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Tuberculosis remains a large global disease burden for which treatment regimens are protracted and monitoring of disease activity difficult. Existing detection methods rely almost exclusively on bacterial culture from sputum which limits sampling to organisms on the pulmonary surface. Advances in monitoring tuberculous lesions have utilized the common glucoside [ 18 F]FDG, yet lack specificity to the causative pathogen Mycobacterium tuberculosis (Mtb) and so do not directly correlate with pathogen viability. Here we show that a close mimic that is also positron-emitting of the non-mammalian Mtb disaccharide trehalose - 2-[ 18 F]fluoro-2-deoxytrehalose ([ 18 F]FDT) - is a mechanism-based reporter of Mycobacteria-selective enzyme activity in vivo. Use of [ 18 F]FDT in the imaging of Mtb in diverse models of disease, including non-human primates, successfully co-opts Mtb-mediated processing of trehalose to allow the specific imaging of TB-associated lesions and to monitor the effects of treatment. A pyrogen-free, direct enzyme-catalyzed process for its radiochemical synthesis allows the ready production of [ 18 F]FDT from the most globally-abundant organic 18 F-containing molecule, [ 18 F]FDG. The full, pre-clinical validation of both production method and [ 18 F]FDT now creates a new, bacterium-selective candidate for clinical evaluation. We anticipate that this distributable technology to generate clinical-grade [ 18 F]FDT directly from the widely-available clinical reagent [ 18 F]FDG, without need for either custom-made radioisotope generation or specialist chemical methods and/or facilities, could now usher in global, democratized access to a TB-specific PET tracer., (© 2024. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and is responsible for the largest human pandemic in 100 years. Thirty-four vaccines are currently approved for use worldwide, and approximately 67% of the world population has received a complete primary series of one, yet countries are dealing with new waves of infections, variant viruses continue to emerge, and breakthrough infections are frequent secondary to waning immunity. Here, we evaluate a measles virus (MV)-vectored vaccine expressing a stabilized prefusion SARS-CoV-2 spike (S) protein (MV-ATU3-S2PΔF2A; V591) with demonstrated immunogenicity in mouse models (see companion article [J. Brunet, Z. Choucha, M. Gransagne, H. Tabbal, M.-W. Ku et al., J Virol 98:e01693-23, 2024, https://doi.org/10.1128/jvi.01693-23]) in an established African green monkey model of disease. Animals were vaccinated with V591 or the control vaccine (an equivalent MV-vectored vaccine with an irrelevant antigen) intramuscularly using a prime/boost schedule, followed by challenge with an early pandemic isolate of SARS-CoV-2 at 56 days post-vaccination. Pre-challenge, only V591-vaccinated animals developed S-specific antibodies that had virus-neutralizing activity as well as S-specific T cells. Following the challenge, V591-vaccinated animals had lower infectious virus and viral (v) RNA loads in mucosal secretions and stopped shedding virus in these secretions earlier. vRNA loads were lower in these animals in respiratory and gastrointestinal tract tissues at necropsy. This correlated with a lower disease burden in the lungs as quantified by PET/CT at early and late time points post-challenge and by pathological analysis at necropsy.IMPORTANCESevere acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the largest human pandemic in 100 years. Even though vaccines are currently available, countries are dealing with new waves of infections, variant viruses continue to emerge, breakthrough infections are frequent, and vaccine hesitancy persists. This study uses a safe and effective measles vaccine as a platform for vaccination against SARS-CoV-2. The candidate vaccine was used to vaccinate African green monkeys (AGMs). All vaccinated AGMs developed robust antigen-specific immune responses. After challenge, these AGMs produced less virus in mucosal secretions, for a shorter period, and had a reduced disease burden in the lungs compared to control animals. At necropsy, lower levels of viral RNA were detected in tissue samples from vaccinated animals, and the lungs of these animals lacked the histologic hallmarks of SARS-CoV-2 disease observed exclusively in the control AGMs., Competing Interests: C.G., A.M., and N.E. are inventors on a patent application describing measles-vectored vaccine candidates against SARS-CoV-2. All other authors declare no financial or non-financial competing interests.

