The PAX LC Trial: A Decentralized, Phase 2, Randomized, Double-blind Study of Nirmatrelvir/Ritonavir Compared with Placebo/Ritonavir for Long COVID.

INTRODUCTION: Individuals with long COVID lack evidence-based treatments and have difficulty participating in traditional site-based trials. Our digital, decentralized trial investigates the efficacy and safety of nirmatrelvir/ritonavir, targeting viral persistence as a potential cause of long COVID. METHODS: The PAX LC trial (NCT05668091) is a Phase 2, 1:1 randomized, double-blind, superiority, placebo-controlled trial in 100 community-dwelling, highly symptomatic adult participants with long COVID residing in the 48 contiguous US states to determine the efficacy, safety, and tolerability of 15 days of nirmatrelvir/ritonavir compared with placebo/ritonavir. Participants are recruited via patient groups, cultural ambassadors, and social media platforms. Medical records are reviewed through a platform facilitating participant-mediated data acquisition from electronic health records nationwide. During the drug treatment, participants complete daily digital diaries using a web-based application. Blood draws for eligibility and safety assessments are conducted at or near participants' homes. The study drug is shipped directly to participants' homes. The primary endpoint is the PROMIS-29 Physical Health Summary Score difference between baseline and Day 28, evaluated by a mixed model repeated measure analysis. Secondary endpoints include PROMIS-29 (Mental Health Summary Score and all items), Modified GSQ-30 with supplemental symptoms questionnaire, COVID Core Outcome Measures for Recovery, EQ-5D-5L (Utility Score and all items), PGIS 1 and 2, PGIC 1 and 2, and healthcare utilization. The trial incorporates immunophenotyping to identify long COVID biomarkers and treatment responders. CONCLUSION: The PAX LC trial uses a novel decentralized design and a participant-centric approach to test a 15-day regimen of nirmatrelvir/ritonavir for long COVID.

Use of "2-dose" regimen of methotrexate to treat ectopic pregnancy.

OBJECTIVE: To evaluate the safety and acceptability of a novel dosing regimen of methotrexate to treat ectopic pregnancy. DESIGN: Prospective study. SETTING: Three academic medical centers. PATIENT(S): One hundred one patients with ectopic pregnancy who elected to have medical therapy. INTERVENTION(S): Intramuscular methotrexate 50 mg/m(2) was administered on days 0 and 4; additional doses of methotrexate were given on day 7 and/or day 11 if hCG levels did not decrease by 15% during the follow-up period. MAIN OUTCOME MEASURE(S): Adverse events, acceptability, and resolution of pregnancy without surgical treatment. RESULT(S): With this protocol, 87% of patients were treated successfully. Of those protocols that were considered failures, only 3% of patients experienced rupture of ectopic pregnancy. Treatment was well-tolerated; most side effects were reported as mild and transient. Ninety-one percent of the 61.5% of patients who responded to the satisfaction questionnaire reported satisfaction with this regimen. CONCLUSION(S): This "2-dose" protocol minimizes the number of injections and surveillance visits, compared with the "multiple dose" regimen, and methotrexate is administered more frequently than with the "single dose" regimen. The protocol may optimize the balance between convenience and efficacy. In a limited number of women, no safety concerns were noted with up to 4 doses of methotrexate in a 2-week period without leucovorin rescue.

Risk factors for ectopic pregnancy in women with symptomatic first-trimester pregnancies.

OBJECTIVE: To evaluate the association between ectopic pregnancy (EP) and clinical and historical factors among women presenting with pain and/or bleeding in early pregnancy. DESIGN: Nested case-control study. SETTING: University medical center. PATIENT(S): Women with symptomatic early pregnancies of unknown location presenting for care between January 1, 1990 and July 31, 1999. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Clinical and historical risk factors were compared between women with EP and women with ongoing intrauterine pregnancies or spontaneous abortions. RESULT(S): The following factors were associated with increased risk of EP: prior EP (odds ratio, 2.98 [95% confidence interval, 1.88-4.73] for one prior EP and 16.04 [5.39-47.72] for 2 or more), pelvic inflammatory disease history (1.5 [1.11-2.05]), pain at presentation (1.42 [1.06-1.92]), vaginal bleeding at presentation (1.42 [1.04-1.93]), and hCG of 501-2,000 mIU/mL (1.73 [1.24-2.42]). Age younger than 25 years (0.59 [0.41-0.85]) and a history of abortion were protective from EP (0.58 [0.38-0.90]). Prior nontubal pelvic surgery, past intrauterine device use, prior cesarean section, and current cervical infection demonstrated no association with EP. CONCLUSION(S): Evaluation of women with a symptomatic early pregnancy confirms and refutes some of the classical risk factors for EP. Prior EP is a strong risk factor, whereas pelvic inflammatory disease has an unexpected weak association. Previous abortion was found to have a negative association, whereas nontubal surgery, cesarean section, and a history of or concomitant cervical infection have no association. Knowledge of historical and clinical factors associated with EP may aid in early diagnosis.

