2024 Guideline for the Primary Prevention of Stroke: A Guideline From the American Heart Association/American Stroke Association.

AIM: The "2024 Guideline for the Primary Prevention of Stroke" replaces the 2014 "Guidelines for the Primary Prevention of Stroke." This updated guideline is intended to be a resource for clinicians to use to guide various prevention strategies for individuals with no history of stroke. METHODS: A comprehensive search for literature published since the 2014 guideline; derived from research involving human participants published in English; and indexed in MEDLINE, PubMed, Cochrane Library, and other selected and relevant databases was conducted between May and November 2023. Other documents on related subject matter previously published by the American Heart Association were also reviewed. STRUCTURE: Ischemic and hemorrhagic strokes lead to significant disability but, most important, are preventable. The 2024 primary prevention of stroke guideline provides recommendations based on current evidence for strategies to prevent stroke throughout the life span. These recommendations align with the American Heart Association's Life's Essential 8 for optimizing cardiovascular and brain health, in addition to preventing incident stroke. We also have added sex-specific recommendations for screening and prevention of stroke, which are new compared with the 2014 guideline. Many recommendations for similar risk factor prevention were updated, new topics were reviewed, and recommendations were created when supported by sufficient-quality published data.

Evolution of Fetal Growth in Symptomatic Sars-Cov-2 Pregnancies.

INTRODUCTION: SARS-CoV-2 is a viral disease with potentially devastating effects. Observational studies of pregnant women infected with SARS-CoV-2 report an increased risk for FGR. This study utilizes data from a prospective SARS-CoV-2 registry in pregnancy, investigating the progression of fetuses to fetal growth restriction (FGR) at birth following maternal SARS-CoV-2 and evaluating the hypothesis of whether the percentage of SGA at birth is increased after maternal SARS-CoV-2 taking into account the time interval between infection and birth. MATERIALS & METHODS: CRONOS is a prospective German registry enrolling pregnant women with confirmed SARS-CoV-2 infection during their pregnancy. SARS-CoV-2 symptoms, pregnancy- and delivery-specific information were recorded. The data evaluated in this study range from March 2020 until August 2021. Women with SARS-CoV-2 were divided into three groups according to the time of infection/symptoms to delivery: Group I<2 weeks, Group II 2-4 weeks, and Group III>4 weeks. FGR was defined as estimated and/or birth weight<10% ile, appropriate for gestational age (AGA) was within 10 and 90%ile, and large for gestational age (LGA) was defined as fetal or neonatal weight>90%ile. RESULTS: Data for a total of 2,650 SARS-CoV-2-positive pregnant women were available. The analysis was restricted to symptomatic cases that delivered after 24+0 weeks of gestation. Excluding those cases with missing values for estimated fetal weight at time of infection and/or birth weight centile, 900 datasets remained for analyses. Group I consisted of 551 women, Group II of 112 women, and Group III of 237 women. The percentage of changes from AGA to FGR did not differ between groups. However, there was a significantly higher rate of large for gestational age (LGA) newborns at the time of birth compared to the time of SARS-CoV-2 infection in Group III (p=0.0024), respectively. CONCLUSION: FGR rates did not differ between symptomatic COVID infections occurring within 2 weeks and>4 weeks before birth. On the contrary, it presented a significant increase in LGA pregnancies in Group III. However, in this study population, an increase in the percentage of LGA may be attributed to pandemic measures and a reduction in daily activity.

Effect of pentaerythritol tetranitrate (PETN) on the development of fetal growth restriction in pregnancies with impaired uteroplacental perfusion at midgestation-a randomized trial.

