Forced Sexual Initiation and Early Sexual Debut and Associated Risk Factors and Health Problems Among Adolescent Girls and Young Women - Violence Against Children and Youth Surveys, Nine PEPFAR Countries, 2007-2018.

Adolescent girls and young women aged 13-24 years are disproportionately affected by HIV in sub-Saharan Africa (1), resulting from biologic, behavioral, and structural* factors, including violence. Girls in sub-Saharan Africa also experience sexual violence at higher rates than do boys (2), and women who experience intimate partner violence have 1.3-2.0 times the odds of acquiring HIV infection, compared with those who do not (3). Violence Against Children and Youth Survey (VACS) data during 2007-2018 from nine countries funded by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) were analyzed to estimate prevalence and assess factors associated with early sexual debut and forced sexual initiation.† Among adolescent girls and young women aged 13-24 years who ever had sex, the prevalence of lifetime sexual violence ranged from 12.5% to 49.3%, and forced sexual initiation ranged from 14.7% to 38.9%; early sexual debut among adolescent girls and young women aged 16-24 years ranged from 14.4% to 40.1%. In multiple logistic regression models, forced sexual initiation was associated with being unmarried, violence victimization, risky sexual behaviors, sexually transmitted infections (STIs), and poor mental health. Early sexual debut was associated with lower education, marriage, ever witnessing parental intimate partner violence during childhood, risky sexual behaviors, poor mental health, and less HIV testing. Comprehensive violence and HIV prevention programming is needed to delay sexual debut and protect adolescent girls and young women from forced sex.

Advancing multiproduct resin reuse for development and clinical manufacturing of an antibody-based therapeutic.

Chromatography resins used for purifying biopharmaceuticals are generally dedicated to a single product. For clinical manufacturing, this can result in resin being used only for a fraction of its potential lifetime. Extending the use of resins to multiple products can significantly reduce resin waste and cost. It can also improve manufacturing flexibility in case of raw material shortage during times such as the COVID-19 pandemic. The work presented herein describes an overarching multiproduct resin reuse (MRR) strategy, which includes a risk assessment, strategic planning, small-scale feasibility runs, and the successful execution of the MRR strategy to support Good manufacturing practice (GMP) clinical manufacturing of an antibody-based therapeutic. Specifically, an anion exchange (AEX) and cation exchange (CEX) MRR strategy is described. Clearance of carryover biological product is demonstrated by first cleaning the AEX and CEX manufacturing columns with sodium hydroxide to ensure inactivation and degradation of the carryover protein and followed by a blank buffer elution that is tested using various analytical methodologies to ensure reduction of the carryover protein to an acceptable level. To our knowledge, this is the first time an MRR approach has been successfully implemented and submitted to health authorities to support biologic GMP clinical manufacture.

Population Estimates of HIV Risk Factors to Inform HIV Prevention Programming for Adolescent Girls and Young Women.

Violence Against Children and Youth Survey (VACS) data from seven countries were analyzed to estimate population-level eligibility for the President's Emergency Plan for AIDS Relief (PEPFAR) Determined, Resilient, Empowered, AIDS-Free, Mentored, and Safe (DREAMS) HIV prevention program for adolescent girls and young women (AGYW). The prevalence of overall eligibility and individual risk factors, including experiences of violence, social, and behavioral risks differ across countries and age groups. A large proportion of AGYW across all countries and age groups examined have at least one risk factor making them eligible for DREAMS. Experiencing multiple risks is also common, suggesting that researchers and programs could work together to identify combinations of risk factors that put AGYW at greatest risk of HIV acquisition, or that explain most new HIV infections, to more precisely target the most vulnerable AGYW. The VACS provides important data for such analyses to refine DREAMS and other youth programming.

Cardiovascular risk, obesity, and myocardial blood flow in postmenopausal women.

