COVID-19 infection in first trimester of pregnancy marked by a liver cytolysis in a woman previously treated by hydroxychloroquine for repeated implantation failure: a case report.

BACKGROUND: In December 2019, a new disease (COVID-19) caused by a novel coronavirus called SARS-CoV-2 emerged in China and spread to many other countries. There is only limited data about the clinical features of COVID-19 during pregnancy, especially in first trimester. CASE PRESENTATION: We report a COVID-19 infection in a 35 years-old patient in first trimester of pregnancy and its consequent medical care. At 7 weeks of pregnancy, the patient, who did not have any pregestational comorbidities, complained of intense nausea and asthenia. An important liver cytolysis was discovered with biological perturbations of transaminases levels. No respiratory symptoms were recorded. Classical viral aetiologies and drug-related toxicity were discarded. Because of the aggravation of the symptoms and the occurrence of the breathlessness, the patient was tested for the COVID-19 in a nasopharyngeal swab. The RTq-PCR assay indicated the presence of SARS-CoV-2 RNA. In the absence of severe symptoms, the patient was monitored at home according to the French government guidelines. After a few days, the symptoms resolved without any complications. The pregnancy is still ongoing without any visible sequelae on the foetus so far. CONCLUSIONS: This first case illustrated the difficulty of COVID-19 diagnosis in patients with isolated digestive symptoms in first trimester of pregnancy that could be confused with gravida hyperemesis. Monitoring of pregnancy after an episode of COVID-19 should be strengthened with bimonthly foetal growth ultrasounds and doppler assessments because of the risks for intrauterine growth restriction. Comprehensive data on larger numbers of first trimester gravid women with COVID-19 are required to better understanding the overall impact of SARS-CoV-2 on maternal and birth outcomes.

Prediction of tumor grade and lymphovascular space invasion in endometrial adenocarcinoma with MR imaging-based radiomic analysis.

PURPOSE: To evaluate the capabilities of two-dimensional magnetic resonance imaging (MRI)-based texture analysis features, tumor volume, tumor short axis and apparent diffusion coefficient (ADC) in predicting histopathological high-grade and lymphovascular space invasion (LVSI) in endometrial adenocarcinoma. MATERIALS AND METHODS: Seventy-three women (mean age: 66±11.5 [SD] years; range: 45-88 years) with endometrial adenocarcinoma who underwent MRI of the pelvis at 1.5-T before hysterectomy were retrospectively included. Texture analysis was performed using TexRAD® software on T2-weighted images and ADC maps. Primary outcomes were high-grade and LVSI prediction using histopathological analysis as standard of reference. After data reduction using ascending hierarchical classification analysis, a predictive model was obtained by stepwise multivariate logistic regression and performances were assessed using cross-validated receiver operator curve (ROC). RESULTS: A total of 72 texture features per tumor were computed. Texture model yielded 52% sensitivity and 75% specificity for the diagnosis of high-grade tumor (areas under ROC curve [AUC]=0.64) and 71% sensitivity and 59% specificity for the diagnosis of LVSI (AUC=0.59). Volumes and tumor short axis were greater for high-grade tumors (P=0.0002 and P=0.004, respectively) and for patients with LVSI (P=0.004 and P=0.0279, respectively). No differences in ADC values were found between high-grade and low-grade tumors and for LVSI. A tumor short axis≥20mm yielded 95% sensitivity and 75% specificity for the diagnosis of high-grade tumor (AUC=0.86). CONCLUSION: MRI-based texture analysis is of limited value to predict high grade and LVSI of endometrial adenocarcinoma. A tumor short axis≥20mm is the best predictor of high grade and LVSI.

Diagnosis of acute overt gastrointestinal bleeding with CT-angiography: Comparison of the diagnostic performance of individual acquisition phases.

