A Systematic Review of the Current Status of Safer Conception Strategies for HIV Affected Heterosexual Couples in Sub-Saharan Africa.

We conducted a systematic review of safer conception strategies (SCS) for HIV-affected couples in sub-Saharan Africa to inform evidence-based safer conception interventions. Following PRISMA guidelines, we searched fifteen electronic databases using the following inclusion criteria: SCS research in HIV-affected couples; published after 2007; in sub-Saharan Africa; primary research; peer-reviewed; and addressed a primary topic of interest (SCS availability, feasibility, and acceptability, and/or education and promotion). Researchers independently reviewed each study for eligibility using a standardized tool. We categorize studies by their topic area. We identified 41 studies (26 qualitative and 15 quantitative) that met inclusion criteria. Reviewed SCSs included: antiretroviral therapy (ART), pre-exposure prophylaxis, timed unprotected intercourse, manual/self-insemination, sperm washing, and voluntary male medical circumcision (VMMC). SCS were largely unavailable outside of research settings, except for general availability (i.e., not specifically for safer conception) of ART and VMMC. SCS acceptability was impacted by low client and provider knowledge about safer conception services, stigma around HIV-affected couples wanting children, and difficulty with HIV disclosure in HIV-affected couples. Couples expressed desire to learn more about SCS; however, provider training, patient education, SCS promotions, and integration of reproductive health and HIV services remain limited. Studies of provider training and couple-based education showed improvements in communication around fertility intentions and SCS knowledge. SCS are not yet widely available to HIV-affected African couples. Successful implementation of SCS requires that providers receive training on effective SCS and provide couple-based safer conception counseling to improve disclosure and communication around fertility intentions and reproductive health.

Menopausal hormone therapy: a better and safer future.

Major advances in menopause hormone therapy (MHT) hold promise in the future of better and safer care for women at and after the menopause. The principal advances are: (1) the critical window or 'window of opportunity' in the 10 years or so after the menopause, during which the benefits of MHT in healthy women exceed any risks; (2) use of transdermal instead of oral administration of estrogen to reduce the risk of venous thromboembolism; (c) investigation of the use of oral micronized progesterone (MP) and vaginal MP to prevent endometrial hyperplasia and carcinoma without any increased risk of breast cancer and venous thromboembolism in postmenopausal women receiving estrogens; vaginal MP prevents endometrial proliferation in the short term but the long-term effects in MHT remain to be established; (4) investigation into the use of intrauterine levonorgestrel-releasing devices (LNG-IUDs), which are an attractive form of MHT in perimenopausal women, providing contraception and reducing uterine bleeding, although the risk of breast cancer with LNG-IUDs requires clarification. Women in the future can look forward to a symptom-free menopause and to safer and more beneficial MHT.

Acceptability and Feasibility of Integrating Point-of-Care Diagnostic Testing of Sexually Transmitted Infections into a South African Antenatal Care Program for HIV-Infected Pregnant Women.

Background: Chlamydia trachomatis (CT), Neisseria gonorrhoeae (NG), and Trichomonas vaginalis (TV) infections may increase the risk of vertical transmission of the human immunodeficiency virus (HIV). In resource-limited settings, symptomatic screening, and syndromic management of sexually transmitted infections (STIs) during pregnancy continue to be the standard of care. In the absence of diagnostic testing, asymptomatic infections in pregnant women go untreated. Objective: To describe the acceptability and feasibility of integrating diagnostic STI screening into first antenatal care visits for HIV-infected pregnant women. Methods: HIV-infected pregnant women were recruited during their first antenatal care visit from three antenatal care clinics in Tshwane District, South Africa, between June 2016 and October 2017. Self-collected vaginal swabs were used to screen for CT, NG, and TV with a diagnostic point-of-care (POC) nucleic acid amplification test. Those with STIs were provided treatment per South African national guidelines. Results: Of 442 eligible women, 430 (97.3%) agreed to participate and were tested. Of those with a positive STI test result (n = 173; 40.2%), 159 (91.9%) received same-day results and treatment; 100% of STI-infected women were treated within seven days. Conclusions: Integration of POC diagnostic STI screening into first-visit antenatal care services was feasible and highly acceptable for HIV-infected pregnant women.

Prevalence of Curable Sexually Transmitted Infections in Pregnant Women in Low- and Middle-Income Countries From 2010 to 2015: A Systematic Review.