BACKGROUND: Fetal growth restriction is strongly associated with impaired placentation and abnormal uteroplacental blood flow. Nitric oxide donors such as pentaerythritol tetranitrate are strong vasodilators and protect the endothelium. Recently, we demonstrated in a randomized controlled pilot study a 38% relative risk reduction for the development of fetal growth restriction or perinatal death following administration of pentaerythritol tetranitrate to pregnant women at risk, identified by impaired uterine perfusion at midgestation. Results of this monocenter study prompted the hypothesis that pentaerythritol tetranitrate might have an effect in pregnancies with compromised placental function as a secondary prophylaxis. OBJECTIVE: This study aimed to test the hypothesis that the nitric oxide donor pentaerythritol tetranitrate reduces fetal growth restriction and perinatal death in pregnant women with impaired placental perfusion at midgestation in a multicenter trial. STUDY DESIGN: In this multicenter, randomized, double-blind, placebo-controlled trial, 2 parallel groups of pregnant women presenting with a mean uterine artery pulsatility index >95th percentile at 19+0 to 22+6 weeks of gestation were randomized to 50-mg Pentalong or placebo twice daily. Participants were assigned to high- or low-risk groups according to their medical history before randomization was performed block-wise with a fixed block length stratified by center and risk group. The primary efficacy endpoint was the composite outcome of perinatal death or development of fetal growth restriction. Secondary endpoints were neonatal and maternal outcome parameters. RESULTS: Between August 2017 and March 2020, 317 participants were included in the study and 307 were analyzed. The cumulative incidence of the primary outcome was 41.1% in the pentaerythritol tetranitrate group and 45.5% in the placebo group (unadjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; adjusted relative risk, 0.90; 95% confidence interval, 0.69-1.17; P=.43). Secondary outcomes such as preterm birth (unadjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; adjusted relative risk, 0.73; 95% confidence interval, 0.56-0.94; P=.01) and pregnancy-induced hypertension (unadjusted relative risk, 0.65; 95% confidence interval, 0.46-0.93; adjusted relative risk, 0.65; 95% confidence interval, 0.46-0.92; P=0.01) were reduced. CONCLUSION: Our study failed to show an impact of pentaerythritol tetranitrate on the development of fetal growth restriction and perinatal death in pregnant women with impaired uterine perfusion at midgestation. Pentaerythritol tetranitrate significantly reduced secondary outcome parameters such as the incidence of preterm birth and pregnancy-induced hypertension in these pregnancies.

The B-cell inhibitory receptor CD22 is a major factor in host resistance to Streptococcus pneumoniae infection.

Streptococcus pneumoniae is a major human pathogen, causing pneumonia and sepsis. Genetic components strongly influence host responses to pneumococcal infections, but the responsible loci are unknown. We have previously identified a locus on mouse chromosome 7 from a susceptible mouse strain, CBA/Ca, to be crucial for pneumococcal infection. Here we identify a responsible gene, Cd22, which carries a point mutation in the CBA/Ca strain, leading to loss of CD22 on B cells. CBA/Ca mice and gene-targeted CD22-deficient mice on a C57BL/6 background are both similarly susceptible to pneumococcal infection, as shown by bacterial replication in the lungs, high bacteremia and early death. After bacterial infections, CD22-deficient mice had strongly reduced B cell populations in the lung, including GM-CSF producing, IgM secreting innate response activator B cells, which are crucial for protection. This study provides striking evidence that CD22 is crucial for protection during invasive pneumococcal disease.

Validation of reference genes for whole blood gene expression analysis in cord blood of preterm and full-term neonates and peripheral blood of healthy adults.

BACKGROUND: Preterm birth is the leading cause of neonatal morbidity and mortality, but research efforts in neonatology are complicated due to the unavailability of large volume blood samples. Whole blood assays can be used to overcome this problem by performing both functional and gene expression studies using small amounts of blood. Gene expression studies using RT-qPCR estimate mRNA-levels of target genes normalized to reference genes. The goal of this study was to identify and validate stable reference genes applicable to cord blood samples obtained from developing neonates of different gestational age groups as well as to adult peripheral blood samples. Eight reference gene candidates (ACTB, B2M, GAPDH, GUSB, HPRT, PPIB, RPLP0, RPL13) were analyzed using the three published software algorithms Bestkeeper, GeNorm and NormFinder. RESULTS: A normalization factor consisting of ACTB and PPIB allows for comparative expression analyses of neonatal samples from different gestational age groups. Normalization factors consisting of GAPDH and PPIB or ACTB and GAPDH are suitable when samples from preterm and full-term neonates and adults are compared. However, all candidate reference genes except RPLP0 exhibited significant intergroup gene expression variance and a higher gene expression towards an older age which resulted in a small but statistically significant systematic bias. Systematic analysis of RNA-seq data revealed new reference gene candidates with potentially superior stability. CONCLUSIONS: The current study identified suitable normalization factors and proposed the use of the additional single gene RPLP0 to avoid systematic bias. This combination will enable comparative analyses not only between neonates of different gestational ages, but also between neonates and adults, as it facilitates more detailed investigations of developmental gene expression changes. The use of software algorithms did not prevent unintended systematic bias. This generally highlights the need for careful validation of such results to prevent false interpretation of potential age-dependent changes in gene expression. To identify the most stable reference genes in the future, RNA-seq based global approaches are recommended.