Objectives: This study aimed to assess the feasibility, safety, and acceptability of asynchronous screening for medication abortion eligibility using a programmed questionnaire., Study Design: For this study, we developed an informational website about medication abortion with a linked questionnaire programmed to produce a conclusion regarding eligibility according to standard criteria. We enrolled people in Colorado and Minnesota who submitted questionnaires indicating eligibility. A study physician reviewed each questionnaire and medical records if available and determined whether the responses warranted treatment without a synchronous clinical consultation or ultrasound. If so, the physician prescribed a standard regimen of mifepristone and misoprostol. We collected posttreatment data on abortion outcome, adverse events, and satisfaction., Results: We received questionnaires from 197 individuals, of whom 160 remained in the study until the physician made a final treatment decision. Physicians prescribed medication abortion to 156 (97.5%) individuals based on the questionnaire responses, whereas four needed further assessment to confirm eligibility. Of the 156 individuals, 130 had sufficient follow-up to assess abortion outcome, and 123 (95%) had complete medication abortions without additional treatment. One participant was hospitalized for bleeding, and one expelled a 15-week fetus; however, it is not clear that conventional synchronous history-based screening would have averted these events. Of the 197 questionnaires, 42% were submitted outside business hours. On satisfaction questionnaires, 134 (96%) of 144 participants said they would recommend the study to a friend who needed an abortion., Conclusions: Data from this pilot project suggest that providing medication abortion based only on a self-administered, programmed questionnaire is likely to be effective, safe, efficient, and acceptable., Implications: A programmed self-administered patient questionnaire to assess eligibility for medication abortion could reduce the cost of the service, augment clinic efficiency, improve quality of care, and enhance access to abortion., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Tuberculosis (TB) continues to be one of the deadliest infectious diseases in the world, causing ~1.5 million deaths every year. The World Health Organization initiated an End TB Strategy that aims to reduce TB-related deaths in 2035 by 95%. Recent research goals have focused on discovering more effective and more patient-friendly antibiotic drug regimens to increase patient compliance and decrease emergence of resistant TB. Moxifloxacin is one promising antibiotic that may improve the current standard regimen by shortening treatment time. Clinical trials and in vivo mouse studies suggest that regimens containing moxifloxacin have better bactericidal activity. However, testing every possible combination regimen with moxifloxacin either in vivo or clinically is not feasible due to experimental and clinical limitations. To identify better regimens more systematically, we simulated pharmacokinetics/pharmacodynamics of various regimens (with and without moxifloxacin) to evaluate efficacies, and then compared our predictions to both clinical trials and nonhuman primate studies performed herein. We used GranSim, our well-established hybrid agent-based model that simulates granuloma formation and antibiotic treatment, for this task. In addition, we established a multiple-objective optimization pipeline using GranSim to discover optimized regimens based on treatment objectives of interest, i.e., minimizing total drug dosage and lowering time needed to sterilize granulomas. Our approach can efficiently test many regimens and successfully identify optimal regimens to inform pre-clinical studies or clinical trials and ultimately accelerate the TB regimen discovery process., Competing Interests: None., (Copyright: © 2023 Budak et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Bacille Calmette-Guerin (BCG), the only approved Mycobacterium tuberculosis (Mtb) vaccine, provides limited durable protection when administered intradermally. However, recent work revealed that intravenous (i.v.) BCG administration yielded greater protection in macaques. Here, we perform a dose-ranging study of i.v. BCG vaccination in macaques to generate a range of immune responses and define correlates of protection. Seventeen of 34 macaques had no detectable infection after Mtb challenge. Multivariate analysis incorporating longitudinal cellular and humoral immune parameters uncovered an extensive and highly coordinated immune response from the bronchoalveolar lavage (BAL). A minimal signature predicting protection contained four BAL immune features, of which three remained significant after dose correction: frequency of CD4 T cells producing TNF with interferon γ (IFNγ), frequency of those producing TNF with IL-17, and the number of NK cells. Blood immune features were less predictive of protection. We conclude that CD4 T cell immunity and NK cells in the airway correlate with protection following i.v. BCG., Competing Interests: Declaration of interests The authors declare no competing interests., (Published by Elsevier Inc.)

Objectives: We conducted a pilot study to evaluate a single dose of letrozole 30 mg prior to misoprostol 800 mcg buccally for medication abortion STUDY DESIGN: We enrolled 40 participants seeking medication abortion up to 63 days' gestation at a site in Salt Lake City, UT. Participants received a single dose of letrozole 30 mg in-clinic followed 2 days later by misoprostol 800 mcg buccally at home. They took a second dose of misoprostol if they had no bleeding within 24 hours of the first. Participants returned 7 to 10 days later for assessment of abortion outcome and side effects RESULTS: Thirty-seven participants (93%) returned for follow-up and 2 (5%) went to another facility from which research staff obtained outcome data. Three-fourths (29/39, 74%, 95% CI: 60%-89%) had a complete abortion; 4 (10%, 95% CI: 0.3%-20%) had an incomplete abortion and opted for aspiration, and 6 (15%, 95% CI: 4%-27%) had an ongoing pregnancy. All subjects with follow-up reported taking the first dose of misoprostol. Ten (27%) took the second dose as well; only three did so due to no bleeding. Nineteen participants (51%) reported side effects after letrozole prior to misoprostol and two people (5%) rated these effects as severe. Side effects following misoprostol occurred in 33 participants (89%) and were as expected based on previous literature. No serious adverse events were reported CONCLUSION: A single dose of letrozole 30 mg followed by misoprostol had lower than desirable efficacy and does not warrant further study., Implications: A single dose of letrozole does not appear to be an effective adjunct to misoprostol for medication abortion., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Mycobacterium tuberculosis infection outcomes have been described as active tuberculosis or latent infection but a spectrum of outcomes is now recognized. We used a nonhuman primate model, which recapitulates human infection, to characterize the clinical, microbiologic, and radiographic patterns associated with developing latent M. tuberculosis infection. Four patterns were identified. "Controllers" had normal erythrocyte sedimentation rate (ESR) without M. tuberculosis growth in bronchoalveolar lavage or gastric aspirate (BAL/GA). "Early subclinicals" showed transient ESR elevation and/or M. tuberculosis growth on BAL/GA for 60 days postinfection, "mid subclinicals" were positive for 90 days, and "late subclinicals" were positive intermittently, despite the absence of clinical disease. Variability was noted regarding granuloma formation, lung/lymph node metabolic activity, lung/lymph node bacterial burden, gross pathology, and extrapulmonary disease. Like human M. tuberculosis infection, this highlights the heterogeneity associated with the establishment of latent infection, underscoring the need to understand the clinical spectrum and risk factors associated with severe disease., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