BACKGROUND: Current literature comparing the prevalence rates of curable sexually transmitted infections (STIs) in pregnant women in various global regions is limited. As a result, antenatal screening practices for curable STIs in pregnant women, specifically Treponema pallidum (syphilis), Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT), and Trichomonas vaginalis (TV) vary around the world, differing by country and particular STI. METHODS: We conducted a systematic review of publications on STI prevalence among pregnant women in 30 different low- and middle-income countries. We searched PubMed for studies reporting prevalence of syphilis, CT, NG, and TV in pregnant women. English language studies published between January 1, 2010, and March 1, 2015, were included. The adjusted mean STI prevalence by region was calculated via multivariable linear regression adjusting for health care setting, women's mean age, study sample size, and sensitivity of diagnostic test. RESULTS: We identified 75 studies that met inclusion criteria, providing 116 point prevalence estimates for curable STIs among 3,489,621 pregnant women. Adjusted mean prevalence for NG ranged from 1.2% (95% confidence interval [CI], 1.0-1.3) in Latin America to 4.6% (95% CI, 4.0-5.2) in Southern Africa; syphilis prevalence ranged from 1.1% (95% CI, 0.5-1.6) in Asia to 6.5% (95% CI, 4.7-6.3) in Southern Africa; CT ranged from 0.8% (95% CI, 0.4-1.1) in Asia to 11.2% (95% CI, 6.0-16.4) in Latin America; and TV ranged from 3.9% (95% CI, 2.2-5.6) in Latin America to 24.6% (95% CI, 17.9-31.4) in Southern Africa. CONCLUSIONS: Although we observed a wide variation in STI burden in pregnancy after adjusting for age, test, and health care setting, further valid comparison may depend on adjustment for access to care and screening practices.

Factors associated with recent unsuppressed viral load in HIV-1-infected patients in care on first-line antiretroviral therapy in South Africa.

Unsuppressed viral load (VL) in patients on antiretroviral therapy (ART) occurs when treatment fails to suppress a person's VL and is associated with decreased survival and increased HIV transmission. The objective of this study was to evaluate factors associated with unsuppressed VL (VL > 400 copies/ml) in patients currently in care on first-line ART for ≥ 6 months attending South African public healthcare facilities. We analysed electronic medical records of ART patients with a VL result on record who started ART between January 2004 and April 2016 from 271 public health facilities. We present descriptive and multivariable logistic regression for unsuppressed VL at last visit using a priori variables. We included 244,370 patients (69% female) on first-line ART in April 2016 for ≥ 6 months. Median age at ART start was 33 years (7% were < 15 years old). Median duration on ART was 3.7 years. Adjusting for other variables, factors associated with having an unsuppressed VL at the most recent visit among patients in care included: (1) < 15 years old at ART start (adjusted odds ratio [aOR]=2.58; 95% CI = 2.37, 2.81) versus 15-49 years at ART start, (2) male gender (aOR = 1.29; 95% CI = 1.25, 1.35), (3) 6-12 months on ART versus longer (aOR = 1.34; 95% CI = 1.29, 1.40), (4) on tuberculosis (TB) treatment (aOR = 1.78; 95% CI = 1.48, 2.13), and (5) prior ART exposure versus none (aOR = 1.20; 95% CI = 1.08, 1.32). Approximately 85% of the ART cohort who were in care had achieved viral suppression, though men, youth/adolescents, patients with prior ART exposure, those with short duration of ART, and patients on TB treatment had increased odds of not achieving viral suppression. There is a need to develop and evaluate targeted interventions for ART patients in care who are at high risk of unsuppressed VL.

Etiology of pure tricuspid regurgitation based on anular circumference and leaflet area: analysis of 45 necropsy patients with clinical and morphologic evidence of pure tricuspid regurgitation.