BACKGROUND: This study was designed to determine whether overweight or obese status is independently associated with myocardial flow reserve (MFR), an established predictor of cardiovascular mortality, in a group of postmenopausal women with no previous cardiovascular disease. Postmenopausal women are the largest group of overweight and physically inactive individuals in the United States. Increased body mass index (BMI) is consistently associated with increased cardiovascular mortality in this population. Whether this is because of obesity itself or the accompanying increase in cardiovascular risk factors (CRFs) remains controversial. METHODS: We examined the relationship of myocardial blood flow (MBF), coronary vascular resistance, and MFR to BMI in 60 postmenopausal women with no coronary heart disease. Subjects underwent dynamic N-13 ammonia positron emission tomography for the measurement of MBF and MFR. Baseline demographics, CRF, and hemodynamic parameters were recorded for each subject. Datasets were divided into 3 groups according to BMI: normal (18 to 24), overweight (25 to 29), and obese (>or=30). RESULTS: The overweight and obese groups showed significantly higher resting MBF and lower MFR than the normal-weight group (both P < .001), even after adjusting for CRF. A further analysis of subjects without any CRF (n = 35) showed that the MFR remained significantly lower in the obese compared with normal-weight subjects (P = .05). Levels of known markers of vascular inflammation (high-sensitivity C-reactive protein and homocysteine) and high-density lipoprotein cholesterol levels correlated with declining MFR. CONCLUSIONS: These findings provide a mechanistic link between obesity and coronary heart disease in this population.

Building a successful DCD program: planning and leading change.

In Canada, there is a growing gap between the number of organs donated each year and the number of organs needed for transplant. This gap is forcing health care professionals to re-examine end-of-life care and donation practices. In 2005, a national forum created recommendations for the development and implementation of donation after cardio-circulatory death programs. In this article, the authors outline the multifaceted approach needed for change in interdisciplinary clinical practice. Clinical nurse specialist leadership, ethics consultation, partnerships with key physician colleagues and administrators, as well as comprehensive workshops are described as essential for success. Lessons learned throughout are shared.

Combined continuous ethinyl estradiol/norethindrone acetate does not improve forearm blood flow in postmenopausal women at risk for cardiovascular events: a pilot study.

OBJECTIVE: This study sought to determine whether combined continuous ethinyl estradiol and norethindrone acetate, a postmenopausal hormone therapy (HT) combination designed to have fewer side effects than cyclical therapies and therapies using medroxyprogesterone acetate (MPA), could improve vascular endothelial function in postmenopausal women with risk factors for cardiovascular disease (CVD). METHODS: Eighteen postmenopausal women (mean age 62 +/- 11 years) participated in a randomized, placebo-controlled, crossover design trial of 10 microg estradiol/1 mg norethindrone acetate given once daily for 3 months, with a 1-month washout period between placebo and active treatment phases. Vascular reactivity was assessed at each phase of the study using high-frequency brachial artery ultrasound in response to flow-mediated hyperemia, cold pressor testing, and sublingual nitroglycerin. Markers of cardiovascular risk, including cholesterol levels, inflammatory markers, fibrinolytic markers, and solubilized adhesion molecules, were also measured at each phase. RESULTS: We found no significant difference in vascular reactivity measurements during active treatment with ethinyl estradiol/norethindrone acetate vs. placebo. C-reactive protein (CRP) levels increased significantly during active treatment, and high-density lipoprotein (HDL) levels decreased significantly. Vascular cell adhesion molecule-1 (VCAM-1) levels declined during active treatment. Plasminogen activator inhibitor-1 (PAI-1) levels were inversely correlated with flow-mediated hyperemic vascular reactivity, independent of active treatment or placebo phases. CONCLUSIONS: In this older postmenopausal population with at least one cardiovascular risk factor, treatment with combined continuous ethinyl estradiol and norethindrone acetate failed to improve vascular endothelial function. The agent's proinflammatory effect or subclinical atherosclerosis in this population may have contributed to this finding.

Transcutaneous ultrasonographic evaluation of gastric distension with fluid in horses.

OBJECTIVE: To develop a transcutaneous ultrasonography (TUS) method for measuring the location of the stomach during various levels of fluid distension and evaluate any correlation between gastric fluid distension and stomach position. ANIMALS: 6 adult horses. PROCEDURES: Known volumes of water were administered in 2 trials. In trial 1, the stomach was evaluated prior to and after the administration of 2, 4, and 6 L of water. In trial 2, the stomach was evaluated after administration of 6, 8, 10, and 12 L of water. The TUS was performed at the 7th through 16th left intercostal spaces (ICSs). For each volume of water, an image was captured at the most dorsal point in each ICS where the dorsolateral aspect of the stomach wall was viewed. The distance between this point and a horizontal line drawn on the skin at the level of the elbow joint was measured. The measurements at all ICSs were used to estimate the gastric wall height at ICS 12, which was subsequently evaluated for statistical association with volume administered. RESULTS: Significant correlation between the estimated height of the stomach wall at ICS 12 and the volume of fluid administered was detected. A regression equation to estimate gastric fluid volume when initial values for gastric wall height (cm) at ICS 12 and fluid volume (L) are known was developed. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that use of TUS for gastric fluid volume estimation is a potentially useful technique.