A retrospective study of abortion facilities in and around Texas by White et al. 1 and a spatial analysis by Rader et al. 2 are combined to illustrate the detrimental effects of abortion bans enacted in the United States., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022. Published by Elsevier Inc.)

Introduction: Prior studies indicate that PAPP-A could serve as a marker of gestational age (GA) with the potential to determine eligibility for medication abortion. The authors validated the relationship between PAPP-A and GA in an actual-use population. Materials & methods: The authors collected blood samples, medical histories and ultrasound-determined GA from patients presenting for abortion services. They measured PAPP-A using two immunoassays and assessed diagnostic accuracy for predicting GA ≥71 days. Results: The Ansh Labs and R&D Systems immunoassays produced an area under the ROC curve of 0.982 (95% CI: 0.958-0.994) and 0.986 (95% CI: 0.963-0.996), respectively, for predicting GA ≥71 days. Conclusion: This validation study in an intended-use population confirmed that PAPP-A has a strong ability to distinguish pregnancies above and below 71 days' gestation. Clinical trial registration : NCT04232189 (ClinicalTrials.gov).

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. Here, we identify and compare the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques. Original granulomas differ in transcription-factor expression within adaptive lymphocytes, with those at 12 weeks showing higher frequencies of CD8 + T-bet + T cells, while CD4 + T-bet + T cells increase at 20 weeks post-infection. The appearance of T-bet + adaptive T cells at 12 and 20 weeks is coincident with a reduction in bacterial burden, suggesting their critical role in Mtb control. This study highlights the evolution of T cell responses within lung granulomas, suggesting that vaccines promoting the development and migration of T-bet + T cells would enhance mycobacterial control., Competing Interests: Declaration of interests Authors from the University of Pittsburgh and University of Michigan have no competing interests., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Mycobacterium tuberculosis lung infection results in a complex multicellular structure: the granuloma. In some granulomas, immune activity promotes bacterial clearance, but in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal positron emission tomography and computed tomography imaging, single-cell RNA sequencing, and measures of bacterial clearance. Bacterial persistence occurred in granulomas enriched for mast, endothelial, fibroblast, and plasma cells, signaling amongst themselves via type 2 immunity and wound-healing pathways. Granulomas that drove bacterial control were characterized by cellular ecosystems enriched for type 1-type 17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks involving diverse cell populations. Granulomas that arose later in infection displayed functional characteristics of restrictive granulomas and were more capable of killing Mtb. Our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB., Competing Interests: Declaration of interests A.K.S. reports compensation for consulting and/or SAB membership from Merck, Honeycomb Biotechnologies, Cellarity, Repertoire Immune Medicines, Third Rock Ventures, Hovione, Relation Therapeutics, FL82, Empress Therapeutics, Ochre Bio, and Dahlia Biosciences.C.L. is a shareholder and consultant for Honeycomb Biotechnologies. T.K.H. is a shareholder and consultant for nference, inc., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Pharmacies in low- and middle-income countries play an important role in increasing the availability of medical abortion to individuals for self-use. We aimed to document the costs to users of medical abortion products at outlets across geographies and understand the diversity of available products, primarily in low- and middle-income countries or in places where access to abortion is restricted. A descriptive analysis of price data was completed for identified medical abortion products at retail outlets visited in 44 countries from November 2017 to February 2018. Median prices and ranges are reported in $US for mifepristone 200 mg tablets, misoprostol 200 mcg tablets, and combipacks. Misoprostol, mifepristone, and combipacks were found in 44, 19, and 16 countries, respectively. Nearly two-thirds of products (321/508) required a prescription. The median price of misoprostol was $0.63 per tablet (range $0.09-$27.63) based on 304 price points. Mifepristone and combipacks had fewer price points available ( n  = 59 and n  = 44, respectively). Median prices were $11.78 per mifepristone tablet (range $1.77-$37.83) and $11.18 per combipack (range $3.50-$35.86). Overall, prices were highest in Latin America and lowest in South/Southeast Asia. Only 11.5% (7/61) of the total unique misoprostol brands were quality-assured (i.e. approved by a stringent regulatory authority or pre-qualified by the World Health Organization), compared to 25.0% (4/16) of unique combipack products. There was wide variation in product pricing and availability across settings. The infrequent availability of mifepristone and combipacks, in addition to the limited availability of quality-assured medicines and high cost of abortion medications, are important factors affecting access to high-quality abortion care.