Human chorionic gonadotropin profile for women with ectopic pregnancy.

OBJECTIVE: To analyze serial human chorionic gonadotropin (hCG) levels in women presenting to the emergency department who were ultimately confirmed to have ectopic pregnancies. METHODS: Human chorionic gonadotropin levels were obtained over time until definitive diagnosis. To be included, women had to have at least 2 hCG measurements. Human chorionic gonadotropin curves were characterized and their slopes calculated. RESULTS: Two hundred women received diagnoses of ectopic pregnancy with the help of serial hCG values and were included in the study. No curve adequately characterized the pattern of hCG values so attention was focused on the initial 2 values. The median slope of log hCG among all subjects was 0.11 (25% increase in 2 days). However, 60% of subjects had an initial rise in hCG, and 40% had an initial fall. The rise in hCG for women with ectopic pregnancies (0.28; 75% increase in 2 days) was slower than the mean increase reported for a viable intrauterine pregnancy. The decline in hCG for women with ectopic pregnancies (-0.225; 27% decline in 2 days) was slower than the mean reported for completed spontaneous abortion. However, 20.8% of women presented with a rise in hCG values similar to the minimal rise for women with a viable gestation, and 8% of women presented with a fall in hCG values similar to women with a completed spontaneous abortion. CONCLUSION: There is no single way to characterize the pattern of hCG for ectopic pregnancy. The number of women with ectopic pregnancy who experience an increase in hCG values is approximately equal to the number of those who experience a decrease. The hCG profile in women with ectopic pregnancy can mimic that of an intrauterine pregnancy or a completed spontaneous abortion in approximately 29% of cases. LEVEL OF EVIDENCE: II-2.

Risk factors for spontaneous abortion in early symptomatic first-trimester pregnancies.

OBJECTIVE: To evaluate the association of an ultimate diagnosis of miscarriage with various clinical symptoms and historical factors in a cohort of women presenting with pain, bleeding, or both in the first trimester of pregnancy. METHODS: This was a case-control study from a population of women presenting for care with pelvic pain or vaginal bleeding in the first trimester of pregnancy whose diagnoses were not definite upon initial evaluation. Analyses were performed in 2 ways. In one instance cases were defined as women ultimately definitively diagnosed with a miscarriage and controls were defined as women with a pregnancy that did not result in miscarriage (ectopic pregnancy or ongoing intrauterine pregnancy). The second analysis compared women with a miscarriage only to women who had an ongoing intrauterine pregnancy. RESULTS: A total of 2,026 women were evaluated, with 1,192 ultimately diagnosed with a spontaneous abortion, 367 with ectopic pregnancy, and 467 with a viable intrauterine pregnancy. Although many risk factors were individually associated with miscarriage in preliminary analysis, in the final analysis only extremes in age (< 25 and > 35) and the complaint of bleeding (odds ratio [OR] 7.35, 95% confidence interval[CI] 5.74-9.41) were associated with miscarriage. The complaint of pain (OR 0.72, 95% CI 0.57-0.92), human chorionic gonadotropin (hCG) value greater than 500 (hCG < or = 500 IU/mL compared with hCG 501-2000: OR 0.52, 95% CI 0.39-0.69) and concurrent cervical infection (OR 0.69, 95% CI 0.55-0.88) were negatively associated with miscarriage. CONCLUSION: Few factors predict miscarriage in women who present with a symptomatic first trimester pregnancy of unknown location. Heavy bleeding was most strongly associated with miscarriage. Concurrent cervical infections should not be overlooked as a cause of bleeding in early pregnancy and were not associated with miscarriage. LEVEL OF EVIDENCE: II-2.

Supplementation with DHEA: effect on muscle size, strength, quality of life, and lipids.

