with ventricular arrhythmia treated with IABCP after transfer between 1992 and 1997.Setting: Tertiary cardiac referral centre.Patients: 21 patients (mean age 58 years) who underwent IABCP for control of ventricular arrhythmia. All had significant left ventricular impairment (mean ejection fraction 28.6%); 18 had coronary artery disease.Results: Before IABCP, 10 patients had incessant monomorphic ventricular tachycardia and 11 had paroxysmal ventricular tachycardia and/or ventricular fibrillation (VT/VF). IABCP resulted in suppression of ventricular arrhythmia in 18 patients, of whom 13 were weaned from IABCP. After stabilisation of ventricular arrhythmia, 10 patients were maintained on medical treatment alone and one underwent endocardial resection. IABCP was maintained until cardiac transplantation in five patients. One patient had a fatal arrest before discharge and one died from progressive heart failure. IABCP failed to control ventricular arrhythmia in three patients and was subsequently discontinued. A cardiac assist device was employed in one of these until cardiac transplantation; the other two were eventually stabilised on medical treatment. Nineteen patients were discharged from hospital. Overall survival was 95% at mean follow up of 25.7 months.Conclusions: IABCP can be an effective means of controlling refractory ventricular arrhythmia, allowing time for the institution of more definitive treatment. [ABSTRACT FROM AUTHOR]

Introduction: This study applied a novel tobacco regulatory science paradigm to characterize inter-product variation in the appeal and sensory features of emerging commercial and therapeutic oral nicotine products (ONPs) among young adults that vape e-cigarettes., Methods: Twenty-three young adults without ONP experience who use e-cigarettes completed a single-blind, single-visit remote lab study. Participants rated appeal and sensory characteristics during 5-minute standardized self-administrations of 8 ONPs (4 fruit, 4 mint) from various brands (Lucy, Rouge, Solace, Nicorette, On!, Velo). Participants were randomized between-subjects to ONP type (pouches or gum)., Results: Gum ONPs were rated sweeter (B = 19.5, 95% CI = 4.3, 34.7), stronger in flavor (B = 25.6, 95% CI = 12.2, 39.0), and lower in tingling sensation (B = -14.0, 95% CI = -27.8, -0.2) than pouches. Fruit-flavored ONPs were sweeter (B = 12.9, 95% CI = 6.1, 19.7) and caused less burning (B = -12.0, 95% CI = -19.5, -4.5) than mint. Product type x flavor interactions found that gum vs. pouch enhanced sweetness and flavor strength more for fruit than mint, while pouch vs. gum increased burning and harshness more for mint. Nicorette White Ice was most appealing, while Rogue Fruit and Nicorette Mint were less so. Appeal correlated with most types of sensory experiences (rs = -.33-.54), except for tingling and burning., Conclusions: Nicotine gums may offer a more pleasant sensory experience than pouches for young adults who use e-cigarettes, with variation across brand/flavor variants., Implications: Results indicate that gum ONPs and fruit flavors may offer greater appeal and a more pleasant sensory experience than pouch ONPs and mint flavors for young adults who use e-cigarettes and are ONP-naïve, with heterogeneity in user experience across some brand/flavor variants. This study also introduces a method for assessing the appeal and sensory features of ONPs, which can inform regulatory efforts and strategies to reduce nicotine dependence among young adults who use e-cigarettes., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Type III CRISPR systems provide immunity against genetic invaders through the production of cyclic oligo-adenylate (cA n ) molecules that activate effector proteins that contain CRISPR-associated Rossman fold (CARF) domains. Here, we characterized the function and structure of an effector in which the CARF domain is fused to an adenosine deaminase domain, CRISPR-associated adenosine deaminase 1 (Cad1). We show that upon binding of cA 4 or cA 6 to its CARF domain, Cad1 converts ATP to ITP, both in vivo and in vitro. Cryoelectron microscopy (cryo-EM) structural studies on full-length Cad1 reveal an hexameric assembly composed of a trimer of dimers, with bound ATP at inter-domain sites required for activity and ATP/ITP within deaminase active sites. Upon synthesis of cA n during phage infection, Cad1 activation leads to a growth arrest of the host that prevents viral propagation. Our findings reveal that CRISPR-Cas systems employ a wide range of molecular mechanisms beyond nucleic acid degradation to provide adaptive immunity in prokaryotes., Competing Interests: Declaration of interests L.A.M. is a cofounder and scientific advisory board member of Intellia Therapeutics, a cofounder of Eligo Biosciences, and a scientific advisory board member of Ancilia Biosciences., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Context: Stretching and strengthening for rheumatoid arthritis of the hand (SARAH) is a progressive and individually designed recommended treatment exercise program., Aims: The aim was to translate the SARAH hand exercise program into Gujarati and assess the adherence rate, usefulness, and understanding of the Gujarati SARAH exercise program., Methods and Materials: Mixed-method qualitative study was conducted among 25 participants at the outpatient departments of Institute Nadiad and Niruj Rheumatology Clinic, Gujarat, and via professional contact, a telephonic semi-structured interview was conducted among 13 participants using an interview guide, and interviews were audio-recorded following transcription verbatim. Overall adherence rates of 25 participants to a 12-week exercise program were determined using the cross-sectional method., Statistical Analysis Used: IBM SPSS software version 23.0 was used for analyzing quantitative data, and NVivo Plus version 11 was used for qualitative data., Results: The adherence rate was 97.22%. Participants completed all 72 sessions ( n = 7) with an adherence rate of 100%. The least number of sessions completed was 25 ( n = 2), with an adherence rate of 34% due to a lack of interest in exercising on a daily basis. Qualitative findings showed that the booklet is understandable, useful, and beneficial in terms of reducing symptoms and improving activities of daily life as well as occupational work., Conclusion: The translated strengthening and stretching for rheumatoid arthritis in the hand exercise booklet is effective and beneficial to patients who exercise at home. Participants can self-track their exercise by using dairy, which eliminates travel costs and attendance at clinic sessions., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