Despite recent renewed interest in the detection of tricuspid valve regurgitation by echocardiographic and Doppler techniques, little morphologic information is available on dysfunctioning tricuspid valves. This report describes 45 necropsy patients with clinical and morphologic evidence of pure (no element of stenosis) tricuspid regurgitation and provides morphometric observations (anular circumference, leaflet area) of the tricuspid valve useful in determining the etiology of pure tricuspid regurgitation. Of 45 patients, 24 (53%) had pure tricuspid regurgitation resulting from an anatomically abnormal valve (prolapse in 7, papillary muscle dysfunction in 6, rheumatic disease in 5, Ebstein's anomaly in 3, infective endocarditis in 2, carcinoid tumor in 1), and 21 (47%) had an anatomically normal valve with systolic pulmonary artery hypertension (cor pulmonale in 12, mitral stenosis in 9). Anular circumference was dilated (greater than 12 cm) in patients with various causes of pulmonary hypertension, floppy valve and Ebstein's tricuspid anomaly. Leaflet area was increased in floppy valve and Ebstein's anomaly. Of the 45 patients, 24 had pulmonary systolic artery pressure measurements available for correlation with tricuspid valve morphology. Pulmonary artery pressures accurately predicted morphologically normal from abnormal valves in 16 patients (89%). Morphologic overlap occurred in six patients with pulmonary pressures of 41 to 54 mm Hg. Of these six, the additional knowledge of normal or dilated anular circumference correctly separated valves with normal and abnormal leaflets.

Death of motorneurons during the postnatal loss of polyneuronal innervation of rat muscles.

A study was made of the decline in the number of motor neurons and axons of the brachial spinal cord of the rat during postnatal development. The injection of horseradish peroxidase (HRP) into the biceps muscle showed that it was innervated by motor neurons located in the dorsolateral position of the lateral motor column in segments C5 and C6; HRP injections into the triceps muscle showed that it was innervated by motor neurons located in the ventrolateral position of the lateral motor column in segments C7 and C8. There was no change in the position of these motor neuron pools between birth and maturity. However, there was a decline in the number of neurons in each pool during the postnatal period; over 35% of the neurons present at birth had disappeared by maturity. This loss of neurons was uniform throughout the rostrocaudal extent of each pool. It was accompanied by a similar percentage loss in the number of axons in a ventral root at the branchial level (C8). Electrophysiological measurements showed that the disappearance of motor neurons was accompanied by a loss in the polyneuronal innervation of synaptic sites in the biceps muscle. The possibility that a decrease in the number of neurons contributes to the loss of polyneuronal innervation is discussed.

The growth of segmental nerves from the brachial myotomes into the proximal muscles of the chick forelimb during development.

A study has been made of the growth of segmental nerves 13 to 16 (SN13 to SN16) into the chick limb bud, from the time when they have just reached the ends to the brachial myotomes (stage 21: Hamburger and Hamilton, '51), until they enter the newly formed ventral (stage 24) and dorsal (stage 25) pre-muscle cell masses in the limb bud. At stage 22 axon bundles of SN13 to SN16 have grown off the ends of their respective myotomes, and converge towards the most densely packed mesenchyme in the limb bud at segmental level 15. As a consequence, the first axon bundles of SN14 and SN16 have almost joined those of SN15, whereas the further removed SN13 axon bundles have not yet reached the level of SN15. By stage 23 the first axon bundles from SN14 to SN16 have joined at segmental level 15 to form a nerve which grows toward the ventral pre-muscle cell mass. At stage 24 axon bundles from SN13 have joined those from SN14 to SN16 to form the brachialis longus inferior nerve, which enters the densest region of the ventral pre-muscle. Other axons from SN13 to SN15 grow along the pathways provided by the early arriving axon bundles towards the ventral pre-muscle, but diverge from those at segmental level 14 to grow to the dorsal pre-muscle. By stage 25 axon bundles from SN13 to SN15 have joined to form the brachialis longus superior nerve which enters the densest region of the dorsal pre-muscle. At stage 26 a plexus has formed due to this pattern of growth of the segmental nerves between stages 22 and 25. It is suggested that pre-muscle cells synthesize a nerve growth factor which directs the growth of axons into the limb bud.

The growth of nerves in relation to the formation of premuscle cell masses in the developing chick forelimb.