Background: Accurate pregnancy dating is critical for maternal and child health and for counseling on safe and effective abortion methods. While last menstrual period and first trimester ultrasound are often used together to determine gestational age (GA), they have limited accuracy and availability, respectively. Prior studies have shown that pregnancy-associated plasma protein-A (PAPP-A) increases exponentially during pregnancy and has the potential to serve as a biochemical marker of GA. We aimed to analyze the relationship between sonographically determined GA and serum PAPP-A concentration measured by different immunoassays and to derive cutoff levels informative for the 70 days GA commonly recommended limit for medical abortion in outpatient settings., Methods: We compared technical characteristics of 4 commercially available PAPP-A immunoassays and tested 120 maternal serum samples (GA range: 34-231 days) along with contrived pool samples and traceable quality controls. These characteristics included area under the receiver operator characteristic (AUROC) plot, sensitivity and specificity based on cutoffs defined by the Youden Index, and likelihood ratios., Results: All 4 immunoassays had sensitivities and specificities ≥80%, and AUROC values ranging from 0.948 to 0.968. Marked differences among absolute PAPP-A values were noted depending on immunoassay. PAPP-A cutoff values at 70 days GA for each individual immunoassay were established along with procedural recommendations that increase equivalence among immunoassays., Conclusions: Maternal serum PAPP-A levels correlated strongly with GA despite differences in immunoassay formats and absolute data output. Serum PAPP-A has biomarker potential for future development of a point-of-care test aimed at increasing access to medical abortion., (© American Association for Clinical Chemistry 2021. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Neutrophilic inflammation correlates with severe tuberculosis (TB), a disease caused by Mycobacterium tuberculosis ( Mtb ). Granulomas are lesions that form in TB, and a PET probe for following neutrophil recruitment to granulomas could predict disease progression. We tested the formyl peptide receptor 1 (FPR1)-targeting peptide FLFLF in Mtb -infected macaques. Preliminary studies in mice demonstrated specificity for neutrophils. In macaques, 64 Cu-FLFLF was retained in lung granulomas and analysis of lung granulomas identified positive correlations between 64 Cu-FLFLF and neutrophil and macrophage numbers (R 2 = 0.8681 and 0.7643, respectively), and weaker correlations for T cells and B cells (R 2 = 0.5744 and 0.5908, respectively), suggesting that multiple cell types drive 64 Cu-FLFLF avidity. By PET/CT imaging, we found that granulomas retained 64 Cu-FLFLF but with less avidity than the glucose analog 18 F-FDG. These studies suggest that neutrophil-specific probes have potential PET/CT applications in TB, but important issues need to be addressed before they can be used in nonhuman primates and humans.

Objective: We aimed to determine the risk of postpartum infection and increased pain associated with use of condom-catheter uterine balloon tamponade (UBT) among women diagnosed with postpartum hemorrhage (PPH) in three low- and middle-income countries (LMICs). We also sought women's opinions on their overall experience of PPH care., Methods: This prospective cohort study compared women diagnosed with PPH who received and did not receive UBT (UBT group and no-UBT group, respectively) at 18 secondary level hospitals in Uganda, Egypt, and Senegal that participated in a stepped wedge, cluster-randomized trial assessing UBT introduction. Key outcomes were reported pain (on a scale 0-10) in the immediate postpartum period and receipt of antibiotics within four weeks postpartum (a proxy for postpartum infection). Outcomes related to satisfaction with care and aspects women liked most and least about PPH care were also reported., Results: Among women diagnosed with PPH, 58 were in the UBT group and 2188 in the no-UBT group. Self-reported, post-discharge antibiotic use within four weeks postpartum was similar in the UBT (3/58, 5.6%) and no-UBT groups (100/2188, 4.6%, risk ratio = 1.22, 95% confidence interval [CI]: 0.45-3.35). A high postpartum pain score of 8-10 was more common among women in the UBT group (17/46, 37.0%) than in the no-UBT group (360/1805, 19.9%, relative risk ratio = 3.64, 95% CI:1.30-10.16). Most women were satisfied with their care (1935/2325, 83.2%). When asked what they liked least about care, the most common responses were that medications (580/1511, 38.4%) and medical supplies (503/1511, 33.3%) were unavailable., Conclusion: UBT did not increase the risk of postpartum infection among this population. Women who receive UBT may experience higher degrees of pain compared to women who do not receive UBT. Women's satisfaction with their care and stockouts of medications and other supplies deserve greater attention when introducing new technologies like UBT., Competing Interests: The authors have declared that no competing interests exist.

Vaccines are urgently needed to combat the global coronavirus disease 2019 (COVID-19) pandemic, and testing of candidate vaccines in an appropriate non-human primate (NHP) model is a critical step in the process. Infection of African green monkeys (AGM) with a low passage human isolate of SARS-CoV-2 by aerosol or mucosal exposure resulted in mild clinical infection with a transient decrease in lung tidal volume. Imaging with human clinical-grade 18F-fluoro-2-deoxy-D-glucose positron emission tomography (18F-FDG PET) co-registered with computed tomography (CT) revealed pulmonary lesions at 4 days post-infection (dpi) that resolved over time. Infectious virus was shed from both respiratory and gastrointestinal (GI) tracts in all animals in a biphasic manner, first between 2-7 dpi followed by a recrudescence at 14-21 dpi. Viral RNA (vRNA) was found throughout both respiratory and gastrointestinal systems at necropsy with higher levels of vRNA found within the GI tract tissues. All animals seroconverted simultaneously for IgM and IgG, which has also been documented in human COVID-19 cases. Young AGM represent an species to study mild/subclinical COVID-19 disease and with possible insights into live virus shedding. Future vaccine evaluation can be performed in AGM with correlates of efficacy being lung lesions by PET/CT, virus shedding, and tissue viral load., Competing Interests: The authors have declared that no competing interests exist.

