Antimicrobial resistance burden pre and post-COVID-19 pandemic with mapping the multidrug resistance in Egypt: a comparative cross-sectional study.

Overuse of antibiotics during coronavirus disease 2019 (COVID-19) in an attempt to reduce COVID-19 mortality in the short term may have contributed to long-term mortality from antimicrobial resistance (AMR). The aim of this study was to evaluate the impact of the COVID-19 pandemic on AMR in Egypt and map the distribution of multidrug-resistant (MDR) and extensive drug-resistant (XDR) across Egypt. Through a multicenter cross-sectional study 2430 culture results were collected in 2019 and 2022 pre and post-COVID-19 pandemic in Egypt, including 400 Klebsiella pneumoniae, 760 Escherichia coli, 650 Acinetobacter baumannii, and 620 Methicillin-resistant staphylococcus aureus (MRSA) culture results. MDR and XDR culture results distribution across Egypt was highlighted through the geographic information system. Mixed effect logistic regression models and sub-group analysis were performed according to the type of specimens to test the impact of COVID-19 on resistance. Adjusted analysis demonstrated K. pneumoniae resistance has increased against quinolones and carbapenems (P < 0.001). Resistance of E. coli has increased significantly against imipenem and meropenem. While E.coli susceptibility has increased to cefoxitin, levofloxacin, and ciprofloxacin. A. baumannii resistance has increased more than double against ceftazidime, cefepime, and piperacillin-tazobactam (P < 0.001). MRSA reserved its susceptibility to vancomycin and linezolid. MDR K. pneumoniae and A. baumannii have increased post-COVID-19 from 67% to 94% and from 79% to 98%, respectively (P < 0.001). XDR K. pneumoniae and A. baumannii have increased from 6% to 46%, and from 47% to 69%, respectively (P < 0.001). COVID-19 has changed the profile of AMR in Egypt so that urgent action is required to mitigate this threat and preserve our capacity to face infections in future decades.

Patterns of recombination in snakes reveal a tug-of-war between PRDM9 and promoter-like features.

In some mammals, notably humans, recombination occurs almost exclusively where the protein PRDM9 binds, whereas in vertebrates lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To determine whether PRDM9 directs recombination in nonmammalian vertebrates, we focused on an exemplar species with a single, intact PRDM9 ortholog, the corn snake (Pantherophis guttatus). Analyzing historical recombination rates along the genome and crossovers in pedigrees, we found evidence that PRDM9 specifies the location of recombination events, but we also detected a separable effect of promoter-like features. These findings reveal that the uses of PRDM9 and promoter-like features need not be mutually exclusive and instead reflect a tug-of-war that is more even in some species than others.

Knowledge, Perceptions and Attitude of Researchers Towards Using ChatGPT in Research.

INTRODUCTION: ChatGPT, a recently released chatbot from OpenAI, has found applications in various aspects of life, including academic research. This study investigated the knowledge, perceptions, and attitudes of researchers towards using ChatGPT and other chatbots in academic research. METHODS: A pre-designed, self-administered survey using Google Forms was employed to conduct the study. The questionnaire assessed participants' knowledge of ChatGPT and other chatbots, their awareness of current chatbot and artificial intelligence (AI) applications, and their attitudes towards ChatGPT and its potential research uses. RESULTS: Two hundred researchers participated in the survey. A majority were female (57.5%), and over two-thirds belonged to the medical field (68%). While 67% had heard of ChatGPT, only 11.5% had employed it in their research, primarily for rephrasing paragraphs and finding references. Interestingly, over one-third supported the notion of listing ChatGPT as an author in scientific publications. Concerns emerged regarding AI's potential to automate researcher tasks, particularly in language editing, statistics, and data analysis. Additionally, roughly half expressed ethical concerns about using AI applications in scientific research. CONCLUSION: The increasing use of chatbots in academic research necessitates thoughtful regulation that balances potential benefits with inherent limitations and potential risks. Chatbots should not be considered authors of scientific publications but rather assistants to researchers during manuscript preparation and review. Researchers should be equipped with proper training to utilize chatbots and other AI tools effectively and ethically.