DNA double-strand breaks that initiate meiotic recombination are formed by the topoisomerase-relative enzyme Spo11, supported by conserved auxiliary factors. Because high-resolution structural data have not been available, many questions remain about the architecture of Spo11 and its partners and how they engage with DNA. We report cryo-electron microscopy structures at up to 3.3-Å resolution of DNA-bound core complexes of Saccharomyces cerevisiae Spo11 with Rec102, Rec104 and Ski8. In these structures, monomeric core complexes make extensive contacts with the DNA backbone and with the recessed 3'-OH and first 5' overhanging nucleotide, establishing the molecular determinants of DNA end-binding specificity and providing insight into DNA cleavage preferences in vivo. The structures of individual subunits and their interfaces, supported by functional data in yeast, provide insight into the role of metal ions in DNA binding and uncover unexpected structural variation in homologs of the Top6BL component of the core complex., (© 2024. The Author(s).)

Premature menopause impacts 1% of women under the age of 40. The women are at risk of premature death, ischemic disease of the heart, neurological conditions, mood disturbances, psychosexual problems, osteoporosis, and subfertility. There is an imperative for less complicated protocols and enhanced approaches for oocyte donation to get pregnant and achieve motherhood in at-risk women. A review of the pertinent literature on premature ovarian insufficiency and selected references was done. A comprehensive review was undertaken by searching the databases PubMed, Scopus, EMBASE, Web of Science, and Science Direct. Pregnancy in women with premature menopause was formerly uncommon, but because of recent advances in oocyte donation, women with premature menopause can now aspire to have a child. Hormone replacement treatment is useful in treating the negative effects of premature ovarian insufficiency. Women who experience early menopause are at risk for early mortality, ischemic heart disease, neurological conditions, mood problems, psychosexual disorder, osteoporosis, and subfertility. Public awareness and education are critical tools for saving women at peril., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Dave et al.)