A description is given of the growth of segmental nerves 13 to 16 (SN13 to SN16) from the brachial myotomes into the ventral and dorsal premuscle cell masses of the chick forelimb. At stage 25 (Hamburger and Hamilton, '51), segmental nerves have converged to form two nerve trunks which enter the ventral and dorsal premuscle cell masses. These nerves grow into the limb, parallel to its proximodistal axis. The nerve trunk in the ventral compartment, the brachialis longus inferior (bli n), grows on the brachial artery as far as the metacarpals. The nerve trunk in the dorsal compartment, the brachialis longus superior (bls n), grows on the precartilage adjacent to a dorsal premuscle density as far as the metacarpals. The brachialis longus inferior and superior nerve trunks give rise to a number of nerves during their growth to the metacarpals. Each of these nerves appears at the time of formation of a new premuscle cell density. At late stage 25, a posterior and ventral premuscle density forms in the middle of the stylopodium; posterior fascicles of the bli n diverge at this level and grow toward this new density to form the ulnar nerve. By stage 26 a posterior and ventral premuscle density is prominent over the bli n, at the junction of the stylopodium and the zeugopodium; ventral fascicles of the bli n grow into this density to form the flexor digitorum profundus nerve. At this stage a posterior and dorsal premuscle density forms just beyond the junction of the stylopodium and zeugopodium. Posterior fascicles of the bls n diverge at this level and grow toward this density to form a nerve from which the extensor metacarpi ulnaris, extensor digitorum communis, and radialis laterialis nerves are destined to form. At stage 29 the premuscle cell masses of the autopodium have formed. The remaining nerve fascicles comprising the bls n (the radialis profundus nerve) grow into the autopodium and branch to innervate each of the dorsal premuscles. The remaining nerve fascicles comprising the bli n (the middle nerve) grow into the autopodium and branch to innervate each of the ventral premuscles.

Growth of segmental nerves to the developing rat diaphragm: absence of pioneer axons.

A study has been made of the growth of cervical nerves C3-C6 to the rat diaphragm. At 11 days of embryonic age these cervical nerves first project out of the spinal cord toward the cardinal veins and later form the left and right phrenic nerve trunks. During the next 2 days, the phrenic nerves grow caudally in close association with the cardinal veins toward the diaphragm. At the growing tips of these nerve trunks the growth cones of axons were observed every 1-2 micrometers. The last axon did not project more than 2 micrometers ahead of any neighbouring axons. At 14 days the phrenic nerves reach the level of the developing diaphragm and converge into pools of premuscle cells. Previous studies have suggested that the phrenic nerve enters the premuscle masses of the diaphragm at an early developmental stage when the premuscle masses are at approximately the segmental levels C3-C6. This study shows that the phrenic nerves must grow to more caudal levels in order to reach the premuscle cells of the diaphragm. Furthermore, the leading axons of the phrenic nerve trunk do not project in a pioneering fashion, far in advance of the trailing axons.

Cardiotonic agents. 1. Novel 8-aryl-substituted imidazo[1,2-a]- and -[1,5-a]pyridines and imidazo[1,5-a]pyridinones as potential positive inotropic agents.

Several 8-arylimidazo[1,2-a]pyridines, 8-arylimidazo[1,5-a]pyridines, and 8-arylimidazo[1,5-a]pyridinones were prepared and tested in vitro for potential cardiac inotropic and electrophysiological activity. Selected analogues were further tested in vivo in canine hemodynamic and cardiac electrophysiology models. Compounds having an imidazole substituent consistently showed activity. A pharmacophoric relationship between heterocycle-phenyl-imidazole and positive inotropic activity was noted. The significance of this relationship is discussed.

Novel compounds possessing potent cAMP and cGMP phosphodiesterase inhibitory activity. Synthesis and cardiovascular effects of a series of imidazo[1,2-a]quinoxalinones and imidazo[1,5-a]quinoxalinones and their aza analogues.

A series of novel imidazoquinoxalinones and their aza analogues were prepared by the cyclization of o-amino(1H-imidazol-1-yl)aryls and heteroaryls with carbonyldiimidazole. The compounds were screened for inhibition of Type I and Type IV phosphodiesterases (PDE's) and evaluated for their vasorelaxant and positive inotropic activities in vitro. In general, compounds having potent PDE inhibitory activity also possessed good inotropic and vasodilator activity, although linear correlations between these activities could not be established.

Synthesis of novel (aryloxy)propanolamines and related compounds possessing both class II and class III antiarrhythmic activity.