Surgical Management of Full-Thickness Macular Holes in Macular Telangiectasia Type 2: A Global Multicenter Study.

PURPOSE: To report on macular hole repair in macular telangiectasia type 2 (MacTel2). DESIGN: Global, multicenter, retrospective case series. PARTICIPANTS: Patients undergoing surgery for MacTel2-associated full-thickness macular hole (MTMH). METHODS: Standardized data collection sheet distributed to all surgeons. MAIN OUTCOME MEASURES: Anatomic closure and visual outcomes of MTMH. RESULTS: Sixty-three surgeries in 47 patients with MTMH were included from 30 surgeons. Mean age was 68.1 years, with 62% female, 72% White, 21% East or South Asian, 2% African American, and 2% Hispanic or Latino. Procedures included 34 internal limiting membrane (ILM) peeling alone, 22 ILM flaps, 5 autologous retinal transplantations (ARTs), 1 retinotomy, and 1 subretinal bleb. For ILM peeling, preoperative visual acuity (VA) was 0.667 ± 0.423 logarithm of the minimum angle of resolution (logMAR). Minimum hole diameter (MHD) was 305.5 ± 159.4 µm (range, 34-573 µm). Sixteen of 34 ILM peels (47%) resulted in MTMH closure. At postoperative month 6, VA was stable at 0.602 ± 0.516 logMAR (P = 0.65). VA improved by at least 2 lines in 43% and at least 4 lines in 24%. For ILM flaps, preoperative VA was 0.878 ± 0.552 logMAR. MHD was 440.8 ± 175.5 µm (range, 97-697 µm), which was significantly larger than for ILM peels (P < 0.01). Twenty of 22 ILM flaps (90%) resulted in MTMH closure, which was significantly higher than for ILM peels (P < 0.01). At postoperative month 6, VA improved to 0.555 ± 0.405 logMAR (P < 0.05). VA improved by at least 2 lines in 56% and at least 4 lines in 28%. For ARTs, preoperative VA was 1.460 ± 0.391 logMAR. MHD was 390.2 ± 203.7 µm (range, 132-687 µm). All 5 ARTs (100%) resulted in MTMH closure. At postoperative month 6, VA was stable at 1.000 ± 0.246 logMAR (P = 0.08). Visual acuity improved at least 2 lines in 25%. CONCLUSIONS: Surgical closure of macular holes improved VA in 57% of MTMHs. Internal limiting membrane flaps achieved better anatomic and functional outcomes than ILM peeling alone. Autologous retinal transplantation may be an option for refractory MTMHs. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Patterns of recombination in snakes reveal a tug of war between PRDM9 and promoter-like features.

In vertebrates, there are two known mechanisms by which meiotic recombination is directed to the genome: in humans, mice, and other mammals, recombination occurs almost exclusively where the protein PRDM9 binds, while in species lacking an intact PRDM9, such as birds and canids, recombination rates are elevated near promoter-like features. To test if PRDM9 also directs recombination in non-mammalian vertebrates, we focused on an exemplar species, the corn snake (Pantherophis guttatus). Unlike birds, this species possesses a single, intact PRDM9 ortholog. By inferring historical recombination rates along the genome from patterns of linkage disequilibrium and identifying crossovers in pedigrees, we found that PRDM9 specifies the location of recombination events outside of mammals. However, we also detected an independent effect of promoter-like features on recombination, which is more pronounced on macro- than microchromosomes. Thus, our findings reveal that the uses of PRDM9 and promoter-like features are not mutually-exclusive, and instead reflect a tug of war, which varies in strength along the genome and is more lopsided in some species than others.

An Update on the Molecular and Cellular Basis of Pharmacotherapy in Type 2 Diabetes Mellitus.