Introduction: Surgeries for chronic pancreatitis are tailored based on disease process and either include parenchymal-preserving surgeries or total pancreatectomy with or without islet cell autotransplantation. It is critical to account for vascular variants as injuries to these are associated with short- and long-term morbidity and mortality. There is a lack of contemporary data on the true incidence of aberrant arterial anatomy, and it is likely to be underreported by nonhepatobiliary radiologists., Methods: This study is a retrospective analysis of all patients undergoing pancreatic resections for chronic pancreatitis at the single center. The presence of vascular variants was compared between standard reporting and preoperative imaging review by a hepatobiliary radiologist and surgeon. Primary outcomes were operative time and blood loss., Results: Of the 72 pancreatic resections for chronic pancreatitis, 50 (69%) satisfied inclusion criteria. Three of fifty (6%) had vascular anomalies reported on standard reporting while 11 (22%) had vascular anomalies identified on preoperative imaging review and confirmed at surgery. Hence, only 27% of patients with variant vascular anatomy were reported on standard imaging. There was no significant difference in operative times or blood loss between those with and without known vascular anomalies., Conclusions: Pancreatic resection is a complex undertaking as long-standing inflammation distorts anatomic planes and increases opportunity for inadvertent vascular injury especially if there are aberrant vessels. In this study, we found that anatomic vascular variants are oftentimes not reported. Dedicated surgical planning with review of cross-sectional imaging identified all cases of anatomic variants resulting in no difference in operative time or incidence of intraoperative hemorrhage., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Introduction: Noninvasive screening methods to identify patients preoperatively with abnormal liver texture remain limited. Aspartate transaminase to platelet ratio index has been validated to predict fibrosis in patients with hepatitis C; however, its use as a predictor of postoperative outcomes in patients without viral hepatitis remains unknown., Methods: We queried the American College of Surgeons National Surgical Quality Improvement Program dataset to identify patients who underwent a major hepatectomy between 2014 and 2021. We excluded patients who underwent emergent operations, patients with viral hepatitis, and patients with ascites. Aspartate transaminase to platelet ratio index was calculated using the following equation: (aspartate transaminase/40)/(platelet count) × 100. An aspartate transaminase to platelet ratio index ≥0.7 was used to identify patients with significant fibrosis. Univariable analysis was performed to identify factors associated with aspartate transaminase to platelet ratio index ≥0.7, perioperative transfusion, serious morbidity, overall morbidity, and 30-day mortality. Multivariable logistic regression analysis was performed to identify adjusted predictors of these outcomes., Results: Of the 8,933 patients who met inclusion criteria, 1,170 (13.1%) patients had an aspartate transaminase to platelet ratio index ≥0.7. A perioperative blood transfusion was administered to 2,497 (28.0%). The number of patients who experienced overall morbidity, serious morbidity, and mortality were 3,195 (35.8%), 2,665 (29.8%), and 238 (2.7%), respectively. Aspartate transaminase to platelet ratio index ≥0.7 was an independent predictor of transfusion (odds ratio: 1.51 [1.32-1.72], P < .001), overall morbidity (1.16 [1.01-1.33], P = .032), and mortality (1.56 [1.12-2.13], P = .006). Transfusion was an independent predictor of overall morbidity (2.50 [2.26-2.76], P < .001), serious morbidity (2.51 [2.26-2.79], P < .001), and mortality (3.28 [2.49-4.33], P < .001)., Conclusion: An aspartate transaminase to platelet ratio index ≥0.7 is associated with perioperative transfusion, overall morbidity, and 30-day mortality. The aspartate transaminase to platelet ratio index may serve as a noninvasive tool to risk stratify patients before elective major hepatectomy., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Preeclampsia, a complex and perplexing disorder unique to pregnancy, is widely recognized as primarily originating from placental dysfunction and can only be resolved by the delivery of the fetus in severe cases. Preeclampsia is a prevalent medical issue during pregnancy and is associated with elevated rates of maternal and infant mortality and morbidity. The exact cause of preeclampsia remains uncertain, although multiple factors have been implicated in its development based on current knowledge. Preeclampsia is characterized by maternal endothelial dysfunction due to the presence of fetal-derived circulatory substances from the placenta. The condition is associated with various risk factors, including maternal comorbidities such as chronic renal disease, hypertension (HTN), and obesity. Additionally, a family history of preeclampsia, nulliparity, multiple gestations, previous instances of preeclampsia, or intrauterine fetal growth restriction (IUGR) are considered risk factors. Electrolytes, including sodium, potassium, and chloride, play a critical role in the function of vascular smooth muscles and may potentially contribute to the pathophysiology of hypertension. In this review, we have summarized the literature on electrolytes in preeclampsia by conducting an extensive systematic search of databases such as PubMed, Excerpta Medica database (EMBASE), and Medical Literature Analysis and Retrieval System Online (MEDLINE)., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Gupta et al.)