PURPOSE: To compare the respective values of arterial phase, portal venous phase and combination of phases using 64-section multidetector computed tomography (MDCT) for diagnosing acute overt gastrointestinal bleeding (AOGIB). PATIENTS AND METHODS: Forty-nine patients with AOGIB were included. There were 30 men and 19 women, with a mean age of 65.4±15.6 (SD) years [range, 34-91years]. Two observers reviewed MDCT examinations in consensus for presence of active bleeding, location of bleeding site and nature of causative lesion. The different acquisition phases were reviewed independently. RESULTS: AOGIB was identified in 28/49 patients (57%) with the multiphasic set, in 26/49 patients (53%) with arterial phase and in 25/49 patients (51%) with portal venous phase. Multiphasic set helped locate the bleeding site in 40/49 patients (82%). The cause was elucidated in 23/49 patients (47%) with multiphasic set. The differences between set performances were not statistically significant. Sensitivity for depicting AOGIB with the multiphasic set was 92% and specificity was 76%. CONCLUSION: Multiphasic 64-section MDCT has high diagnostic performances in patients with AOGIB. Further studies with a larger population are needed to reach statistical significance and demonstrate better diagnostic performance of multiphasic MDCT in comparison with the arterial or portal phase alone.

Treatment of primary hypogonadism in men by the transdermal administration of testosterone.

We tested the efficacy of a thin flexible testosterone-impregnated membrane applied to the scrotum for the long term treatment of male hypogonadism. Ten men with primary hypogonadism were treated for 3 months (2 men) or 13 months (8 men). Serum testosterone concentrations increased in all 10 men, to within the normal range in 8. Serum dihydrotestosterone concentrations increased to supranormal values in all of the men, decreased to the normal range in 6, indicating the biological effectiveness of the testosterone in those subjects. Two men whose serum LH concentrations did not fall to normal had small or distorted scrotal surfaces. Seven of the 8 men whose serum testosterone concentrations became normal said that their hypogonadal symptoms were corrected by this treatment. We conclude that the transdermal administration of testosterone is an effective means of treating the majority of hypogonadal men who have a normal scrotum.

Transdermal delivery of testosterone.

We administered testosterone transdermally to six hypogonadal men by applying a thin flexible polymeric membrane containing testosterone to the scrotum. Each man wore a placebo membrane and three doses (5, 10, and 15 mg) of testosterone-containing membranes for 22 h/day. Each dose was worn for 1 week, and one dose was worn a second week. Blood was sampled frequently for one 22 h period on the seventh day of each treatment period. After the application of a membrane, the serum testosterone concentration rose rapidly, reached a peak in 2-3 h, and decreased slowly to 60-80% of the peak value by 22 h. The mean (+/- SE) 22-h average testosterone concentration during the wearing period was dependent on the testosterone content of the membrane (placebo, 135 +/- 38 ng/dl; 5 mg, 348 +/- 66 ng/dl; 10 mg, 455 +/- 77 ng/dl; and 15 mg, 624 +/- 65 ng/dl; P less than 0.001, by analysis of variance). When the same dose was worn twice, the mean coefficient of variation was 13.9%. We conclude that the transdermal application of testosterone to hypogonadal men reproducibly raises their serum testosterone concentrations to within the normal range, and that it, therefore, warrants evaluation as a treatment for male hypogonadism.

Human buccal assay for evaluation of the mucosal irritation potential of drugs.

We applied drugs in aqueous gels to the buccal mucosae of normal volunteers to develop an assay of gastrointestinal irritation potential. We studied effects of pH, concentrations, and formulations. We evaluated irritation by subjects' reports of their sensations and observers' grading of visible reactions. On an irritation log ranking scaled 0 to 5, placebo gels produced virtually no irritation, except those formulated at pH 1, 2, and 14. Albuterol, furosemide, and methyldopa produced essentially no irritation. Minutes of exposure to sodium indomethacin, sodium naproxen, and propranolol (at, respectively, pH 8.2, 9.6, and 4.8 and concentrations of 12%, 40%, and 8%) caused ulceration that took up to weeks to heal. Acid forms of naproxen and indomethacin caused minimal or no irritation. Although irritation models based on one gastrointestinal area have limitations, our results indicate that the minimally invasive buccal assay allows ranking of contact irritation potential of drugs and formulations that could aid in selecting optimum formulations for clinical use.

Kinetics of osmotically controlled indomethacin delivery systems after repeated dosing.

Two osmotically driven, controlled-release dosage forms of indomethacin were evaluated in a multiple-dose crossover study in 12 healthy subjects. Following equivalent daily doses, less frequent dosing of both controlled-release forms resulted in plasma concentration profiles that are more uniform than those following capsule regimens. After the first day, morning predose plasma levels wer significantly higher for the controlled-release treatments. Renal clearances were similar between days and among treatments. Total urinary recoveries were comparable for all regimens.