Identification of infrared absorption spectral characteristics of synovial fluid of horses with osteochondrosis of the tarsocrural joint.

OBJECTIVE: To determine the feasibility of the use of Fourier-transform infrared (FTIR) spectroscopy within the midinfrared range to differentiate synovial fluid samples of joints with osteochondrosis from those of control samples. ANIMALS: 33 horses with osteochondrosis of the tarsocrural joint and 31 horses free of tarsocrural joint disease. PROCEDURES: FTIR spectroscopy of synovial fluid was used. Sixty-four synovial fluid samples from the tarsocrural joint were collected. Of these, 33 samples were from horses with radiographic evidence of osteochondrosis of the tarsocrural joint and 31 from control joints. Disease-associated features within infrared spectra of synovial fluid were statistically selected for spectral classification, and the variables identified were used in a classification model. Linear discriminant analysis and leave-one-out cross-validation were used to develop a classifier to identify joints with osteochondrosis. RESULTS: 12 significant subregions were identified that met the selection criteria. The stepwise discriminant procedure resulted in the final selection of 6 optimal regions that most contributed to the discriminatory power of the classification algorithm. Infrared spectra derived from synovial fluid of joints with osteochondrosis were differentiated from the control samples with accuracy of 77% (81% specificity and 73% sensitivity). CONCLUSIONS AND CLINICAL RELEVANCE: The disease-associated characteristics of infrared spectra of synovial fluid from joints with osteochondrosis may be exploited via appropriate feature selection and classification algorithms to differentiate joints with osteochondrosis from those of control joints. Further study with larger sample size including age-, breed-, and sex-matched control horses would further validate the clinical value of infrared spectroscopy for the diagnosis of osteochondrosis in horses.

Use of infrared spectroscopy for diagnosis of traumatic arthritis in horses.

OBJECTIVE: To evaluate use of infrared spectroscopy for diagnosis of traumatic arthritis in horses. ANIMALS: 48 horses with traumatic arthritis and 5 clinically and radiographically normal horses. PROCEDURES: Synovial fluid samples were collected from 77 joints in 48 horses with traumatic arthritis. Paired samples (affected and control joints) from 29 horses and independent samples from an affected (n = 12) or control (7) joint from 19 horses were collected for model calibration. A second set of 20 normal validation samples was collected from 5 clinically and radiographically normal horses. Fourier transform infrared spectra of synovial fluids were acquired and manipulated, and data from affected joints were compared with controls to identify spectroscopic features that differed significantly between groups. A classification model that used linear discriminant analysis was developed. Performance of the model was determined by use of the 2 validation datasets. RESULTS: A classification model based on 3 infrared regions classified spectra from the calibration dataset with overall accuracy of 97% (sensitivity, 93%; specificity, 100%). The model, with cost-adjusted prior probabilities of 0.60:0.40, yielded overall accuracy of 89% (sensitivity, 83%; specificity, 100%) for the first validation sample dataset and 100% correct classification of the second set of independent normal control joints. CONCLUSIONS AND CLINICAL RELEVANCE: The infrared spectroscopic patterns of fluid from joints with traumatic arthritis differed significantly from the corresponding patterns for controls. These alterations in absorption patterns may be used via an appropriate classification algorithm to differentiate the spectra of affected joints from those of controls.

Genes overexpressed in cerebral arteries following salt-induced hypertensive disease are regulated by angiotensin II, JunB, and CREB.