Context: There are few studies on the prevalence of sarcopenia and frailty in India., Aims: The aim of this study was to assess sarcopenia and frailty using simple clinical tools among the elderly population in the community., Settings and Design: This was an observational study. The elderly population with an age group of >60 years residing in villages within 10-15 km of Sumandeep Vidyapeeth, Vadodara, formed the sampling frame of the study., Methods and Material: A total of 785 participants were approached, of whom 556 were included in the study based on inclusion criteria. Participants were assessed for grip strength, muscle mass, gait speed, and frailty., Statistical Analysis Used: The data were analyzed using STATA-IC statistical software version 13. A nonparametric Chi-square (χ2) test was used for categorical variables, and an independent-samples t -test was used to analyze the difference between various variables. Statistical significance was considered at P < 0.05 with a 95% confidence interval (CI)., Results: Based on the Indian criteria, 205 participants (36.1%) were diagnosed as having sarcopenia, and 351 participants (63%) were diagnosed as having "no sarcopenia." 5.6% of participants were found to be frail, 19.2% to be pre-frailty, and 75.2% to be no frailty. The χ 2 analysis showed a significant association of sarcopenia with gender and different age groups ( P value < 0.001)., Conclusions: In this study, 36.9% of the elderly participants were found to have "sarcopenia," and 5.6% of the participants had frailty. Simple clinical tools used were easy to administer and suitable for field screening., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Journal of Family Medicine and Primary Care.)

Introduction: Fibrosis and cirrhosis are associated with worse outcomes after hepatectomy. Aspartate transaminase to platelet ratio index (APRI) is associated with fibrosis and cirrhosis in hepatitis C patients. However, APRI has not been studied to predict outcomes after hepatectomy in patients without viral hepatitis., Methods: We reviewed the ACS-NSQIP dataset to identify patients who underwent a minor hepatectomy between 2014 and 2021. We excluded patients with viral hepatitis or ascites as well as patients who underwent emergent operations or biliary reconstruction. APRI was calculated using the following equation: (AST/40)/(platelet count) × 100. APRI ≥0.7 was used to identify significant fibrosis. Univariable analysis was performed to identify factors associated with APRI ≥0.7, transfusion, serious morbidity, overall morbidity, and 30-day mortality. Multivariable logistic regression was performed to identify adjusted predictors of these outcomes., Results: Of the 18,069 patients who met inclusion criteria, 1630 (9.0%) patients had an APRI ≥0.7. A perioperative blood transfusion was administered to 2139 (11.8%). Overall morbidity, serious morbidity, and mortality were experienced by 3162 (17.5%), 2475 (13.7%), and 131 (.7%) patients, respectively. APRI ≥0.7 was an independent predictor of transfusion (adjusted OR: 1.48 [1.26-1.74], P < .001), overall morbidity (1.17 [1.02-1.33], P = .022), and mortality (1.97 [1.22-3.06], P = .004). Transfusion was an independent predictor of overall morbidity (3.31 [2.99-3.65], P < .001), serious morbidity (3.70 [3.33-4.11], P < .001), and mortality (5.73 [4.01-8.14], P < .001)., Conclusions: APRI ≥0.7 is associated with perioperative transfusion, overall morbidity, and 30-day mortality. APRI may serve as a noninvasive tool to risk stratify patients prior to elective minor hepatectomy., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Benign uterine tumors, known as leiomyomas or uterine fibroids, can result in severe pain, bleeding, and infertility. They impact a woman's overall well-being, ability to conceive, and the course of her pregnancy. Fibroids are associated with increasing maternal age. When a patient with fibroids is considering pregnancy, ultrasonography and a detailed pelvic examination should be performed to determine the size and location of any fibroids. This case study details a 30-year-old female patient who had fibroids during her pregnancy and responded well to treatment., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

The integration of artificial intelligence (AI) in obstetrics and gynecology (OB/GYN) is revolutionizing the landscape of women's healthcare. This review article explores the transformative impact of AI technologies on the diagnosis, treatment, and management of obstetric and gynecological conditions. We examine key advancements in AI-driven imaging techniques, predictive analytics, and personalized medicine, highlighting their roles in enhancing prenatal care, improving maternal and fetal outcomes, and optimizing gynecological interventions. The article also addresses the challenges and ethical considerations associated with the implementation of AI in clinical practice. This paper highlights the potential of AI to greatly improve the standard of care in OB/GYN, ultimately leading to better health outcomes for women, by offering a thorough overview of present AI uses and future prospects., Competing Interests: Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Patel et al.)