Androgen therapy of hypogonadal men with transscrotal testosterone systems.

The need for improved controlled delivery of testosterone to hypogonadal men stimulated the development of a self-adherent transscrotal testosterone system to provide programmed testosterone delivery through the uniquely permeable scrotal skin. In this short- and long-term efficacy trial, the responses of testosterone and its metabolites to the application of transscrotal testosterone systems of varying testosterone content were compared with the response to 200 mg of testosterone enanthate. Daily transscrotal testosterone system administration resulted in a rapid increase of testosterone and bioavailable, non-sex hormone binding globulin-bound testosterone levels to normal, peaking at two hours, followed by a slow decline over 23 hours, resembling the diurnal variation of endogenous testosterone. One year of daily transscrotal testosterone system therapy demonstrated continued reliable absorption of testosterone and suppression to normal of the luteinizing hormone in two of three patients. There was a greatly disproportionate increase of serum dihydrotestosterone over testosterone, suggesting 5-alpha reduction at the scrotal site. The subjects reported marked subjective improvement. Thus, the transscrotal testosterone system is a novel, effective, and well-tolerated method of delivering testosterone to hypogonadal patients.

Visual effects of pilocarpine in glaucoma comparative study of administration by eyedrops or by ocular therapeutic systems.

Eighteen glaucoma patients each received four pilocarpine regimens in random sequence: 1% and 4% eyedrops and 20mug/hr and 40mug/hr ocular therapeutic systems. Unimportant changes in refraction, near vision, and distance vision occurred during the use of either ocular therapeutic system. Miosis with ocular therapeutic systems was almost always less intense and variable than with eyedrops. Refractive changes occurred in 12 patients following 1% pilocarpine and in 16 patients following 4% pilocarpine drops; decreased distance vision occurred in nine patients after 1% drops and in 12 patients after 4% drops. Fewer patients showed decreases in near vision. In all cases, visual effects peaked one half hour after eyedrop instillations and returned gradually toward normal in the next two to three hours. Intraocular pressure levels were within comparable ranges during all four treatments, but the ocular therapeutic systems maintained pressure at a more constant level.

A double-blind, placebo-controlled evaluation of the erectile response to transurethral alprostadil.

OBJECTIVES: Previous studies have indicated that the urethra may provide an effective route for administering vasoactive medication for the treatment of erectile dysfunction. We evaluated the safety and efficacy of alprostadil administered intraurethrally at home for the treatment of this disorder. METHODS: This prospective, multicenter, double-blind, placebo-controlled study evaluated the erectile response to randomly assigned doses of transurethral alprostadil at home in 68 men with long-standing (mean 41 months) erectile dysfunction of primarily organic etiology. Patients completing the study each administered a random sequence of four different doses (125, 250, 500, and 1000 micrograms) and placebo over a 2 to 4-week period. Assessments included the couples' ability to have intercourse, patient ratings of erectile response by both categorical and visual analogue scales, penile volume measurements, and overall assessments of comfort and ease of administration. RESULTS: Overall, 75.4% (49 of 65) of study patients achieved full enlargement of the penis and 49.2% (32 of 65) achieved an erection judged by the patient to be sufficient for intercourse. In addition, 63.6% (42 of 66) of patients reported intercourse. Efficacy was similar across etiologies. The most common side effect was penile pain, which occurred in association with 9.1% to 18.3% of alprostadil administrations, depending on dose. Mean comfort ratings ranged from 79 to 87, depending on dose, where 0 = severe discomfort and 100 = comfortable; ease of administration scores were above 90 for each dose, where 0 = difficult and 100 = easy. There were no episodes of priapism in this study. CONCLUSIONS: Short-term treatment with transurethral alprostadil produced erections resulting in sexual intercourse in most patients with chronic erectile dysfunction. This therapy may be a useful treatment option for patients with erectile dysfunction.

Progestasert: a uterine therapeutic system for long-term contraception: I. Philosophy and clinical efficacy.