Although changes in gene expression are necessary for arterial remodeling during hypertension, the genes altered and their mechanisms of regulation remain uncertain. The goal of this study was to identify cerebral artery genes altered by hypertension and define signaling pathways important in their regulation. Intact cerebral arteries from Dahl salt-sensitive normotensive and hypertensive high-salt (HS) rats were examined by immunostaining, revealing an increased phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and expression of the proliferative marker Ki-67 in arteries from hypertensive animals. Arterial RNA analyzed by microarray and validated with RT-quantitative PCR revealed that jun family member junB and matricellular genes plasminogen activator inhibitor-1 (PAI-1) and osteopontin (OPN) were significantly overexpressed in HS arteries. Fisher exact test and annotation-based gene subsets showed that genes upregulated by Jun and Ca(2+)/cAMP-response element-binding protein (CREB) were overrepresented. A model of cultured rat cerebrovascular smooth muscle cells was used to test the hypothesis that angiotensin II (ANG II), JunB, and CREB are important in the regulation of genes identified in the rat hypertension model. ANG II induced a transient induction of junB and a delayed induction of PAI-1 and OPN mRNA levels, which were reduced by ERK inhibition with U-0126. Silencing junB using small-interfering RNA reduced mRNA levels of OPN but not PAI-1. The silencing of CREB reduced PAI-1 induction by ANG II but enhanced the transcription of OPN. Together, these results suggest that salt-induced hypertensive disease promotes changes in matricellular genes that are stimulated by ANG II, regulated by ERK, and selectively regulated by JunB and CREB.

Comparison of retinal arteriolar and venular variability in healthy subjects.

Study of retinal autoregulation is important because vascular dysfunction is a precursor of many retinal diseases. Previous research has focused on venular blood flow because the minimal venular pulsatility was thought to provide more reproducible results. This study compared the variability of arteriolar and venular blood flow measurements in response to isocapnic hyperoxia, a provocation known to constrict blood vessels and reduce blood velocity. Data was collected using a non-invasive laser Doppler instrument that permitted the simultaneous measurement of retinal blood velocity and vessel diameter, allowing the derivation of blood flow. Measurements were collected from 20 young subjects before, during and after exposure to hyperoxia. Isocapnia was maintained throughout hyperoxia using a previously validated sequential re-breathing circuit. Arteriolar and venular diameters decreased during hyperoxia by 8.7% (p=0.0001) and 14.2% (p=0.0001), respectively. Hyperoxia caused significant decreases in arteriolar and venular blood velocity (31.2%, p=0.0001 and 18.0%, p=0.0001, respectively) and flow (43.2%, p=0.0001 and 40.0%, p=0.0002, respectively). The coefficients of variation for intra-individual measurements of diameter, velocity and flow were comparable in magnitude between the two vessel types. Measures of arteriolar pulsatility, such as Pulsatility ratio, Resistivity ratio and Pulsatility index, increased significantly during hyperoxia, indicating increased downstream vascular resistance. We conclude that retinal arterioles and venules provide equally reproducible results for autoregulation studies and that arteriolar pulsatility profiles provide additional useful information regarding vascular resistance.

Standing myelography in the horse using a nonionic contrast agent.

Standing myelography in the horse has been previously described. In that study, metrizamide was used and significant complications were reported. In recent years, the introduction of less-toxic nonionic contrast media has reduced the incidence of complications. This study was undertaken to determine whether standing myelography using a nonionic contrast medium could provide a diagnostic study and be performed safely in the equine patient. Standing myelography was performed in eight horses. The contrast medium used was iohexol. In five horses a myelogram of diagnostic quality was achieved; in one horse contrast flowed only to the level of C6 and in two horses contrast medium did not reach the cervical subarachnoid space. Owing to the difficulty in achieving good flow of the contrast medium in some horses, this procedure may be of limited utility. However, if puncture of the lumbosacral subarachnoid space can be achieved easily and quickly, standing myelography may be a clinically useful procedure. It may be attempted in cases in which the economic value of the patient makes myelography under general anesthesia impractical. In patients presenting for evaluation of ataxia it may be possible to perform a standing myelogram at the time of CSF sample collection from the lumbosacral space.

Excitation-transcription coupling in smooth muscle.