OBJECTIVE: To evaluate the effects of combination estrogen/androgen therapy on muscle mass, strength and endurance, serum hormone and lipid profiles, and quality of life measures in postmenopausal women. METHODS: Prospective, randomized, placebo-controlled pilot study at a tertiary care medical center. Fifty postmenopausal women were randomized to a 12-week course of (1) dehydroepiandrostenedione (DHEA) 50 mg daily, (2) conjugated equine estrogen (CEE) 0.625 mg daily, (3) DHEA 50 mg+CEE 0.625 mg daily, or (4) placebo. Main outcome measures of lower extremity muscle (calf) mass, functional muscle parameters, serum hormone and lipid levels, and quality of life (QOL) were obtained at baseline and after treatment. Statistical analysis compared percent change from baseline values and treatment differences among outcomes. RESULTS: Significant increases in mean DHEA, DHEA sulfate (DHEA-S), testosterone, and androstenedione levels were noted with DHEA alone or combined DHEA/CEE treatments when compared with placebo. Compared with no hormone therapy, none of the supplemental hormone groups caused significant changes in muscle mass, muscle strength, muscle endurance, feelings of well-being, sleep, or sexual function. CONCLUSIONS: Androgen replacement therapy, with DHEA, to menopausal women increases serum androgen levels without any appreciable effect on muscle cross-sectional area, muscle strength, muscle function, or improvement in health-related QOL.

Decline of serum human chorionic gonadotropin and spontaneous complete abortion: defining the normal curve.

OBJECTIVE: We sought to estimate a standard curve of serum human chorionic gonadotropin (hCG) decline that characterizes spontaneous abortion. METHODS: Data were extracted from a clinical database of women with symptomatic early pregnancies and nondiagnostic ultrasonography who required follow-up with serial hCG levels. The evaluation was restricted to women who had a pregnancy of unknown location, a decrease in serum levels, and who were ultimately diagnosed with miscarriage (a decrease in serum hCG to < 5 mIU/mL in the absence of surgical intervention or confirmation of products of conception after dilation and curettage). The starting point of the curve was the hCG concentration at presentation, with serial levels plotted until the time of definitive diagnosis. Semiparametric statistical techniques were used to characterize the shape of the curve. We present slopes for the decrease in log hCG levels and the projected rate of fall. RESULTS: Of the 1,543 patients, 710 were diagnosed with miscarriage. A quadratic curve for log hCG with a steeper rate of decline for large initial hCG values best described the pattern of change. One curve could not fully estimate the decline because the rate was dependent on the initial hCG level. In other words, more rapid decline was associated with a higher starting concentration. The rate of decline ranged from 21% to 35% at 2 days and 60% to 84% at 7 days, depending on initial hCG value. CONCLUSION: The rate of hCG decrease in spontaneous abortions is described by a quadratic profile, with a faster decline in hCG value with higher presentation levels. A rate of decline less than 21% at 2 days or 60% at 7 days suggests retained trophoblasts or an ectopic pregnancy.

Symptomatic patients with an early viable intrauterine pregnancy: HCG curves redefined.

OBJECTIVE: To analyze the change in serial human chorionic gonadotropin (hCG) levels in women symptomatic with pain or bleeding who presented with nondiagnostic ultrasonography but were ultimately confirmed to have a viable intrauterine pregnancy. METHODS: The rise in serial hCG measures were modeled over time, with the start point defined in 2 ways: by last menstrual period and by date of presentation for care. Both semiparametric (spline) curves and linear random-effects models were explored. The slope and projected increase of hCG were calculated to define 99% of viable intrauterine pregnancies. RESULTS: A total of 287 subjects met inclusion criteria and contributed 861 measurements of hCG. On average, these subjects contributed 3.00 observations and were followed up for 5.25 days. A linear increase in log hCG best described the pattern of rise. Curves derived from last menstrual period and day of presentation do not differ substantially. The median slope for a rise of hCG after 1 day was 1.50, (or a 50% increase); 2.24 after 2 days (or a 124% rise), and 5.00 after 4 days. The fastest rise was 1.81 at 1 day, 3.28 at 2 days, and 10.76 at 4 days. The slowest or minimal rise for a normal viable intrauterine pregnancy was 24% at 1 day and 53% at 2 days. CONCLUSION: These data define the slowest rise in serial hCG values for a potentially viable gestation and will aid in distinguishing a viable early pregnancy from a miscarriage or ectopic pregnancy. The minimal rise in serial hCG values for women with a viable intrauterine pregnancy is "slower" than previously reported, suggesting that intervention to diagnosis and treat an abnormal gestation should be more conservative.