Prokaryotes are equipped with a variety of resistance strategies to survive frequent viral attacks or invading mobile genetic elements. Among these, CRISPR-Cas surveillance systems are abundant and have been studied extensively. This Review focuses on CRISPR-Cas type VI Cas13 systems that use single-subunit RNA-guided Cas endonucleases for targeting and subsequent degradation of foreign RNA, thereby providing adaptive immunity. Notably, distinct from single-subunit DNA-cleaving Cas9 and Cas12 systems, Cas13 exhibits target RNA-activated substrate RNase activity. This Review outlines structural, biochemical and cell biological studies toward elucidation of the unique structural and mechanistic principles underlying surveillance effector complex formation, precursor CRISPR RNA (pre-crRNA) processing, self-discrimination and RNA degradation in Cas13 systems as well as insights into suppression by bacteriophage-encoded anti-CRISPR proteins and regulation by endogenous accessory proteins. Owing to its programmable ability for RNA recognition and cleavage, Cas13 provides powerful RNA targeting, editing, detection and imaging platforms with emerging biotechnological and therapeutic applications., (© 2024. Springer Nature America, Inc.)

Salivary alpha-amylase (sAA) has gained popularity as an easily collected biomarker for sympathetic nervous system activation, and research has shown increases in sAA after completing experimental stress tasks in certain groups. However, recent work suggests that salivary cortisol, another stress biomarker, is suppressed after a speech task among experimentally induced exclusion in young women. The present analysis investigated the sAA response in biologically female undergraduates (n=31) who completed a game of Cyberball and then a speech anticipation task. Results showed that women in the social exclusion experimental group had a greater decrease in sAA compared to young women in the inclusion group after the speech task. Results of this study provide support for stress response suppression in women who have experienced social exclusion. The present findings provide pilot evidence for future, larger studies to advance the tend-and-befriend theory., (Copyright © 2024. Published by Elsevier Inc.)

This comprehensive review delves into the multifaceted landscape of postpartum depression (PPD), exploring its prevalence, impact on maternal and infant well-being, and the efficacy of existing screening and intervention practices. PPD emerges as a critical concern, with implications extending beyond individual mental health to encompass the dynamics of mother-infant relationships and societal well-being. The analysis underscores the complexity of addressing PPD, emphasizing the challenges associated with screening tools and the importance of evidence-based interventions. A call to action resonates throughout, urging healthcare providers, policymakers, and stakeholders to prioritize mental health support for new mothers through enhanced screening protocols and improved accessibility to interventions. Furthermore, the review highlights the need for destigmatization and awareness campaigns to foster a supportive environment. Future research directions are outlined, emphasizing the refinement of screening tools, developing innovative interventions, and exploring cultural and socioeconomic influences on PPD outcomes. The review envisions a collaborative effort to dispel the shadows of PPD, striving for a future where mothers receive comprehensive support, ensuring optimal mental health and overall well-being., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2024, Gupta et al.)

