A cluster-randomized, non-inferiority trial comparing use of misoprostol for universal prophylaxis vs. secondary prevention of postpartum hemorrhage among community level births in Egypt.

BACKGROUND: Previous community-based research shows that secondary prevention of postpartum hemorrhage (PPH) with misoprostol only given to women with above-average measured blood loss produces similar clinical outcomes compared to routine administration of misoprostol for prevention of PPH. Given the difficulty of routinely measuring blood loss for all deliveries, more operational models of secondary prevention are needed. METHODS: This cluster-randomized, non-inferiority trial included women giving birth with nurse-midwives at home or in Primary Health Units (PHUs) in rural Egypt. Two PPH management approaches were compared: 1) 600mcg oral misoprostol given to all women after delivery (i.e. primary prevention, current standard of care); 2) 800mcg sublingual misoprostol given only to women with 350-500 ml postpartum blood loss estimated using an underpad (i.e. secondary prevention). The primary outcome was mean change in pre- and post-delivery hemoglobin. Secondary outcomes included hemoglobin ≥2 g/dL and other PPH interventions. RESULTS: Misoprostol was administered after delivery to 100% (1555/1555) and 10.7% (117/1099) of women in primary and secondary prevention clusters, respectively. The mean drop in pre- to post-delivery hemoglobin was 0.37 (SD: 0.91) and 0.45 (SD: 0.76) among women in primary and secondary prevention clusters, respectively (difference adjusted for clustering = 0.01, one-sided 95% CI: < 0.27, p = 0.535). There were no statistically significant differences in secondary outcomes, including hemoglobin drop ≥2 g/dL, PPH diagnosis, transfer to higher level, or other interventions. CONCLUSIONS: Misoprostol for secondary prevention of PPH is comparable to universal prophylaxis and can be implemented using local materials, such as underpads. TRIAL REGISTRATION: Clinicaltrials.gov NCT02226588, date of registration 27 August 2014.

Clinical and service delivery outcomes following medication abortion provided with or without pre-treatment ultrasound or pelvic examination: an updated comparative analysis.

OBJECTIVE: To compare medication abortion outcomes among people screened without or with ultrasound or pelvic examination. STUDY DESIGN: We used data collected from March 24, 2020 to September 27, 2021 at five TelAbortion Project sites that provided medication abortion with mifepristone and misoprostol by mail. Using logistic regression weighted on propensity scores, we compared outcomes in participants who had neither ultrasound nor exam before treatment (No-Test group) or had such tests (Test group). We analyzed outcomes separately for participants screened early in the analysis period (before September 15, 2020) or later. Outcomes included: procedural abortion completion or ongoing pregnancy, serious adverse events, and unplanned post-treatment abortion-related clinical visits. RESULTS: Among 416 participants in the early period, the No-Test group had a significantly higher risk than the Test group of procedural abortion completion or ongoing pregnancy (5.6% vs. 0.9%, risk difference 4.6%, 95% CI 1.5%, 7.7%) and abortion-related clinical visits (13.3% vs. 6.3%; risk difference 7.0%; 95% CI 1.1%, 12.8%). Among 364 participants screened later, the risk of procedural abortion completion or ongoing pregnancy did not differ by group, while unplanned abortion-related clinical visits were less common in the No-Test group (9.9% vs. 20.5%; risk difference -10.6%; 95% CI -20.1%, -1.1%). Risk of serious adverse events did not differ by group in either period. CONCLUSIONS: When providers first began omitting ultrasound or pelvic exam before medication abortion, the practice was associated with increased risks of failure of complete abortion and post-treatment clinical visits; however, these increased risks resolved over time. IMPLICATIONS: Medication abortion without pretreatment ultrasound or examination is effective and safe. This model should be routinely offered to eligible patients.

Implications of using home urine pregnancy tests versus facility-based tests for assessment of outcome following medication abortion provided via telemedicine.