Calcium (Ca2+) signals affect virtually every biological process, including both contraction and gene transcription in smooth muscle. Ca2+-regulated gene transcription is known to be important for both physiological and pathological responses in smooth muscle. The aim of this review is to discuss the current understanding of gene transcription regulated by excitation through Ca2+ signalling using a comparison of the two most characterized Ca2+-regulated transcription factors in smooth muscle, Ca2+-cyclic AMP response element binding protein (CREB) and nuclear factor of activated T-cells (NFAT). Recent studies have shown commonalities and differences in the regulation of CREB and NFAT through both voltage- and non-voltage-gated Ca2+ channels that lead to expression of smooth muscle cell specific differentiation markers as well as markers of proliferation. New insights into the regulation of specific genes through companion elements on the promoters of Ca2+-regulated genes have led to new models for transcriptional regulation by Ca2+ that are defined both by the source and duration of the Ca2+ signal and the composition of enhancer elements found within the regulatory regions of specific genes. Thus the combination of signalling pathways elicited by particular Ca2+ signals affect selective promoter elements that are key to the ultimate pattern of gene transcription.

Synthesis and biological activity of tetralone abscisic acid analogues.

Bicyclic analogues of the plant hormone abscisic acid (ABA) were designed to incorporate the structural elements and functional groups of the parent molecule that are required for biological activity. The resulting tetralone analogues were predicted to have enhanced biological activity in plants, in part because oxidized products would not cyclize to forms corresponding to the inactive catabolite phaseic acid. The tetralone analogues were synthesized in seven steps from 1-tetralone and a range of analogues were accessible through a second route starting with 2-methyl-1-naphthol. Tetralone ABA 8 was found to have greater activity than ABA in two bioassays. The absolute configuration of (+)-8 was established by X-ray crystallography of a RAMP hydrazone derivative. The hydroxymethyl compounds 10 and 11, analogues for studying the roles of 8- and 9-hydroxy ABA 3 and 6, were also synthesized and found to be active.

A phase II study of sequential neoadjuvant gemcitabine and paclitaxel, radiation therapy with cisplatin and 5-fluorouracil and surgery in locally advanced esophageal carcinoma.

OBJECTIVE: To evaluate the feasibility and efficacy of sequential neoadjuvant chemotherapy, chemoradiation, and surgery in patients with locally advanced esophageal cancer. PATIENTS AND METHODS: There were 29 patients who received paclitaxel 150 mg/m2 and gemcitabine 3000 mg/m2 2 weeks apart. Two weeks later, patients received cisplatin 75 mg/m2 and 5-fluorouracil (5-FU) 1000 mg/m2/d continuous infusion for 4 days with concurrent radiotherapy in 15 fractions to a total dose of 4000 cGy. After 6 weeks, cisplatin and 5-FU were repeated at the above doses. After 4 to 6 weeks, patients were restaged and underwent surgical resection. RESULTS: All 29 patients completed the prescribed gemcitabine, paclitaxel, and radiation therapy. Febrile neutropenia occurred in 1 patient and 4 patients received growth factor support. After neoadjuvant treatment, 1 patient refused surgery, 23 underwent R0 resection (82%), while 5 developed progressive disease. Four patients developed anastomotic leaks (17%). Four patients had complete pathologic responses (14%) and 4 (14%) had only residual microscopic disease. Nine patients remain alive at a median follow-up of 48 months. Three-year survival for the entire cohort was 36%. CONCLUSION: This regimen was associated with a high rate of compliance and induction therapy had an acceptable toxicity profile. The R0 resection rate and 3-year survival data are similar to recently reported studies. While active, gemcitabine and paclitaxel induction therapy was associated with an increased rate of postoperative complications, but no increase in survival. Patterns of failure continue to demonstrate the need for regimens incorporating greater emphasis on systemic therapy for locally advanced esophageal cancer.

Intracranial meningioma causing internal ophthalmoparesis in a dog.

A 10-year-old, spayed female, Irish water spaniel was presented with a 2-week history of anisocoria characterized by mydriasis of the right eye compared to the left eye in ambient light. Ophthalmic and neurological examinations, combined with pharmacological testing, identified a disease process affecting the right parasympathetic nucleus of cranial nerve 3 (CN III) and/or the parasympathetic component of CN III. Magnetic resonance imaging (MRI) identified a mass involving the right midbrain and extending caudally to the rostral border of the medulla oblongata. The dog became comatose within 12 h following MRI and was euthanized. Histopathology identified the intracranial mass as a meningioma.