Heart failure with improved ejection fraction (HFimpEF) has better outcomes than HF with reduced EF (HFrEF). However, factors contributing to HFimpEF remain unclear. This study aimed to evaluate clinical and longitudinal characteristics associated with subsequent HFimpEF. This was a single-center retrospective HFrEF cohort study. Data were collected from 2014 to 2022. Patients with HFrEF were identified using International Classification of Diseases codes, echocardiographic data, and natriuretic peptide levels. The main end points were HFimpEF (defined as EF >40% at ≥3 months with ≥10% increase) and mortality. Cox proportional hazards and mixed effects models were used for analyses. The study included 1,307 patients with HFrEF with a median follow-up of 16.3 months (interquartile range 8.0 to 30.6). The median age was 65 years; 68% were male whereas 57% were White. On follow-up, 38.7% (n = 506) developed HFimpEF, whereas 61.3% (n = 801) had persistent HFrEF. A multivariate Cox regression model identified gender, race, co-morbidities, echocardiographic, and natriuretic peptide as significant covariates of HFimpEF (p <0.05). The HFimpEF group had better survival compared with the persistent HFrEF group (p <0.001). Echocardiographic and laboratory trajectories differed between groups. In this HFrEF cohort, 38.7% transitioned to HFimpEF and approximately 50% met the definition within the first 12 months. In a HFimpEF model, gender, co-morbidities, echocardiographic parameters, and natriuretic peptide were associated with subsequent HFimpEF. The model has the potential to identify patients at risk of subsequent persistent or improved HFrEF, thus informing the design and implementation of targeted quality-of-care improvement interventions., Competing Interests: Declaration of Competing Interest The authors have no competing interests to declare. Funding sources were not involved in the collection and interpretation of data, preparation of the manuscript, and decisions for publication. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication. This study was reviewed and approved by University of California Davis Institutional Review Board. All data used were deidentified before analysis., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Prokaryotic type III CRISPR-Cas systems provide immunity against viruses and plasmids using CRISPR-associated Rossman fold (CARF) protein effectors 1-5 . Recognition of transcripts of these invaders with sequences that are complementary to CRISPR RNA guides leads to the production of cyclic oligoadenylate second messengers, which bind CARF domains and trigger the activity of an effector domain 6,7 . Whereas most effectors degrade host and invader nucleic acids, some are predicted to contain transmembrane helices without an enzymatic function. Whether and how these CARF-transmembrane helix fusion proteins facilitate the type III CRISPR-Cas immune response remains unknown. Here we investigate the role of cyclic oligoadenylate-activated membrane protein 1 (Cam1) during type III CRISPR immunity. Structural and biochemical analyses reveal that the CARF domains of a Cam1 dimer bind cyclic tetra-adenylate second messengers. In vivo, Cam1 localizes to the membrane, is predicted to form a tetrameric transmembrane pore, and provides defence against viral infection through the induction of membrane depolarization and growth arrest. These results reveal that CRISPR immunity does not always operate through the degradation of nucleic acids, but is instead mediated via a wider range of cellular responses., (© 2024. The Author(s).)

Stimulator of interferon genes (STING) agonists are promising candidates for vaccine adjuvants and antitumor immune stimulants. The most potent natural agonist of STING, 2',3'-cyclic GMP-AMP (2',3'-cGAMP), is subject to nuclease-mediated inherent metabolic instability, thereby placing limits on its clinical efficacy. Here, we report on a new class of chemically synthesized sugar-modified analogs of 2',3'-cGAMP containing arabinose and xylose sugar derivatives that bind mouse and human STING alleles with high affinity. The co-crystal structures demonstrate that such analogs act as 2',3'-cGAMP mimetics that induce the "closed" conformation of human STING. These analogs show significant resistance to hydrolysis mediated by ENPP1 and increased stability in human serum, while retaining similar potency as 2',3'-cGAMP at inducing IFN-β secretion from human THP1 cells. The arabinose- and xylose-modified 2',3'-cGAMP analogs open a new strategy for overcoming the inherent nuclease-mediated vulnerability of natural ribose cyclic nucleotides, with the additional benefit of high translational potential as cancer therapeutics and vaccine adjuvants., Competing Interests: Declaration of interests T.T. is a cofounder and scientific advisor, and D.J.P. and L.L. are consultants of Ventus Therapeutics., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The Smc5/6 complex (Smc5/6) is important for genome replication and repair in eukaryotes. Its cellular functions are closely linked to the ATPase activity of the Smc5 and Smc6 subunits. This activity requires the dimerization of the motor domains of the two SMC subunits and is regulated by the six non-SMC subunits (Nse1 to Nse6). Among the NSEs, Nse5 and Nse6 form a stable subcomplex (Nse5-6) that dampens the ATPase activity of the complex. However, the underlying mechanisms and biological significance of this regulation remain unclear. Here, we address these issues using structural and functional studies. We determined cryo-EM structures of the yeast Smc5/6 derived from complexes consisting of either all eight subunits or a subset of five subunits. Both structures reveal that Nse5-6 associates with Smc6's motor domain and the adjacent coiled-coil segment, termed the neck region. Our structural analyses reveal that this binding is compatible with motor domain dimerization but results in dislodging the Nse4 subunit from the Smc6 neck. As the Nse4-Smc6 neck interaction favors motor domain engagement and thus ATPase activity, Nse6's competition with Nse4 can explain how Nse5-6 disfavors ATPase activity. Such regulation could in principle differentially affect Smc5/6-mediated processes depending on their needs of the complex's ATPase activity. Indeed, mutagenesis data in cells provide evidence that the Nse6-Smc6 neck interaction is important for the resolution of DNA repair intermediates but not for replication termination. Our results thus provide a molecular basis for how Nse5-6 modulates the ATPase activity and cellular functions of Smc5/6.