Diabetes mellitus (DM) is a chronic illness with an increasing global prevalence. More than 537 million cases of diabetes were reported worldwide in 2021, and the number is steadily increasing. The worldwide number of people suffering from DM is projected to reach 783 million in 2045. In 2021 alone, more than USD 966 billion was spent on the management of DM. Reduced physical activity due to urbanization is believed to be the major cause of the increase in the incidence of the disease, as it is associated with higher rates of obesity. Diabetes poses a risk for chronic complications such as nephropathy, angiopathy, neuropathy and retinopathy. Hence, the successful management of blood glucose is the cornerstone of DM therapy. The effective management of the hyperglycemia associated with type 2 diabetes includes physical exercise, diet and therapeutic interventions (insulin, biguanides, second generation sulfonylureas, glucagon-like peptide 1 agonists, dipeptidyl-peptidase 4 inhibitors, thiazolidinediones, amylin mimetics, meglitinides, α-glucosidase inhibitors, sodium-glucose cotransporter-2 inhibitors and bile acid sequestrants). The optimal and timely treatment of DM improves the quality of life and reduces the severe burden of the disease for patients. Genetic testing, examining the roles of different genes involved in the pathogenesis of DM, may also help to achieve optimal DM management in the future by reducing the incidence of DM and by enhancing the use of individualized treatment regimens.

Probiotic lactic acid bacteria as a means of preventing in vitro urinary catheter colonization and biofilm formation.

BACKGROUND: Catheter-associated urinary tract infections (CAUTIs) are the most common infections found in healthcare facilities. Urinary catheters predispose the development of CAUTIs by destroying natural barriers and providing a source for infection and biofilm formation (BF). This study aimed to evaluate probiotic lactic acid bacteria (LAB) as a means of preventing in vitro urinary catheter colonization and BF. METHODS: Cross-sectional screening, followed by an experimental study, was conducted on 120 catheterized patients admitted to the urology department in a tertiary care hospital for 7 months. The isolated and identified uropathogens were tested for their antimicrobial susceptibility patterns by the disk diffusion method according to Clinical and Laboratory Standards Institute recommendations and examined for their ability to produce biofilms using a microtiter plate (MtP) assay. Five LAB (Lactobacillus acidophilus (L. acidophilus), Bifidobacterium bifidum (B. bifidum), L. paracasei, L. pentosus, and L. plantarum) were identified and examined for preventing in vitro colonization and BF of some isolated uropathogens on Foley urinary catheter surfaces. RESULTS: Of the 120 samples collected, 32.5% were found to be associated with CAUTIs. Of isolated organisms, 74.4% were gram-negative bacilli, while gram-positive cocci represented 14%, and only 11.6% were of the Candida species. About two-thirds of isolated uropathogens were biofilm formers. All five probiotic strains had inhibitory effects on the growth of all the uropathogens tested but with varying intensities according to the duration of application after 2, 4, and 6 days. CONCLUSIONS: The prevalence of CAUTIs was high, and the predominant bacterial isolates were gram-negative bacilli. Many of the studied uropathogens were biofilm formers. The bacterial isolates had a higher prevalence of resistance to commonly prescribed antimicrobial agents. Probiotics have the potential to prevent in vitro urinary catheter colonization and inhibit BF. Pre-coating urinary catheters with probiotics is recommended after ensuring the safety of probiotics' use in vivo by carrying out further large-scale studies.

Effects of cannabinoids on ligand-gated ion channels.

Phytocannabinoids such as Δ9-tetrahydrocannabinol and cannabidiol, endocannabinoids such as N-arachidonoylethanolamine (anandamide) and 2-arachidonoylglycerol, and synthetic cannabinoids such as CP47,497 and JWH-018 constitute major groups of structurally diverse cannabinoids. Along with these cannabinoids, CB1 and CB2 cannabinoid receptors and enzymes involved in synthesis and degradation of endocannabinoids comprise the major components of the cannabinoid system. Although, cannabinoid receptors are known to be involved in anti-convulsant, anti-nociceptive, anti-psychotic, anti-emetic, and anti-oxidant effects of cannabinoids, in recent years, an increasing number of studies suggest that, at pharmacologically relevant concentrations, these compounds interact with several molecular targets including G-protein coupled receptors, ion channels, and enzymes in a cannabinoid-receptor independent manner. In this report, the direct actions of endo-, phyto-, and synthetic cannabinoids on the functional properties of ligand-gated ion channels and the plausible mechanisms mediating these effects were reviewed and discussed.