Several (aryloxy)propanolamines and related compounds (i.e. 5-13, 16-18, 20-24, 27-33, 35, 37-39, 41, and 42) were synthesized and investigated for their class III electrophysiological activity and class II (beta-blocking) effects with use of in vitro and in vivo models. Structure-activity relationships are discussed for a series of 30 compounds. A number of these compounds prolonged the action potential duration at 95% repolarization of isolated canine cardiac Purkinje fibers by 20% (C20APD95) at concentrations of less than 1.0 microM, with no significant effects on cardiac conduction. beta-Adrenergic receptor binding studies showed that some of these compounds were 2-20 times more potent for cardiac beta 1 receptors than for beta 2 receptors. In particular, compounds 32, 41, 1, and especially (S)-1 were found to be orally active class III agents in anesthetized mongrel dogs (1 or 3 mg/kg, id) and efficacious at suppressing programmed electrical stimulation induced arrhythmias in halothane-anesthetized dogs. The profile of these compounds was similar to that found for sotalol. Compound (S)-1, which was more potent than sotalol in the PES study and equieffective in the halothane/epinephrine dog model, is being investigated further as a combined class III/II antiarrhythmic agent.

Synthesis and antiarrhythmic activity of novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega- hydroxyalkyl]-1H-imidazolium salts and related compounds.

Novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega-hydroxyalkyl]-1H -imidazolium salts were synthesized and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structure-activity relationships are discussed for a series of 25 compounds. Compound 3, 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, prolonged the functional refractory period in anesthetized dogs when given intraduodenally and was also effective in preventing reentrant ventricular tachycardia induced by programmed electrical stimulation when administered intravenously in anesthetized dogs 24 h after an acute myocardial infarction. Both enantiomers of 3 were synthesized. No enantioselectivity was found in the electrophysiological effects of 3.

Synthesis and antiarrhythmic activity of novel 3-alkyl-1-[omega-[4-[(alkylsulfonyl)amino]phenyl]-omega- hydroxyalkyl]-1H-imidazolium salts and related compounds. 2.

Novel analogues of the class III antiarrhythmic agent 1-[2-hydroxy-2-[4-[(methylsulfonyl)amino]phenyl]ethyl]-3-methyl-1H- imidazolium chloride, 1 (CK-1649), were prepared and investigated for their class III electrophysiological activity on isolated canine cardiac Purkinje fibers and ventricular muscle tissue. Structure-activity relationships are discussed for a series of 11 compounds. One compound, N-[4-[1-hydroxy-2-(4,5-dihydro-2-methyl-1H-imidazol-1- yl)ethyl]phenyl]methanesulfonamide hydrochloride, 9, was comparable in activity to 1 in vitro and prolonged the functional refractory period in anesthetized dogs when given intraduodenally. Unlike 1, compound 9 was ineffective at preventing ventricular tachycardia induced by programmed electrical stimulation in anesthetized dogs 24 h after an acute myocardial infarction.

Cardiotonic agents. 5. Fragments from the heterocycle-phenyl-imidazole pharmacophore.

To examine the role of each component in the heterocycle-phenyl-imidazole inotropic pharmacophore, several imidazolone derivatives, an arylimidazole, a substituted 3,4-dihydro-4-oxopyrimidine, and a quinolin-2(1H)-one derivative were prepared as structural fragments or representatives from this relationship. Tests for cardiac inotropic activity in ferret papillary muscle strips (FPM) and for inhibition of crude cAMP phosphodiesterase obtained from canine cardiac tissue suggest that, while all three components contribute significantly toward potent activity (active at less than 1 microM concentrations in FPM), any combination of two components, in approximately a preferred geometry, represents the minimal requirements for weak activity (active at less than 25 microM concentrations). No single component appears to be requisite in an absolute sense.

Synthesis and class III antiarrhythmic activity of (phenylbut-2-enyl)ammonium salts. Effect of conformation on activity.

The syntheses of seven 4-(substituted phenyl)but-2-en(or yn)yl quaternary ammonium salts and four related tertiary amines are described. The Meerwein arylation reaction was the preferred synthetic method for the required intermediate 1-aryl-4-halo-2-butenes (15a-c, 18). In the case of 18, the trans stereochemistry of the Meerwein adduct of 2,3-dimethylbutadiene was established unambiguously by 2D NMR and X-ray studies. The title compounds represent conformationally restricted analogues of the class III antiarrhythmic agent clofilium (1) and exhibit comparable potency and efficacy in the in vitro evaluation using isolated canine Purkinje fibers. These results suggest that the alkylene chain in 1 is extended in the active conformation. Computer-aided conformational analysis (MM2) supports this conclusion. Selective catalytic hydrogen conditions were developed for the conversion of the unsaturated analogue 2 to clofilium (1) with minimal hydrogenolysis of the allylic quaternary ammonium moiety, thus completing a novel and efficient synthesis of this substance.

Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.

A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.