Facilitating Virtual Visitation in Critical Care Units During a Pandemic.

Presence of support persons enhances patient and family satisfaction. The introduction of the coronavirus disease-2019 (COVID-19) pandemic has impacted hospital operations and has reduced visitation. A virtual visitation program was implemented in critical care units to replicate visitation by video chat to ease stress on patients and family members to improve communication.

Neonatal and young infant sepsis by Group B Streptococci and Escherichia coli: a single-center retrospective analysis in Germany-GBS screening implementation gaps and reduction in antibiotic resistance.

The last nationwide surveillance study on neonatal and young infant sepsis due to Group B Streptococci (GBS) and Escherichia coli in Germany was conducted between 2009 and 2010. The aim of this study is to provide longitudinal epidemiological data on neonatal and young infant sepsis caused by GBS and E. coli to reevaluate existing data and to inform clinical decision-making. Every positive blood culture for GBS and E. coli within the first 90 days of life that occurred at our center from 2008 until 2018 was identified. The epidemiological, clinical, laboratory, and microbiological data of all affected patients were analyzed through retrospective chart review, along with the pathogen's antimicrobial susceptibility results. In total, 106 episodes of neonatal sepsis were described; 31% (n = 33) being caused by GBS and 69% (n = 73) by E. coli; 87% of GBS early-onset disease (EOD) cases did not receive intrapartum antibiotic prophylaxis (IAP). Contrary to general trends, the proportion of resistant E. coli isolates decreased for all tested antibiotics over time. Coincidentally, antenatal antibiotic use beyond IAP during that period decreased significantly in our center.Conclusions: (1) Data at our center suggests at least a regional implementation gap in GBS screening and IAP. (2) The decline in the resistance rate of E. coli for all antimicrobial substances might indicate that the reduction of prenatal antibiotics use is beneficial and that neonatal antibiotic stewardship programs should include pregnant women as well. What is Known: • GBS screening and intrapartum antibiotic prophylaxis led to a 32%-reduction in GBS disease in Germany with a 0.75 (92:122) ratio of early-onset disease to late-onset disease in 2009-2010. • Prenatal antibiotic use might increase the risk of E. coli early-onset disease and antibiotic resistances. What is New: • The GBS early-onset disease rates were twice as high as those of late-onset disease, the ratio was 1.75 (21:12) in 2008-2018 at our institution. This suggests that there are at least regional implementation gaps in the antenatal GBS screening in Germany. • We found a decline in E. coli resistance rates over time for all antimicrobial substances. Reduction in use of prenatal antibiotics might be an explanation.

How Does Patient Radiation Exposure Compare With Low-dose O-arm Versus Fluoroscopy for Pedicle Screw Placement in Idiopathic Scoliosis?

BACKGROUND: Intraoperative C-arm fluoroscopy and low-dose O-arm are both reasonable means to assist in screw placement for idiopathic scoliosis surgery. Both using pediatric low-dose O-arm settings and minimizing the number of radiographs during C-arm fluoroscopy guidance decrease patient radiation exposure and its deleterious biological effect that may be associated with cancer risk. We hypothesized that the radiation dose for C-arm-guided fluoroscopy is no less than low-dose O-arm scanning for placement of pedicle screws. METHODS: A multicenter matched-control cohort study of 28 patients in total was conducted. Fourteen patients who underwent O-arm-guided pedicle screw insertion for spinal fusion surgery in 1 institution were matched to another 14 patients who underwent C-arm fluoroscopy guidance in the other institution in terms of the age of surgery, body weight, and number of imaged spine levels. The total effective dose was compared. A low-dose pediatric protocol was used for all O-arm scans with an effective dose of 0.65 mSv per scan. The effective dose of C-arm fluoroscopy was determined using anthropomorphic phantoms that represented the thoracic and lumbar spine in anteroposterior and lateral views, respectively. The clinical outcome and complications of all patients were documented. RESULTS: The mean total effective dose for the O-arm group was approximately 4 times higher than that of the C-arm group (P<0.0001). The effective dose for the C-arm patients had high variability based on fluoroscopy time and did not correlate with the number of imaged spine levels or body weight. The effective dose of 1 low-dose pediatric O-arm scan approximated 85 seconds of the C-arm fluoroscopy time. All patients had satisfactory clinical outcomes without major complications that required returning to the operating room. CONCLUSIONS: Radiation exposure required for O-arm scans can be higher than that required for C-arm fluoroscopy, but it depends on fluoroscopy time. Inclusion of more medical centers and surgeons will better account for the variability of C-arm dose due to distinct patient characteristics, surgeon's preference, and individual institution's protocol. LEVEL OF EVIDENCE: Level III-case-control study.