Gluteal Region Reshaping of Massive Weight Loss Patients-A Decision-Making Strategy.

Background Massive weight loss (MWL) is a very common presentation that you may face as a plastic surgeon. Each patient has his own individual criteria, so, you should work according to a well-organized plan, especially when such cases have concerns about their gluteal area contour that were neglected before by many surgeons. A decision-making strategy was used to give a personalized treatment for targeting gluteal region reshaping of MWL patients. Methods This study considered all patients with MWL subjected to buttock reshaping. There was no randomization in treatment; there was a case-by-case assessment. We analyzed the features of the buttocks, the type of surgery performed, the outcomes, and the complications. Results Fifty two patients were included (41 females and 11 males), ages ranged between 21 and 66 years. Demographic data, preoperative body mass index (BMI), duration of surgery, type of surgery, and postoperative complications were collected. Statistically significant improvements were observed in gluteal ptosis and patient satisfaction grades. Conclusion Aesthetic improvement of the buttocks involves either augmentation or contouring that may be obtained by liposculpture, surgical lifting, or combination. Patients with MWL have high expectations and are often treated with multiple procedures. Thus, an easy strategic approach personalized on each patient to treat multiple adjacent areas in one operation is necessary. Adipose tissue distribution, gluteal skin status, and BMI were the main factors that can forcefully affect our plan to guarantee reduction of unpleasant results and complications and improve patient satisfaction.

Preparation and Characterization of a Novel Mucoadhesive Carvedilol Nanosponge: A Promising Platform for Buccal Anti-Hypertensive Delivery.

Carvedilol (CRV) is a non-selective third generation beta-blocker used to treat hypertension, congestive heart failure and angina pectoris. Oral administration of CRV showed poor bioavailability (25%), which might be ascribed to its extensive first-pass metabolism. Buccal delivery is known to boost drugs bioavailability. The aim of this study is to investigate the efficacy of bilosomes-based mucoadhesive carvedilol nanosponge for enhancing the oral bioavailability of CRV. The bilosomes were prepared, optimized and characterized for particle size, surface morphology, encapsulation efficiency and ex-vivo permeation studies. Then, the optimized formula was incorporated into a carboxymethyl cellulose/hydroxypropyl cellulose (CMC/HPC) composite mixture to obtain buccal nanosponge enriched with CRV bilosomes. The optimized bilosome formula (BLS9), showing minimum vesicle size, maximum entrapment, and highest cumulative in vitro release, exhibited a spherical shape with 217.2 nm in diameter, 87.13% entrapment efficiency, and sustained drug release for up to 24 h. In addition, ex-vivo drug permeation across sheep buccal mucosa revealed enhanced drug permeation with bilosomal formulations, compared to aqueous drug suspension. Consecutively, BLS9 was incorporated in a CMC/HPC gel and lyophilized for 24 h to obtain bilosomal nanosponge to enhance CRV buccal delivery. Morphological analysis of the prepared nanosponge revealed improved swelling with a porosity of 67.58%. The in vivo assessment of rats indicated that CRV-loaded nanosponge efficiently enhanced systolic/diastolic blood pressure, decreased elevated oxidative stress, improved lipid profile and exhibited a potent cardio-protective effect. Collectively, bilosomal nanosponge might represent a plausible nanovehicle for buccal delivery of CRV for effective management of hypertension.

Predictors of post-COVID symptoms in Egyptian patients: Drugs used in COVID-19 treatment are incriminated.