Objective: To examine the possibility that serum or urine concentrations of pregnancy-associated plasma protein A (PAPP-A), a disintegrin and metalloproteinase 12 (ADAM-12), placental growth factor (PlGF), human placental lactogen (HPL), glypican-3, pregnancy specific beta-1-glycoprotein 1 (PSG-1) or prolactin could predict gestational age (GA) >70 days, the currently recommended limit for medical abortion in the United States., Study Design: In this exploratory observational study, we collected serum and urine specimens from 245 healthy individuals with singleton intrauterine pregnancies at GA <40 weeks by ultrasound. We assayed the serum specimens for all seven proteins and the urine specimens for PAPP-A and ADAM-12. We used scatterplots and receiver operating characteristic curves to identify a concentration for each protein that would differentiate GAs above and below 70 days., Results: All seven proteins showed significant ability to distinguish GAs >70 days from earlier gestations. A PAPP-A concentration ≥5.591 ng/ml provided 100% sensitivity and 90% specificity for identifying GAs >70 days. An ADAM-12 concentration of ≥3.11 ng/ml provided 98.5% sensitivity and 77% specificity for identifying GAs >70 days. Serum concentrations of the other compounds showed less diagnostic discrimination. PAPP-A was not detected in urine, and urinary ADAM-12 concentrations were not useful in identifying GAs above 70 days., Conclusion: PAPP-A and ADAM-12 showed considerable promise as bases for a sensitive and specific serum test for identifying pregnancies with GA >70 days. If these results are confirmed by future research, such a test could obviate the need for routine ultrasound before medical abortion., Implications: Two placental proteins, PAPP-A and ADAM-12, showed considerable promise as bases for a serum test for identifying pregnancies with gestational age >70 days. Such a test could be highly useful in screening patients for eligibility for medical abortion., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objectives: To evaluate the characteristics, clinical information, and storage instructions contained in package inserts from medical abortion commodities collected in low- and middle-income countries., Study Design: From November 2017 to February 2018 mifepristone, misoprostol, and combined mifepristone-misoprostol (combipack) products were collected to populate the Medical Abortion Commodities Database. We extracted stated indications for use, storage instructions, and date of last revision from each package insert obtained. For those inserts listing medical abortion as an indication, we also extracted eligibility criteria, recommended regimens, side effects, and contraindications., Results: We identified 41 package inserts from 20 countries; 19 (46%) listed medical abortion as an indication including all 7 combipacks, all 7 mifepristone products, and 5/27 (19%) misoprostol products. Date of last insert revision ranged from 1991 to 2016. Gestational age limits for early medical abortion ranged from 49 days to "first trimester." Three (43%) mifepristone products recommended a 600 mg oral dose and two (29%) recommended regimens with gemeprost. Eighteen (67%) misoprostol and one (14%) combipack inserts recommended protection from moisture., Conclusions: The characteristics, clinical information, and storage instructions in medical abortion product package inserts from a variety of field settings in low- and middle-income countries included inadequate storage instructions and outdated gestational age limits and regimens., Implications: There is an urgent need to revisit approved inserts for medical abortion products in low- and middle-income countries to ensure information is accurate and reflects the current evidence base. Simultaneously, providing supplemental instructions targeted at users may fill some gaps. People have a right to accurate information to ensure a safe and effective medical abortion experience., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Objective: To assess the effectiveness of introducing condom-catheter uterine balloon tamponade (UBT) for postpartum haemorrhage (PPH) management in low- and middle-income settings., Design: Stepped wedge, cluster-randomised trial., Setting: Eighteen secondary-level hospitals in Uganda, Egypt and Senegal., Population: Women with vaginal delivery from October 2016 to March 2018., Methods: Use of condom-catheter UBT for PPH management was introduced using a half-day training and provision of pre-packaged UBT kits. Hospitals were randomised to when UBT was introduced. The incident rate (IR) of study outcomes was compared in the control (i.e. before UBT) and intervention (i.e. after UBT) periods. Mixed effects regression models accounted for clustering (random effect) and time period (fixed effect)., Main Outcome Measures: Combined IR of PPH-related invasive surgery and/or maternal death., Results: There were 28 183 and 31 928 deliveries in the control and intervention periods, respectively. UBT was used for 9/1357 and 55/1037 women diagnosed with PPH in control and intervention periods, respectively. PPH-related surgery or maternal death occurred in 19 women in the control period (IR = 6.7/10 000 deliveries) and 37 in the intervention period (IR = 11.6/10 000 deliveries). The adjusted IR ratio was 4.08 (95% confidence interval 1.07-15.58). Secondary outcomes, including rates of transfer and blood transfusion, were similar in the trial periods., Conclusions: Introduction of condom-catheter UBT in these settings did not improve maternal outcomes and was associated with an increase in the combined incidence of PPH-related surgery and maternal death. The lack of demonstrated benefit of UBT introduction with respect to severe outcomes warrants reflection on its role., Tweetable Abstract: Stepped wedge trial shows UBT introduction does not reduce the combined incidence of PPH-related surgery or death., (© 2019 Gynuity Health Projects. BJOG: An International Journal of Obstetrics and Gynaecology published by John Wiley & Sons Ltd on behalf of Royal College of Obstetricians and Gynaecologists.)