Switching to a Pediatric Dose O-Arm Protocol in Spine Surgery Significantly Reduced Patient Radiation Exposure.

BACKGROUND: Intraoperative computed tomography and image-guided navigation improve the accuracy of screw placement. Radiation exposure to the patient remains a primary drawback. The objective of the present study was to compare the total intraoperative radiation dose and assess the resultant image quality for O-arm-assisted pedicle screw insertion, among 3 protocols: default (manufacturer recommended), institutional (reduced dose utilized in our institution), and pediatric (new protocol with lowest dose). METHODS: Thirty-seven consecutive patients under the age of 18 years underwent posterior instrumentation of the spine and underwent an intraoperative O-arm scan. Techniques (kV and mAs) for default and institutional dose settings were manually adjusted based on spinal level and body weight. Pediatric dose techniques were 80 kV/80 mAs with no adjustment for level or weight. The number of scans repeated because of inadequate imaging was assessed, and the mean estimated effective dose between the 3 protocols was compared. RESULTS: Sixty-eight scans were performed in 37 consecutive patients with mean age of 14 years and mean weight of 55 kg. For reference, the effective radiation dose of a chest x-ray is approximately 0.10 mSv. Use of the default protocol resulted in higher mean effective dose per scan of 4.65 mSv, whereas institutional protocol resulted in 2.37 mSv. The pediatric protocol reduced the mean dose to 0.65 mSv. The total effective dose per surgery was: 1.17 mSv (pediatric), 3.83 mSv (institutional), and 12.79 mSv (default) (P<0.0001 each). All scans lead to satisfactory image quality except in 1 patient >100 kg with stainless steel implants. There were no neurological or other implant-related complications. The pediatric protocol resulted in satisfactory image quality with the lowest total radiation dose, only 1/10 of that of the default protocol. CONCLUSIONS: We successfully switched to a pediatric low-dose O-arm protocol in clinical practice, reducing the dose to <1/4 of the mean annual natural background radiation. This may allow use of intraoperative computed tomography and navigation for pedicle screw placement without excessive radiation exposure to young patients. LEVEL OF EVIDENCE: Level III-retrospective comparative study.

Comparison of depth of necrosis using cryotherapy by gas and number of freeze cycles.

OBJECTIVE: This study aimed to establish the noninferiority of a single-freeze application with CO2 or N2O compared with the standard double freeze with N2O for cryotherapy treatment. MATERIALS AND METHODS: Sixty women undergoing hysterectomy for reasons other than cervical cancer or precancer were randomized to 1 of 3 techniques as follows: (1) double freeze with N2O, (2) single freeze with N2O, or (3) single freeze with CO2. The cervix was separated and cut into anterior and posterior segments, and the deepest area of necrosis was recorded. Comparisons were made using regression analysis. The margin of noninferiority was defined as 0.8 mm. RESULTS: On the anterior lip, a single freeze with N2O was noninferior to a double freeze of the same gas, but on the posterior lip, the single freeze was not. The single freeze of CO2 did not provide sufficient depth of necrosis in either lip to infer noninferiority versus the double freeze with N2O. CONCLUSIONS: A single freeze with N2O is noninferior to a double-freeze technique in the anterior but not the posterior lip. However, the result for posterior lips was close to reaching statistical significance. In addition, CO2 had approximately 1 mm shallower depth of necrosis compared with N2O techniques; however, the clinical implications are unknown. Given the extensive use of CO2 globally, further clinical evaluation is needed.

Biodegradable Janus nanoparticles for local pulmonary delivery of hydrophilic and hydrophobic molecules to the lungs.