OBJECTIVES: COVID-19 is a multisystem disease, and some patients suffer from physical or psychological symptoms for weeks or even months after infection, which is described as post-COVID syndrome. The goal of this study is evaluating the prevalence of post-COVID-19 symptoms among Egyptian patients and detecting the factors associated with the presence of these symptoms. METHODS: An on-line cross-sectional survey using Google Forms was used to conduct the present study, which took place between June and August 2021. RESULTS: Three hundred and ninety-six participants filled in the survey. The mean age of participants was 41.4 years. Most participants had mild to moderate COVID-19 (81.31%). The prevalence of post-COVID-19 symptoms was 87.63%, where the most frequent symptom was fatigue (60.86%). Female sex, the presence of comorbidities, lower degree of education, longer disease duration, as well as severe and critical forms of the disease were significantly associated with the presence of post-COVID symptoms. Using regression analysis, the predictors of post-COVID symptoms were severe and critical forms of the disease and intake of antibiotics and corticosteroids for treatment of COVID-19. CONCLUSIONS: COVID-19 is followed by high prevalence of post-COVID symptoms. To the best of our knowledge, this is the first study to report the relationship between the use of antibiotics and the development of post-COVID symptoms. We recommend further studies to understand this relationship. We also recommend restricting the use of these drugs to indicated cases according to the international guidelines. More studies are needed to gain better understanding of post-COVID symptoms especially in females.

Correction: Atezolizumab-Induced Hypothyroidism in a Patient With Pre-existing Triiodothyronine (T3) Thyrotoxicosis Due to Graves' Disease: A Case Report and Literature Review.

[This corrects the article DOI: 10.7759/cureus.19736.].

Atezolizumab-Induced Hypothyroidism in a Patient With Pre-existing Triiodothyronine (T3) Thyrotoxicosis Due to Graves' Disease: A Case Report and Literature Review.

The use of immune checkpoint inhibitors has improved the management and prognosis of many solid tumors. Because of their mechanism of action, and as checks on the immune systems are reduced, immune-related adverse events are common, including the exacerbation of the pre-existing autoimmune disease. The literature is scanty regarding reports of the use of immune checkpoint inhibitors in patients with pre-existing Graves' disease. We report a case of a woman with pre-existing triiodothyronine (T3) thyrotoxicosis (hyperthyroidism) secondary to Graves' disease, who developed thyroiditis followed by severe hypothyroidism after receiving an immune checkpoint inhibitor (atezolizumab) for the treatment of small-cell lung cancer. She had been on an anti-thyroid drug for Graves' disease for two and a half years and was on the waiting list for a total thyroidectomy. However, the discovery of the severe hypothyroidism following atezolizumab-induced thyroiditis resulted in the need for long-term thyroid replacement therapy, and the planned surgery was no longer required. This case is one of the very few published reports of the use of atezolizumab in a patient with pre-existing Graves' disease, resulting in the conversion from pre-existing T3-thyrotoxicosis to overt hypothyroidism. A multidisciplinary team approach is required when using immune checkpoint inhibitors in patients with pre-existing Graves' disease or any other autoimmune disease.

In Vitro and In Vivo Antidiabetic Potential of Monoterpenoids: An Update.

Diabetes mellitus (DM) is a chronic metabolic condition characterized by persistent hyperglycemia due to insufficient insulin levels or insulin resistance. Despite the availability of several oral and injectable hypoglycemic agents, their use is associated with a wide range of side effects. Monoterpenes are compounds extracted from different plants including herbs, vegetables, and fruits and they contribute to their aroma and flavor. Based on their chemical structure, monoterpenes are classified into acyclic, monocyclic, and bicyclic monoterpenes. They have been found to exhibit numerous biological and medicinal effects such as antipruritic, antioxidant, anti-inflammatory, and analgesic activities. Therefore, monoterpenes emerged as promising molecules that can be used therapeutically to treat a vast range of diseases. Additionally, monoterpenes were found to modulate enzymes and proteins that contribute to insulin resistance and other pathological events caused by DM. In this review, we highlight the different mechanisms by which monoterpenes can be used in the pharmacological intervention of DM via the alteration of certain enzymes, proteins, and pathways involved in the pathophysiology of DM. Based on the fact that monoterpenes have multiple mechanisms of action on different targets in in vitro and in vivo studies, they can be considered as lead compounds for developing effective hypoglycemic agents. Incorporating these compounds in clinical trials is needed to investigate their actions in diabetic patients in order to confirm their ability in controlling hyperglycemia.