Background: Advance provision of misoprostol to women during antenatal care aims to achieve broader access to uterotonics for the prevention of postpartum hemorrhage. Studies of this community-based approach usually involve antenatal education as well as timely postpartum follow-up visits to confirm maternal and neonatal outcomes. The MamaMiso study in Mbale, Uganda sought to assess the feasibility of conducting follow-up visits in the postpartum period following advance provision of misoprostol for postpartum hemorrhage prevention. MamaMiso recruited women during antenatal care visits. Participants were asked to contact the research team within 48 h of giving birth so that postpartum follow-up visits could be carried out at their homes. Women's baseline and delivery characteristics were collected and analyzed with respect to follow-up time ('on time' ≤ 7 days, 'late' > 7 days, and 'lost to follow up'). Every woman who was followed up late due to a failure to report the delivery was asked for the underlying reasons for the delay. When attempts at following up participants were unsuccessful, a file note was generated explaining the details of the failure. We abstracted data and identified themes from these notes., Results: Of 748 recruited women, 700 (94%) were successfully followed up during the study period, 465 (62%) within the first week postpartum. The median time to follow up was 4 days and was similar for women who delivered at home or in facilities and for women who had attended or unattended births. Women recruited at the urban hospital site (as opposed to rural health clinics) were more likely to be lost to follow up or followed up late. Of the women followed up late, 202 provided a reason. File notes explaining failed attempts at follow up were generated for 164 participants. Several themes emerged from qualitative analysis of these notes including phone difficulties, inaccurate baseline information, misperceptions, postpartum travel, and the condition of the mother and neonate., Conclusions: Keeping women connected to the health system in the postpartum period is feasible, though reaching them within the first week of their delivery is challenging. Understanding characteristics of women who are harder to reach can help tailor follow-up efforts and elucidate possible biases in postpartum study data. Trial Registration Number ISRCTN70408620 December 28, 2011.

Mycobacterium tuberculosis remains the number one infectious agent in the world today. With the emergence of antibiotic resistant strains, new clinically relevant methods are needed that evaluate the disease process and screen for potential antibiotic and vaccine treatments. Positron Emission Tomography/Computed Tomography (PET/CT) has been established as a valuable tool for studying a number of afflictions such as cancer, Alzheimer's disease, and inflammation/infection. Outlined here are a number of strategies that have been employed to evaluate PET/CT images in cynomolgus macaques that are infected intrabronchially with low doses of M. tuberculosis. Through evaluation of lesion size on CT and uptake of 18 F-fluorodeoxyglucose (FDG) in lesions and lymph nodes in PET images, these described methods show that PET/CT imaging can predict future development of active versus latent disease and the propensity for reactivation from a latent state of infection. Additionally, by analyzing the overall level of lung inflammation, these methods determine antibiotic efficacy of drugs against M. tuberculosis in the most clinically relevant existing animal model. These image analysis methods are some of the most powerful tools in the arsenal against this disease as not only can they evaluate a number of characteristics of infection and drug treatment, but they are also directly translatable to a clinical setting for use in human studies.

Human infections with highly pathogenic avian influenza A (H5N1) virus are frequently fatal but the mechanisms of disease remain ill-defined. H5N1 infection is associated with intense production of proinflammatory cytokines, but whether this cytokine storm is the main cause of fatality or is a consequence of extensive virus replication that itself drives disease remains controversial. Conventional intratracheal inoculation of a liquid suspension of H5N1 influenza virus in nonhuman primates likely results in efficient clearance of virus within the upper respiratory tract and rarely produces severe disease. We reasoned that small particle aerosols of virus would penetrate the lower respiratory tract and blanket alveoli where target cells reside. We show that inhalation of aerosolized H5N1 influenza virus in cynomolgus macaques results in fulminant pneumonia that rapidly progresses to acute respiratory distress syndrome with a fatal outcome reminiscent of human disease. Molecular imaging revealed intense lung inflammation coincident with massive increases in proinflammatory proteins and IFN-α in distal airways. Aerosolized H5N1 exposure decimated alveolar macrophages, which were widely infected and caused marked influx of interstitial macrophages and neutrophils. Extensive infection of alveolar epithelial cells caused apoptosis and leakage of albumin into airways, reflecting loss of epithelial barrier function. These data establish inhalation of aerosolized virus as a critical source of exposure for fatal human infection and reveal that direct viral effects in alveoli mediate H5N1 disease. This new nonhuman primate model will advance vaccine and therapeutic approaches to prevent and treat human disease caused by highly pathogenic avian influenza viruses., (Copyright © 2017 by The American Association of Immunologists, Inc.)