The aim of the present work is to synthesize, characterize, and test self-assembled anisotropic or Janus particles designed to load anticancer drugs for lung cancer treatment by inhalation. The particles were synthesized using binary mixtures of biodegradable and biocompatible materials. The particles did not demonstrate cyto- and genotoxic effects. Janus particles were internalized by cancer cells and accumulated both in the cytoplasm and nuclei. After inhalation delivery, nanoparticles accumulated preferentially in the lungs of mice and retained there for at least 24 h. Two drugs or other biologically active components with substantially different aqueous solubility can be simultaneously loaded in two-phases (polymer-lipid) of these nanoparticles. In the present proof-of-concept investigation, the particles were loaded with two anticancer drugs: doxorubicin and curcumin as model anticancer drugs with relatively high and low aqueous solubility, respectively. However, there are no obstacles for loading any hydrophobic or hydrophilic chemical agents. Nanoparticles with dual load were used for their local inhalation delivery directly to the lungs of mice with orthotopic model of human lung cancer. In vivo experiments showed that the selected nanoparticles with two anticancer drugs with different mechanisms of action prevented progression of lung tumors. It should be stressed that anticancer effects of the combined treatment with two anticancer drugs loaded in the same nanoparticle significantly exceeded the effect of either drug loaded in similar nanoparticles alone.

Acceptability of self-collection sampling for HPV-DNA testing in low-resource settings: a mixed methods approach.

BACKGROUND: Vaginal self-sampling with HPV-DNA tests is a promising primary screening method for cervical cancer. However, women's experiences, concerns and the acceptability of such tests in low-resource settings remain unknown. METHODS: In India, Nicaragua, and Uganda, a mixed-method design was used to collect data from surveys (N = 3,863), qualitative interviews (N = 72; 20 providers and 52 women) and focus groups (N = 30 women) on women's and providers' experiences with self-sampling, women's opinions of sampling at home, and their future needs. RESULTS: Among surveyed women, 90% provided a self- collected sample. Of these, 75% reported it was easy, although 52% were initially concerned about hurting themselves and 24% were worried about not getting a good sample. Most surveyed women preferred self-sampling (78%). However it was not clear if they responded to the privacy of self-sampling or the convenience of avoiding a pelvic examination, or both. In follow-up interviews, most women reported that they didn't mind self-sampling, but many preferred to have a provider collect the vaginal sample. Most women also preferred clinic-based screening (as opposed to home-based self-sampling), because the sample could be collected by a provider, women could receive treatment if needed, and the clinic was sanitary and provided privacy. Self-sampling acceptability was higher when providers prepared women through education, allowed women to examine the collection brush, and were present during the self-collection process. Among survey respondents, aids that would facilitate self-sampling in the future were: staff help (53%), additional images in the illustrated instructions (31%), and a chance to practice beforehand with a doll/model (26%). CONCLUSION: Self-and vaginal-sampling are widely acceptable among women in low-resource settings. Providers have a unique opportunity to educate and prepare women for self-sampling and be flexible in accommodating women's preference for self-sampling.

Perilous Uncertainty: Situating Women's Breast-Health Seeking in Northern Peru.

Breast cancer rates in Peru, as in other low- and middle-income countries, continue to rise, and survival rates are poor, in part because many women are diagnosed with late-stage disease. As part of a pilot project to improve breast cancer screening and diagnostic services in remote regions of Peru, the Program for Appropriate Technology in Health (PATH) partnered with Peruvian organizations to train community health workers in breast health promotion and providers in clinical breast exam (CBE). To inform these strategies, we undertook a qualitative study to determine factors that influence Peruvian women's decisions to seek CBE. Anthropological approaches incorporating the PRECEDE/PROCEED public health model guided our conversations with providers and women living in the region of the pilot intervention. Grounded theory analysis helped us uncover a central theme of uncertainty, a state of doubt and insecurity that created a sense of impotent worry and impeded clinical health-seeking behaviors.

Pentaerythrityl tetranitrate improves the outcome of children born to mothers with compromised uterine perfusion-12-months follow-up and safety data of the double-blind randomized PETN trial.