Autologous Retinal Transplantation for Primary and Refractory Macular Holes and Macular Hole Retinal Detachments: The Global Consortium.

PURPOSE: To report the anatomic and functional outcomes of autologous retinal transplantation (ART). DESIGN: Multicenter, retrospective, interventional, consecutive case series. PARTICIPANTS: One hundred thirty eyes of 130 patients undergoing ART for the repair of primary and refractory macular holes (MHs), as well as combined MH-rhegmatogenous retinal detachment (MH-RRD), between January 2017 and December 2019. METHODS: All patients underwent pars plana vitrectomy and ART, with surgeon modification of intraoperative variables. A large array of preoperative, intraoperative, and postoperative data was collected. Two masked reviewers graded OCT images. Multivariate statistical analysis and subgroup analysis were performed. MAIN OUTCOME MEASURES: Macular hole closure rate, visual acuity (VA), external limiting membrane and ellipsoid zone (EZ) band integrity, and alignment of neurosensory layers (ANL) on OCT. RESULTS: One hundred thirty ART surgeries were performed by 33 vitreoretinal surgeons worldwide. Patient demographics were: mean age of 63 ± 6.3 years, 58% female, 41% White, 23% Black, 19% Asian, and 17% Latino. Preoperative VA was 1.37 ± 0.12 logarithm of the minimum angle of resolution (logMAR; Snellen equivalent, approximately 20/500), which improved significantly to 1.05 ± 0.09 logMAR (Snellen equivalent, approximately 20/225; P < 0.001) after surgery (mean follow-up, 8.6 ± 0.8 months). Autologous retinal transplantation was performed for primary MH repair in 27% of patients (n = 35), for refractory MH in 58% of patients (n = 76; mean number of previous surgeries, 1.6 ± 0.2), and for MH-RRD in 15% of patients (n = 19). Mean maximum MH diameter was 1470 ± 160 µm, mean minimum diameter was 840 ± 94 µm, and mean axial length was 24.6 ± 3.2 mm. Overall, 89% of MHs closed (78.5% complete; 10% small eccentric defect), with a 95% closure rate in MH-RRD (68.4% complete; 26.3% small eccentric defect). Visual acuity improved by at least 3 lines in 43% of eyes and by at least 5 lines in 29% of eyes. Reconstitution of the EZ (P = 0.02) and ANL (P = 0.01) on OCT were associated with better final VA. Five cases of ART graft dislocation (3.8%), 5 cases of postoperative retinal detachment (3.8%), and 1 case of endophthalmitis (0.77%) occurred. CONCLUSIONS: In this global experience, patients undergoing ART for large primary and refractory MHs and MH-RRDs achieved good anatomic and functional outcomes, with low complication rates despite complex surgical pathologic features.

Impact of the mucoadhesive lyophilized wafer loaded with novel carvedilol nano-spanlastics on biochemical markers in the heart of spontaneously hypertensive rat models.

The purpose of this investigation was to encapsulate carvedilol, a model beta-blocker antihypertensive into nano-spanlastics, followed by incorporation into 1% CMC wafer to afford a mucoadhesive buccal drug delivery system, targeting to sidestep the first-pass metabolism, improving the drug absorption and pharmacological effect, achieving non-invasive buccal delivery for treating hypertension. Carvedilol-loaded nano-spanlastics were rendered by ethanol injection technique, using 23 factorial design. The effect of formulation variables was investigated on nano-spanlastic characteristics. The optimal nano-spanlastic formulation (S2; containing 20% Brij 97) exhibited particle size (239.8 ± 5 nm), entrapment efficiency (98. 16 ± 1.44%), deformability index (8.74 ± 0.42 g), and the flux after 24 h (Jmax) (22.5 ± 0.25 (µg/cm2/h) with enhancement ratio 2.87 as well as excellent stability after storage. Permeation study verified the preeminence of the S2 formula. A confocal laser scanning microscope showed deep penetration of S2 through sheep buccal mucosa formula compared to rhodamine B solution. S2-based wafer showed acceptable characters (pH, swelling, drug content, residence time, and release rate). In vivo studies (pharmacodynamic study and biochemical evaluation) showed considerable improvement in blood pressure, the profile of the lipid, oxidant stress biomarkers, and cardiac markers. Histopathological studies revealed the superiority of S2 wafer in the protection of heart tissues over Carvid®. The results achieved indicate that nano-spanlastic-based wafer offers a promising improving trans-buccal carvedilol delivery system. Graphical abstract.