OBJECTIVES: To assess whether planning high-sensitivity urine pregnancy tests (HSPT) rather than facility-based tests for medication abortion follow-up may increase risk of unplanned clinical visits or procedural completion of the abortion. STUDY DESIGN: We used data from the TelAbortion Project, a 5-year study assessing the safety and feasibility of providing mifepristone and misoprostol by telemedicine and mail in the United States. We categorized participants by whether the pretreatment follow-up plan included HSPT at home 3-5 weeks after treatment or facility-based tests (ultrasound or serum human chorionic gonadotropin) within 2 weeks after treatment. We used multivariable logistic regression to compare likelihood of post-treatment unplanned, abortion-related clinical visits and procedural intervention in these groups. RESULTS: Of 1324 patients who planned HSPT follow-up and 576 who planned facility-based tests, 85% and 83%, respectively, provided outcome information. Post-treatment clinical visits were less frequent in the HSPT group (19%) than in the facility-based test group (79%); most of the latter were to obtain the planned test. However, unplanned, abortion-related visits were significantly more common in the HSPT group (adjusted risk difference: 6.5%; p < 0.01). The likelihood of procedural completion did not differ by group. Planned follow-up test was not associated with delay in procedural completion or detection of ongoing pregnancy. CONCLUSIONS: Follow-up of medication abortion with home HSPT was associated with fewer post-treatment clinical visits, modestly more unplanned, abortion-related clinical visits, and no increase in the risk of procedural interventions or delayed identification or management of treatment failures. This option is an appropriate follow-up approach after medication abortion. IMPLICATIONS: Use of home high-sensitivity pregnancy tests rather than facility-based tests for outcome assessment after medication abortion is associated with a modest increase in unplanned clinical visits but does not lead to an increase in procedural interventions or delays identification and management of treatment failure.

Active case finding and prevention of tuberculosis among a cohort of contacts exposed to infectious tuberculosis cases in New York City.

BACKGROUND: Tuberculosis contact investigation identifies individuals who may be recently infected with tuberculosis and are thus at increased risk for disease. Contacts with latent tuberculosis infection (LTBI) are offered chemoprophylaxis to prevent active disease; however, the effectiveness of this intervention is unclear as treatment completion is generally low. METHODS: A retrospective cohort study of 30 561 contacts identified during investigation of 5182 cases of tuberculosis diagnosed in New York City, 1997-2003, was performed. We searched the NYC tuberculosis registry to identify contacts developing active tuberculosis within 4 years of follow-up. We estimated the following: number of contacts undergoing evaluation (ie, tuberculin skin test and/or chest radiograph) per prevalent case diagnosed; number of contacts with LTBI that need to be treated with standard chemoprophylaxis to prevent 1 active case. RESULTS: Of 30 561 contacts, 27 293 (89%) were evaluated and 268 prevalent cases were diagnosed (102 contacts evaluated per prevalent case diagnosed, 95% confidence interval [CI], 90-115). LTBI was diagnosed in 7597 contacts, including 6001 (79%) who initiated chemoprophylaxis, 3642 (61%) who later completed treatment, and 2359 (39%) who did not complete treatment. During 4 years of follow-up, active tuberculosis was diagnosed in 46 contacts with LTBI, including 22 of 6001 (0.4%) who initiated chemoprophylaxis and 24 of 1596 (1.5%) who did not initiate treatment. The absolute risk reduction afforded by chemoprophylaxis initiation was 1.1% (95% CI, .6%-1.9%), leading to an estimated 88 contacts treated to prevent 1 tuberculosis case (95% CI, 53-164). CONCLUSIONS: Contact investigation facilitates active case finding and tuberculosis prevention, even when completion rates of chemoprophylaxis are suboptimal.

Efficacy, safety and tolerability of linezolid containing regimens in treating MDR-TB and XDR-TB: systematic review and meta-analysis.

Linezolid is used off-label to treat multidrug-resistant tuberculosis (MDR-TB) in absence of systematic evidence. We performed a systematic review and meta-analysis on efficacy, safety and tolerability of linezolid-containing regimes based on individual data analysis. 12 studies (11 countries from three continents) reporting complete information on safety, tolerability, efficacy of linezolid-containing regimes in treating MDR-TB cases were identified based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analysis was performed using the individual data of 121 patients with a definite treatment outcome (cure, completion, death or failure). Most MDR-TB cases achieved sputum smear (86 (92.5%) out of 93) and culture (100 (93.5%) out of 107) conversion after treatment with individualised regimens containing linezolid (median (inter-quartile range) times for smear and culture conversions were 43.5 (21-90) and 61 (29-119) days, respectively) and 99 (81.8%) out of 121 patients were successfully treated. No significant differences were detected in the subgroup efficacy analysis (daily linezolid dosage ≤ 600 mg versus >600 mg). Adverse events were observed in 63 (58.9%) out of 107 patients, of which 54 (68.4%) out of 79 were major adverse events that included anaemia (38.1%), peripheral neuropathy (47.1%), gastro-intestinal disorders (16.7%), optic neuritis (13.2%) and thrombocytopenia (11.8%). The proportion of adverse events was significantly higher when the linezolid daily dosage exceeded 600 mg. The study results suggest an excellent efficacy but also the necessity of caution in the prescription of linezolid.