BACKGROUND: This is a follow-up study to the pentaerythrityl tetranitrate randomized controlled multicenter trial that reports neonatal outcome data of newborns admitted to neonatal intensive care units and outcome data of the offspring at 12 months of age. OBJECTIVE: We present data on adverse events reported during the study to document the safety of pentaerythrityl tetranitrate treatment during pregnancy. To further evaluate the effects of pentaerythrityl tetranitrate on neonatal and long-term outcomes, we present follow up data from of 240 children at 12 months of age, including information on height, weight, head circumference, developmental milestones, and the presence of chronic disease and of 144 newborns admitted to the neonatal intensive care unit during the trial. STUDY DESIGN: The pentaerythrityl tetranitrate trial was a randomized, double-blind, placebo-controlled study designed to assess the efficacy and safety of the nitric oxide-donor pentaerythrityl tetranitrate in the prevention of fetal growth restriction and perinatal death in pregnancies complicated by abnormal placental perfusion. RESULTS: Results at 12 months demonstrated that significantly more children were age appropriately developed without impairments in the pentaerythrityl tetranitrate group (P=.018). In addition, the presence of chronic disease was lower in the pentaerythrityl tetranitrate group (P=.041). Outcome data of the 144 newborns admitted to the neonatal intensive care unit did not reveal differences between the treatment and placebo groups. There were no differences in the number or nature of reported adverse events between the study groups. CONCLUSION: The analysis shows that study children born in the pentaerythrityl tetranitrate cohort have a clear advantage compared with the placebo group at the age of 12 months, as evidenced by the increased incidence of normal development without the presence of chronic disease. Although safety has been proven, further follow-up studies are necessary to justify pentaerythrityl tetranitrate treatment during pregnancies complicated by impaired uterine perfusion.

Screen-and-treat approach to cervical cancer prevention using visual inspection with acetic acid and cryotherapy: experiences, perceptions, and beliefs from demonstration projects in Peru, Uganda, and Vietnam.

Cervical cancer is preventable but continues to cause the deaths of more than 270,000 women worldwide each year, most of them in developing countries where programs to detect and treat precancerous lesions are not affordable or available. Studies have demonstrated that screening by visual inspection of the cervix using acetic acid (VIA) is a simple, affordable, and sensitive test that can identify precancerous changes of the cervix so that treatment such as cryotherapy can be provided. Government partners implemented screening and treatment using VIA and cryotherapy at demonstration sites in Peru, Uganda, and Vietnam. Evaluations were conducted in the three countries to explore the barriers and facilitating factors for the use of services and for incorporation of screen-and-treat programs using VIA and cryotherapy into routine services. Results showed that use of VIA and cryotherapy in these settings is a feasible approach to providing cervical cancer prevention services. Activities that can help ensure successful programs include mobilizing and educating communities, organizing services to meet women's schedules and needs, and strengthening systems to track clients for follow-up. Sustainability also depends on having an adequate number of trained providers and reducing staff turnover. Although some challenges were found across all sites, others varied from country to country, suggesting that careful assessments before beginning new secondary prevention programs will optimize the probability of success.

Screen-and-treat approach to cervical cancer prevention using visual inspection with acetic acid and cryotherapy: experiences, perceptions, and beliefs from demonstration projects in Peru, Uganda, and Vietnam.

Cervical cancer is preventable but continues to cause the deaths of more than 270,000 women worldwide each year, most of them in developing countries where programs to detect and treat precancerous lesions are not affordable or available. Studies have demonstrated that screening by visual inspection of the cervix using acetic acid (VIA) is a simple, affordable, and sensitive test that can identify precancerous changes of the cervix so that treatment such as cryotherapy can be provided. Government partners implemented screening and treatment using VIA and cryotherapy at demonstration sites in Peru, Uganda, and Vietnam. Evaluations were conducted in the three countries to explore the barriers and facilitating factors for the use of services and for incorporation of screen-and-treat programs using VIA and cryotherapy into routine services. Results showed that use of VIA and cryotherapy in these settings is a feasible approach to providing cervical cancer prevention services. Activities that can help ensure successful programs include mobilizing and educating communities, organizing services to meet women's schedules and needs, and strengthening systems to track clients for follow-up. Sustainability also depends on having an adequate number of trained providers and reducing staff turnover. Although some challenges were found across all sites, others varied from country to country, suggesting that careful assessments before beginning new secondary prevention programs will optimize the probability of success.

Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

Introduction: Studies have shown that pregnant women with COVID-19 have a higher risk of intensive care unit admission and invasive mechanical ventilation support than non-pregnant women. Pregnancy-associated physiological changes in respiratory function may contribute to the elevated risk. Alteration in lung volumes and capacities are attributed to the mechanical impediment caused by the growing fetus. Multiple pregnancies may therefore compromise functional lung capacity earlier than singleton pregnancies and contribute to severe respiratory symptoms of COVID-19. Materials and Methods: A total of 5514 women with a symptomatic SARS-CoV-2 infection during pregnancy registered in the COVID-19 Related Obstetric and Neonatal Outcome Study were included. The COVID-19-related adverse maternal outcomes were compared in 165 multiple versus 5349 singleton pregnancies. Combined adverse maternal outcome was defined as presence of COVID-19-related hospitalization and/or pneumonia and/or oxygen administration and/or transfer to ICU and/or death. Multivariate logistic regression was used to estimate the odds ratios and 95% confidence intervals were calculated. Results: The frequency of dyspnea, likelihood of developing dyspnea in a defined pregnancy week and duration of the symptomatic phase of the COVID-19 infection did not differ between the two groups. On average, COVID-19-related combined adverse outcome occurred earlier during pregnancy in women expecting more than one child than in singleton pregnancies. The overall incidence of singular and combined COVID-19-associated adverse maternal outcomes was not significantly different between groups. However, regression analysis revealed that multiple gestation, preconceptional BMI > 30 kg/m 2 and gestational age correlated significantly with an increased risk of combined adverse maternal outcome. Conversely, maternal age and medically assisted reproduction were not significant risk factors for combined adverse maternal outcome. Conclusion: Our data show that multiple gestation alone is a risk factor for COVID-19-associated combined adverse maternal outcome. Moreover, severe courses of COVID-19 in women expecting more than one child are observed earlier in pregnancy than in singleton pregnancies.

Correction: Multiple Gestation as a Risk Factor for SARS-CoV-2-Associated Adverse Maternal Outcome: Data From the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS).

[This corrects the article DOI: 10.1055/a-2196-6224.].

Inhibition of connective tissue growth factor by small interfering ribonucleic acid prevents increase in extracellular matrix molecules in a rodent model of diabetic retinopathy.

PURPOSE: Connective tissue growth factor (CTGF) is a profibrotic factor that induces extracellular matrix (ECM) production and angiogenesis, two processes involved in diabetic retinopathy (DR). In this study, we examined whether insulin therapy or a CTGF-specific small interfering RNA (siRNA) administered to diabetic rats decreased the levels of CTGF and of selected putative downstream genes in the retina. METHODS: Rats with streptozotocin-induced diabetes were used. Animals received either no treatment for 12 weeks or were administered constant insulin therapy. MRNA and protein levels of CTGF and select ECM genes were determined using real-time PCR and western blotting of the retina. Localization of CTGF in the retina was visualized using immunohistochemistry. A group of diabetic rats received intravitreal injection of CTGF siRNA, and the retinas were examined three days later. RESULTS: CTGF mRNA and protein significantly increased in the retinas of diabetic rats. Immunohistochemistry indicated that retinal Müller cells of diabetic rats expressed CTGF. Hyperglycemia upregulated mRNA levels of fibronectin, laminin ß1, collagen IVα3, and vascular endothelial growth factor (VEGF), and this increase was prevented by insulin therapy. Treatment of diabetic rats with CTGF siRNA decreased laminin ß1, collagen IVα3 mRNA, and CTGF mRNA and protein but did not affect fibronectin or vascular endothelial growth factor mRNA levels. CONCLUSIONS: These results indicate that CTGF and ECM genes can be regulated using insulin. Importantly, these results also suggest that CTGF regulates changes in ECM molecules in DR.

Production and characterization of anisotropic particles from biodegradable materials.

In recent years, production and characterization of anisotropic particles has become of interest in a wide range of scientific fields including polymer chemistry, drug delivery, electronics, energy, and nanotechnology. In this work, we demonstrate a novel formulation for production of anisotropic particles via an internal phase separation of biodegradable components. Specifically, binary mixtures of biodegradable polymers poly(lactic-co-glycolic acid), polycaprolactone, and biodegradable lipid Precirol (glyceryl palmitostearate) were dissolved in dichloromethane, emulsified, and prepared into anisotropic particles using a modified solvent evaporation technique. During the slow evaporation process the components self-assembled into anisotropic particles with distinct morphologies. Polymer/polymer formulations resulted in compartmentalized anisotropic heterodimer particles, while polymer/lipid combinations yielded "ice cream cone" shaped particles. It was found that addition of certain active pharmaceuticals resulted in an altered, pox-like segregation at the particle surface of polymer/polymer formulations. The anisotropic nature of the particles was subsequently characterized using optical microscopy, scanning electron microscopy, zeta potential, electrophoresis, and X-ray diffraction. Successful formulations presented here may potentially be employed as multicompartmental drug carriers with staggered drug release rates or alternatively as a colloidal excipient for an arsenal of pharmaceutical applications.