Effectiveness and safety of ranibizumab 0.5 mg in treatment-naïve patients with diabetic macular edema: Results from the real-world global LUMINOUS study.

PURPOSE: To assess the one-year effectiveness and safety of ranibizumab 0.5 mg in treatment- naïve patients with diabetic macular edema (DME) enrolled in the real-world LUMINOUS study. PATIENTS AND METHODS: A 5-year, prospective, observational, open-label, global study which recruited 30,138 patients across all approved indications. Consenting patients (≥18 years) who were treatment-naïve or previously treated with ranibizumab or other ocular treatments were treated as per the local ranibizumab label. Here, we present the change in visual acuity (VA) (Early Treatment Diabetic Retinopathy Study letter score; primary treated eye) at Year 1, as well as the change in VA based on injection frequencies (≤4 and ≥5), treatment exposure, and the overall adverse events (AEs) and serious AEs (SAEs) in treatment-naïve DME patients. RESULTS: Of the 4,710 DME patients enrolled in the study, 1,063 were treatment-naïve. At baseline, mean age was 64.5 years, 54.7% were male, and 69.2% were white. At 1 year, mean VA letter score improved by +3.5 (n = 502) from a baseline of 57.7 with a mean of 4.5 injections. Presented by injection frequencies ≤4 and ≥5, VA letter score gains were 0.5 (n = 264) and 6.9 (n = 238) from baseline letter scores of 56.6 and 59.0, respectively. Over 5 years, the incidence of ocular/non-ocular AEs and SAEs was 7.2%/10.1% and 0.3%/5.8%, respectively. No endophthalmitis cases were reported. CONCLUSIONS: The LUMINOUS study included patients with DME with more diverse baseline characteristics than those in randomized clinical trials. The 1-year data showed improvement in VA with low number of injections in treatment- naïve patients with DME. Greater VA gains were observed in patients who received ≥5 injections. No new safety findings were identified. LUMINOUS confirms the effectiveness and safety of ranibizumab for the treatment of patients with DME in a real-world clinical practice.

Dual histone methyl reader ZCWPW1 facilitates repair of meiotic double strand breaks in male mice.

Meiotic crossovers result from homology-directed repair of DNA double-strand breaks (DSBs). Unlike yeast and plants, where DSBs are generated near gene promoters, in many vertebrates DSBs are enriched at hotspots determined by the DNA binding activity of the rapidly evolving zinc finger array of PRDM9 (PR domain zinc finger protein 9). PRDM9 subsequently catalyzes tri-methylation of lysine 4 and lysine 36 of Histone H3 in nearby nucleosomes. Here, we identify the dual histone methylation reader ZCWPW1, which is tightly co-expressed during spermatogenesis with Prdm9, as an essential meiotic recombination factor required for efficient repair of PRDM9-dependent DSBs and for pairing of homologous chromosomes in male mice. In sum, our results indicate that the evolution of a dual histone methylation writer/reader (PRDM9/ZCWPW1) system in vertebrates remodeled genetic recombination hotspot selection from an ancestral static pattern near genes towards a flexible pattern controlled by the rapidly evolving DNA binding activity of PRDM9.

The Arms Race Between KRAB-Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals.

Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat to genome integrity and cell/organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.