Clinical and service delivery implications of omitting ultrasound before medication abortion provided via direct-to-patient telemedicine and mail in the U.S.

OBJECTIVES: To compare outcomes among patients who did or did not have pre-abortion ultrasound or pelvic exam before obtaining medication abortion (MA) via direct-to-patient telemedicine and mail. STUDY DESIGN: We analyzed data from participants screened for enrollment into the TelAbortion study at five sites from March 25 to September 15, 2020. We compared participants who had preabortion ultrasound or pelvic exam ("test-MA") to those who did not ("no-test MA"). Outcomes were: abortion not complete with pills alone (i.e., had procedure intervention or ongoing pregnancy), ongoing pregnancy separately, ectopic pregnancy, hospitalization and/or blood transfusion, and unplanned clinical encounters. We used propensity score weighting and multivariable logistic regression to adjust for baseline characteristics. RESULTS: Our analysis included 287 participants who had no-test MA and 125 who had test-MA. Abortion was not complete with pills alone in 16of 287 (5.6%) no-test MA patients compared to 2of 123 (1.9%) test-MA patients (adjusted risk difference [aRD] = 4.3%, 95% confidence interval [CI]: 1.4%-7.1%). No ectopic pregnancies were detected. Groups did not differ regarding hospitalization and/or blood transfusion (p = 0.76) or ongoing pregnancy diagnosis (p = 0.59). Unplanned clinical encounters were more common in no-test MA patients (35of 287, 12.5%) than test-MA patients (10of 125, 8.0%, aRD = 6.7%, 95% CI: 0.5%-13.1%). CONCLUSIONS: Compared to patients who had pre-abortion ultrasound, patients who had no-test MA via telemedicine were more likely to have abortions that were not complete with pills alone and/or unplanned clinical encounters. However, both no-test and test-MA patients had similar and very low rates of ongoing pregnancy and hospitalization or blood transfusion. IMPLICATIONS: Omitting pre-abortion ultrasound before provision of medication abortion via telemedicine does not appear to compromise safety or result in more ongoing pregnancies. However, compared to patients who have preabortion ultrasound, patients who do not have pre-abortion tests may be more likely to seek post-treatment care and have procedural interventions.

"False positive" urine pregnancy test results after successful medication abortion.

OBJECTIVE: To examine the proportion of high-sensitivity urine pregnancy test (HSPT) results that were positive by time after successful medication abortion. STUDY DESIGN: We used data from an ongoing study that provides mifepristone and misoprostol for medication abortion by direct-to-patient telemedicine and mail. Providers evaluated abortion outcomes by patient interview and clinical tests per clinical judgment and participant preference. We identified all participants enrolled July 2016 to September, 2020 who had an HSPT result and no indication of viable pregnancy after treatment. We used logistic regression to examine the association between the timing of the initial post-treatment HSPT, gestational age, and the proportion of HSPTs that gave a positive result. RESULTS: Of the 472 participants in our analysis, 88 (19%) had positive initial HSPTs. The proportions that were positive at ≤20 days, 21 to 27 days, 28 to 34 days, and ≥35 days after mifepristone ingestion was 14 of 29 (48%), 15 of 58 (26%), 49 of 258 (19%), and 10 of 127 (8%), respectively (p < 0.001). Gestational age at mifepristone ingestion was not significantly related to positive HSPT results (p = 0.28). Multivariable logistic regression confirmed both findings and did not identify a statistically significant interaction between these variables. In the 67 participants who relied solely on further HSPTs to confirm abortion outcome, the median interval between the initial positive test and first negative test was 14 days. CONCLUSIONS: The proportion of participants with positive HSPTs declined with time after successful medication abortion. However, nearly one-fifth of participants with complete abortion had positive tests 4 weeks after treatment. IMPLICATIONS: HSPTs provide an inexpensive, convenient option for confirming success of medication abortion at home. However, a substantial minority of patients without ongoing pregnancy have positive HSPT results. Development of a symptom-based strategy for medication abortion outcome assessment without any confirmatory tests should be a priority.