Objectives: The aim of the study was to compare the pharmacokinetic parameters of 800 μg oral, sublingual and buccal misoprostol in healthy non-pregnant women., Methods: This was an open-label, randomised study with a three-way crossover design. Eighteen participants were randomly assigned to treatment sequences of 800 μg oral, sublingual and buccal misoprostol administered under fasting conditions, with a 7-day washout period. Ten participants completed all routes. The primary pharmacokinetic parameters measured were the area under the plasma misoprostol acid concentration-time curve (AUC) from dosing to last quantifiable concentration (AUC0-t), the AUC from 0 to infinity (AUC0-∞) and the maximum plasma concentration (Cmax). Secondary parameters included the plasma elimination rate constant (ke), the half-life and the mean residence time (MRT)., Results: There were statistically significant differences in AUC0-∞, AUC0-t and Cmax at the p < 0.05 level for the three routes of administration. The sublingual route achieved the highest bioavailability, and the buccal route achieved the lowest peak concentration. The oral and buccal routes had a similar AUC0-∞ and the buccal route had the highest MRT and ke. There were no differences in half-lives, and no serious adverse events were reported., Conclusions: This study shows variability in Cmax and AUC by three by-mouth routes of misoprostol administration. The dose in this study was 800 μg, which is among the highest doses seen in current guidelines. These data contribute to the understanding of efficacy and safety of different routes and could provide a basis for deciding whether certain routes are preferable for particular indications.

Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection.

Background: 600 mcg of oral misoprostol reduces the incidence of postpartum haemorrhage (PPH), but in previous research this medication has been administered by health workers. It is unclear whether it is also safe and effective when self-administered by women., Methods: This placebo-controlled, double-blind randomised trial enrolled consenting women of at least 34 weeks gestation, recruited over a 2-month period in Mbale District, Eastern Uganda. Participants had their haemoglobin measured antenatally and were given either 600 mcg misoprostol or placebo to take home and use immediately after birth in the event of delivery at home. The primary clinical outcome was the incidence of fall in haemoglobin of over 20% in home births followed-up within 5 days., Results: 748 women were randomised to either misoprostol (374) or placebo (374). Of those enrolled, 57% delivered at a health facility and 43% delivered at home. 82% of all medicine packs were retrieved at postnatal follow-up and 97% of women delivering at home reported self-administration of the medicine. Two women in the misoprostol group took the study medication antenatally without adverse effects. There was no significant difference between the study groups in the drop of maternal haemoglobin by >20% (misoprostol 9.4% vs placebo 7.5%, risk ratio 1.11, 95% confidence interval 0.717 to 1.719). There was significantly more fever and shivering in the misoprostol group, but women found the medication highly acceptable., Conclusions: This study has shown that antenatally distributed, self-administered misoprostol can be appropriately taken by study participants. The rarity of the primary outcome means that a very large sample size would be required to demonstrate clinical effectiveness., Trial Registration: This study was registered with the ISRCTN Register (ISRCTN70408620).

Objective: To determine the acceptability of taking mifepristone at home for early medical abortion in the United States., Study Design: This prospective, non-randomized, open-label study at six Planned Parenthood centers gave women with pregnancies up to 63 days' gestation seeking medical abortion the choice of taking mifepristone in the center or at home. Participants were interviewed at a follow-up visit 1-2 weeks after mifepristone administration to assess their experience with the option they selected., Results: Four-hundred women were enrolled between April 2013 and June 2014 of which 32% (n=128) chose to take mifepristone at home. Abortion success rates did not differ between home and center users (96% and 97%). Among home users, 82% reported taking the mifepristone at the time they planned with their provider and no participant took it after 63 days' gestation. The most common reason cited for selecting home use was scheduling flexibility and significantly more home users took misoprostol on the weekend (50% vs. 36%, p=.02). Home users were more likely than center users to report missing no days of work due to the abortion (47% vs. 28%, p=.08). Ninety-nine percent of home users reported that they would take mifepristone at home again and 96% would recommend home use to a friend. Offering this option did not increase the service delivery burden on study providers, who would recommend home use in the future for most participants., Conclusions: Home use of mifepristone is a highly acceptable practice for which there is current demand, and it should be offered as part of routine medical abortion services., Implications: Offering the option of home use of mifepristone to medical abortion patients can provide women and clinics with more flexibility while maintaining a safe, effective and acceptable service. These results provide support for telemedicine or pharmacy distribution., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objectives: Routine provision of antibiotics following medical abortion is common yet practitioners and professional societies differ on its utility. Our study compares the side effects experienced by women who were prescribed doxycycline following medical abortion to those who were not and assesses the adherence to one prescribed regimen., Study Design: This was a prospective, observational, open-label study from a convenience sample. Women seeking medical abortion were enrolled in nine study sites, including four clinics that routinely prescribe a seven-day course of doxycycline (Doxycycline arm) and five clinics that do not routinely prescribe any antibiotics (No Doxycycline arm). Seven to fourteen days following the administration of mifepristone, women were asked to self-administer a computer-based survey. The survey asked about side effects experienced (both arms) and adherence to the regimen (Doxycycline arm only)., Results: Five hundred eighty-one women were enrolled (278 in the Doxycycline arm and 303 in the No Doxycycline arm). There was a trend toward increased nausea in the Doxycycline arm (47.8% vs. 40.9%; p=.056) and a statistically significant difference in vomiting (25.2% vs. 18.5%; p=.032). Almost all women in the Doxycycline arm reported taking at least one pill, however only 28.3% reported "perfect adherence." The most common reasons reported for taking fewer pills than instructed were that participants were still taking them (beyond 7 days) or that they forgot to take them., Conclusion: Women who were prescribed doxycycline following medical abortion reported moderate adherence and experienced significantly more vomiting than their counterparts., Implications: In the absence of robust evidence that prescribing 7 days of doxycycline following medical abortion is effective at reducing serious infections, these data can assist the public health community with deciding whether routine provision is the most appropriate strategy., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Efforts to prosecute women for induced abortion have included allegations that misoprostol was found in body fluids. These claims, however, are questionable owing to the timing of specimen collection for accurate results, the scarcity and expense of validated assays, and the onerous lab procedures required to determine the presence of the substance. Adequate scrutiny should be applied each time such a claim is made., (Copyright © 2014. Published by Elsevier Ireland Ltd.)