Postpartum mood disorders pose significant challenges to women's mental health and well-being during the postpartum period. This review article provides insights into these disorders' diagnosis, prevention, and treatment. The article begins by discussing the background information on postpartum mood disorders, their significance, and the purpose of understanding them. It then delves into the classification and types of postpartum mood disorders, emphasizing the need for accurate diagnosis and differentiation. Prevalence and incidence rates are explored to highlight the scope and impact of these disorders. The review examines various risk factors associated with postpartum mood disorders, including biological, psychological, and socioeconomic factors. Understanding these risk factors helps identify high-risk populations and guide targeted interventions. Screening and diagnosis of postpartum mood disorders are crucial for early detection and intervention. The article provides an overview of screening tools, highlights the challenges in diagnosis, and emphasizes the importance of early identification for better outcomes. Prevention strategies are explored, including antenatal education, psychosocial support programs, and the role of healthcare professionals in promoting preventive measures. Effective prevention interventions and their outcomes are discussed to guide healthcare providers and policymakers in implementing evidence-based strategies. Treatment approaches for postpartum mood disorders include pharmacological interventions, psychotherapy options, alternative and complementary therapies, and multidisciplinary approaches. The article discusses the effectiveness and considerations of each approach, highlighting the importance of individualized care. Challenges and barriers in diagnosing, preventing, and treating postpartum mood disorders are addressed, including stigma, limited access to healthcare services, and gaps in healthcare provider knowledge and training. Recommendations are provided for healthcare professionals and policymakers to overcome these challenges and improve outcomes. The review concludes by highlighting the need for future research, innovations in prevention and treatment approaches, and collaborative efforts in the field of postpartum mood disorders. Promising areas for research are identified, including long-term outcomes, understanding risk factors, and cultural considerations. The article emphasizes the importance of interdisciplinary collaboration and stakeholder engagement in advancing the field., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Garapati et al.)

Upon activation by double-stranded DNA (dsDNA), the cytosolic dsDNA sensor cyclic GMP-AMP synthase (cGAS) synthesizes the diffusible cyclic dinucleotide 2'3'-cGAMP (cyclic GMP-AMP), which subsequently binds to the adaptor STING, triggering a cascade of events leading to an inflammatory response. Recent studies have highlighted the role of 2'3'-cGAMP as an 'immunotransmitter' between cells, a process facilitated by gap junctions as well as by specialized membrane-spanning importer and exporter channels. This review highlights recent advances from a structural perspective of intercellular trafficking of 2'3'-cGAMP, with particular emphasis on the binding of importer SLC19A1 to 2'3'-cGAMP, as well as the significance of associated folate nutrients and antifolate therapeutics. This provides a path forward for structure-guided understanding of the transport cycle in immunology, as well as for candidate targeting approaches towards therapeutic intervention in inflammation., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

The metazoan cGAMP-activated cGAS-STING innate immunity pathway is triggered in response to genomic instability and DNA damage, thereby providing host defense against microbial pathogens. This pathway also impacts on autophagy, cellular senescence and antitumor immunity, while its overactivation triggers autoimmune and inflammatory diseases. Metazoan cGAS generates cGAMP containing distinct combinations of 3'-5' and 2'-5' linkages, which target the adaptor protein STING and activate the innate immune response through a signaling cascade leading to upregulation of cytokine and interferon production. This Review highlights a structure-based mechanistic perspective of recent advances in cGAMP-activated cGAS-STING innate immune signaling by focusing on the cGAS sensor, cGAMP second messenger and STING adaptor components, thereby elucidating the specificity, activation, regulation and signal transduction features of the pathway. In addition, the Review addresses progress towards identification of inhibitors and activators targeting cGAS and STING, as well as strategies developed by pathogens to evade cGAS-STING immunity. Most importantly, it highlights cyclic nucleotide second messengers as ancient signaling molecules that elicit a potent innate immune response that originated in bacteria and evolved through evolutionary adaptation to metazoans., (© 2023. Springer Nature America, Inc.)