Postpartum infection, pain and experiences with care among women treated for postpartum hemorrhage in three African countries: A cohort study of women managed with and without condom-catheter uterine balloon tamponade.

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.

Expansion of a direct-to-patient telemedicine abortion service in the United States and experience during the COVID-19 pandemic.

OBJECTIVE: To present updated evidence on the safety, efficacy and acceptability of a direct-to-patient telemedicine abortion service and describe how the service functioned during the COVID-19 pandemic. STUDY DESIGN: We offered the study at 10 sites that provided the service in 13 states and Washington DC. Interested individuals obtained any needed preabortion tests locally and had a videoconference with a study clinician. Sites sent study packages containing mifepristone and misoprostol by mail and had remote follow-up consultations within one month by telephone (or by online survey, if the participant could not be reached) to evaluate abortion completeness. The analysis was descriptive. RESULTS: We mailed 1390 packages between May 2016 and September 2020. Of the 83% (1157/1390) of abortions for which we obtained outcome information, 95% (1103/1157) were completed without a procedure. Participants made 70 unplanned visits to emergency rooms or urgent care centers for reasons related to the abortion (6%), and 10 serious adverse events occurred, including 5 transfusions (0.4%). Enrollment increased substantially with the onset of COVID-19. Although a screening ultrasound was required, sites determined in 52% (346/669) of abortions that occurred during COVID that those participants should not get the test to protect their health. Use of urine pregnancy test to confirm abortion completion increased from 67% (144/214) in the 6 months prior to COVID to 90% (602/669) in the 6 months during COVID. Nearly all satisfaction questionnaires (99%, 1013/1022) recorded that participants were satisfied with the service. CONCLUSIONS: This direct-to-patient telemedicine service was safe, effective, and acceptable, and supports the claim that there is no medical reason for mifepristone to be dispensed in clinics as required by the Food and Drug Administration. In some cases, participants did not need to visit any facilities to obtain the service, which was critical to protecting patient safety during the COVID-19 pandemic. IMPLICATIONS: Medical abortion using telemedicine and mail is effective and can be safely provided without a pretreatment ultrasound. This method of service delivery has the potential to greatly improve access to abortion care in the United States.

Linezolid use for treatment of multidrug-resistant and extensively drug-resistant tuberculosis, New York City, 2000-06.

UNLABELLED: Rationale Linezolid may be effective for the treatment of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB); however, serious adverse events are common and there is little information on the management of these toxicities. METHODS: We retrospectively reviewed public health and medical records of 16 MDR TB patients, including 10 patients with XDR TB, who were treated with linezolid in New York City between January 2000 and December 2006, to determine treatment outcomes and describe the incidence, management and predictors of adverse events. RESULTS: Linezolid was added to MDR TB regimens for a median duration of 16 months (range: 1-29). Eleven patients (69%) completed treatment, four (25%) died and one (6%) discontinued treatment without relapse. Myelosuppression occurred in 13 (81%) patients a median of 5 weeks (range: 1-11) after starting linezolid, gastrointestinal adverse events occurred in 13 (81%) patients after a median of 8 weeks (range: 1-57) and neurotoxicity occurred in seven (44%) patients after a median of 16 weeks (range: 10-111). Adverse events were managed by combinations of temporary suspension of linezolid, linezolid dose reduction and symptom management. Five (31%) patients required eventual discontinuation of linezolid. Myelosuppression was more responsive to clinical management strategies than was neurotoxicity. Leucopenia and neuropathy occurred more often in males and older age was associated with thrombocytopenia (P < 0.05). CONCLUSIONS: The majority of MDR TB patients on linezolid had favourable treatment outcomes, although treatment was complicated by adverse events that required extensive clinical management.

Viral delivery of an epitope from Haemophilus influenzae induces central nervous system autoimmune disease by molecular mimicry.