The Regional Biocontainment Laboratory (RBL) at the University of Pittsburgh is a state-of-the-art ABSL-3 facility that supports research on highly pathogenic viruses and bacteria. Recent advances in radiologic imaging provide several noninvasive, in vivo imaging modalities that can be used to longitudinally monitor animals following experimental infection or vaccination. The University of Pittsburgh RBL provides digital radiography, bioluminescence imaging, and PET/CT. Operating these platforms in an ABSL-3 poses unique challenges. This review will discuss the development and refinement of these imaging platforms in high containment, emphasizing specific challenges and how they were overcome., (© 2014 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved.)

Cynomolgus macaques infected with low-dose Mycobacterium tuberculosis develop both active tuberculosis and latent infection similar to those of humans, providing an opportunity to study the clinically silent early events in infection. (18)Fluorodeoxyglucose radiotracer with positron emission tomography coregistered with computed tomography (FDG PET/CT) provides a noninvasive method to measure disease progression. We sought to determine temporal patterns of granuloma evolution that distinguished active-disease and latent outcomes. Macaques (n = 10) were infected with low-dose M. tuberculosis with FDG PET/CT performed during infection. At 24 weeks postinfection, animals were classified as having active disease (n = 3) or latent infection (n = 6), with one "percolator" monkey. Imaging characteristics (e.g., lesion number, metabolic activity, size, mineralization, and distribution of lesions) were compared among active and latent groups. As early as 3 weeks postinfection, more pulmonary granulomas were observed in animals that would later develop active disease than in those that would develop latent infection. Over time, new lesions developed in active-disease animals but not in latent animals. Granulomas and mediastinal lymph nodes from active-disease but not latent animals consistently increased in metabolic activity at early time points. The presence of fewer lesions at 3 weeks and the lack of new lesion development in animals with latent infection suggest that innate and rapid adaptive responses are critical to preventing active tuberculosis. A greater emphasis on innate responses and/or rapid recruitment of adaptive responses, especially in the airway, should be emphasized in newer vaccine strategies.

Trials to test new drugs currently in development against tuberculosis in humans are impractical. All animal models to prioritize new regimens are imperfect, but nonhuman primates (NHPs) infected with Mycobacterium tuberculosis develop active tuberculosis (TB) disease with a full spectrum of lesion types seen in humans. Serial 2-deoxy-2-[ 18 F]-fluoro-d-glucose (FDG) positron emission tomography (PET) with computed tomography (CT) imaging was performed on cynomolgus macaques during infection and chemotherapy with individual agents or the four-drug combination therapy most widely used globally. The size and metabolic activity of lung granulomas varied among animals and even within a single animal during development of disease. Individual granulomas within untreated animals had highly local and independent outcomes, some progressing in size and FDG uptake, while others waned, illustrating the highly dynamic nature of active TB. At necropsy, even untreated animals were found to have a proportion of sterile lesions consistent with the dynamics of this infection. A more marked reduction in overall metabolic activity in the lungs (decreased FDG uptake) was associated with effective treatment. A reduction in the size of individual lesions correlated with a lower bacterial burden at necropsy. Isoniazid treatment was associated with a transient increase in metabolic activity in individual lesions, whereas a net reduction occurred in most lesions from rifampin-treated animals. Quadruple-drug therapy resulted in the highest decrease in FDG uptake. The findings of PET-CT imaging may provide an important early correlate of the efficacy of novel combinations of new drugs that can be directly translated to human clinical trials., (Copyright © 2013, American Society for Microbiology. All Rights Reserved.)

Private-sector initiatives, like the one launched in Cincinnati, have significantly improved the management of health care programs. The initiatives were made through voluntary hospital and physician practice changes without new contract restrictions, price controls, legislative mandates, and utilization management.