Multiple sclerosis (MS) is an autoimmune CNS demyelinating disease in which infection may be an important initiating factor. Pathogen-induced cross-activation of autoimmune T cells may occur by molecular mimicry. Infection with wild-type Theiler's murine encephalomyelitis virus induces a late-onset, progressive T cell-mediated demyelinating disease, similar to MS. To determine the potential of virus-induced autoimmunity by molecular mimicry, a nonpathogenic neurotropic Theiler's murine encephalomyelitis virus variant was engineered to encode a mimic peptide from protease IV of Haemophilus influenzae (HI), sharing 6 of 13 aa with the dominant encephalitogenic proteolipid protein (PLP) epitope PLP(139-151). Infection of SJL mice with the HI mimic-expressing virus induced a rapid-onset, nonprogressive paralytic disease characterized by potent activation of self-reactive PLP(139-151)-specific CD4(+) Th1 responses. In contrast, mice immunized with the HI mimic-peptide in CFA did not develop disease, associated with the failure to induce activation of PLP(139-151)-specific CD4(+) Th1 cells. However, preinfection with the mimic-expressing virus before mimic-peptide immunization led to severe disease. Therefore, infection with a mimic-expressing virus directly initiates organ-specific T cell-mediated autoimmunity, suggesting that pathogen-delivered innate immune signals may play a crucial role in triggering differentiation of pathogenic self-reactive responses. These results have important implications for explaining the pathogenesis of MS and other autoimmune diseases.

Initiation and exacerbation of autoimmune demyelination of the central nervous system via virus-induced molecular mimicry: implications for the pathogenesis of multiple sclerosis.

Epidemiological studies indicate that infectious agents are important in the pathogenesis of multiple sclerosis (MS). Our previous reports showed that the infection of SJL mice with a nonpathogenic variant of Theiler's murine encephalomyelitis virus (TMEV) engineered to express a naturally occurring Haemophilus influenzae-encoded molecular mimic (HI574-586) of an immunodominant self-myelin proteolipid protein epitope (PLP139-151) induced a rapid-onset demyelinating disease associated with the activation of PLP139-151-specific Th1 responses. The current results extend our previous findings in four critical respects. We show that disease initiation by the H. influenzae mimic is prevented by tolerance to the self PLP139-151 epitope, definitively proving the occurrence of infection-induced molecular mimicry. We demonstrate that the H. influenzae mimic epitope can be processed from the flanking sequences within the native mimic protein. We show that the H. influenzae mimic epitope only induces an immunopathologic self-reactive Th1 response and subsequent clinical disease in the context of the TMEV infection and not when administered in complete Freund's adjuvant, indicating that molecular mimicry-induced disease initiation requires virus-activated innate immune signals. Lastly, we show that the infection of SJL mice with TMEV expressing the H. influenzae mimic can exacerbate a previously established nonprogressive autoimmune disease of the central nervous system. Collectively, these findings illustrate the evolving mechanisms by which virus infections may contribute to both the initiation and exacerbation of autoimmune diseases, and they have important implications for MS pathogenesis.

Cutting edge: CD4+CD25+ regulatory T cells suppress antigen-specific autoreactive immune responses and central nervous system inflammation during active experimental autoimmune encephalomyelitis.

Autoreactive CD4(+) T cells exist in normal individuals and retain the capacity to initiate autoimmune disease. The current study investigates the role of CD4(+)CD25(+) T-regulatory (T(R)) cells during autoimmune disease using the CD4(+) T cell-dependent myelin oligodendrocyte glycoprotein (MOG)-specific experimental autoimmune encephalomyelitis model of multiple sclerosis. In vitro, T(R) cells effectively inhibited both the proliferation of and cytokine production by MOG(35-55)-specific Th1 cells. In vivo, adoptive transfer of T(R) cells conferred significant protection from clinical experimental autoimmune encephalomyelitis which was associated with normal activation of autoreactive Th1 cells, but an increased frequency of MOG(35-55)-specific Th2 cells and decreased CNS infiltration. Lastly, transferred T(R) cells displayed an enhanced ability to traffic to the peripheral lymph nodes and expressed increased levels of the adhesion molecules ICAM-1 and P-selectin that may promote functional interactions with target T cells. Collectively, these findings suggest that T(R) cells contribute notably to the endogenous mechanisms that regulate actively induced autoimmune disease.