PIP: An intrauterine steroid delivery system the Progestasert system, is described and studies of its clinical efficacy are reported. The Progestasert system combines the advantageous features of IUDs and oral minidose progestogen preparations. An internal device continuously delivers progesterone for 1 year to the uterine lumen and endometrium. A T-shaped Progestasert which releases 65 mcg/day has been selected for wide scale clinical use. A total of 3121 parous women used Progestasert systems for 25,389 woman-months. The pregnancy rate was 1%, the expulsion rate 2.8%, and the total removal rate was 13%. The total continuation rate of the Progestasert system of 83.2% compares favorable with that of the Tatum-T-shaped IUD of 68.7%. These initial results aft er 1 year of use are most encouraging and suggest that the goals originally set for a contraceptive approach using intrauterine progester one are well within reach.^ieng

Comparative pharmacologic effects of pilocarpine administered to normal subjects by eyedrops or by ocular therapeutic systems.

Normal volunteers used 1, 2, and 4% pilocarpine eyedrops, three times daily, or ocular therapeutic systems placed in the conjunctival cul-de-sac to control intraocular pressure. The systems continuously release 20 and 40 mug/hour of pilocarpine for one week. Although the amount of drug delivered to the eye from the ocular therapeutic system was one fifth that obtained from the eyedrops, the decrease of intraocular pressure was comparable. The ocular therapeutic systems produced small, constant effects on visual acuity, refractive error, and miosis that did not cause visual handicaps or require correction. The effects of eyedrops on these visual factors were large and varied and produced marked visual handicaps that were not correctable with spectacles. Despite its comparable hypotensive effect in normal subjects, continuous delivery of pilocarpine by means of an ocular therapeutic system elicits less severe side effects than pilocarpine eyedrops.

Effect of food on bioavailability of pseudoephedrine and brompheniramine administered from a gastrointestinal therapeutic system.

The purpose of this study was to determine how a high-fat meal affects the delivery and absorption of pseudoephedrine and brompheniramine maleate when delivered from a gastrointestinal therapeutic system (GITS). This study was a randomized, complete crossover trial with 12 healthy male volunteers who were given single doses of the 24-h GITS under fed and fasted conditions. Pharmacokinetic parameters for both drugs were comparable between fed and fasted treatments, except for a shorter time to maximum concentration of pseudoephedrine for fed subjects (p = 0.002). Bioavailability of pseudoephedrine was 91% for fed relative to fasted treatment; for brompheniramine it was 89%. These results indicate that codelivery of the two drugs from the GITS is reliable and prolonged, and that the resulting absorption of pseudoephedrine and brompheniramine is minimally affected by food.

Elementary osmotic pump for indomethacin.

Based on the principles of an elementary osmotic pump, systems were designed to deliver indomethacin in solution at a constant rate, Z, to contain a total amount of drug, Mt, and to deliver 80% of their content at time t80. To allow selection of the optimal delivery rate into the body, three different prototypes were prepared with respective values for Z, Mt, and t80 of: 7 mg/hr, 85 mg, 11 hr; 9 mg/hr, 85 mg, 8 hr; and 12 mg/hr, 85 mg, 6 hr. These systems were found to deliver 70% of each system's contents at zero-order rates. Delivery rates were independent of pH, method of measurement, and stirring rate. In keeping with these results, the systems in the GI tract of dogs delivered at the same rate as in vitro, which qualifies the in vitro test as a bioanalogous method predictive of the in vivo performance of the dosage forms. Preliminary results in normal volunteers yielded similar urinary recoveries, while plasma profiles were different from each other and distinct from those following conventional capsules.

Progress in the development of the Progestasert TM 65 progesterone therapeutic system for contraception.

PIP: The primary objective in the design of the Progestasert 65 system, a progesterone uterine therapeutic system, has been to influence the intrauterine environment and produce fertility control by means of local steroid action. It has an average release rate of 65 mcg progesterone/day to the uterine lumen for a period of 400 days. Although the system was developed as a method of local steroid contraception rather than as an intrauterine device (IUD), information gained from experience with IUDs guided certain aspects of the design specifications; e.g., the T configuration was selected and modified for easier insertion. The progesterone core composition is contained within the verticle system of the T maintaining the flexibility and softness of this portion. The inserter is a smooth cylindrical unit, precurved and malleable so the angle can be changed if necessary. This inserter design has provided over 3000 insertions with no perforations. Clinical data come from 32 clinics. It is concluded that this development is a highly efficacious local hormonal system of contraception.^ieng

Steroid delivery systems for contraception.

Scientific disciplines not normally associated with pharmaceutical development have been employed to enhance the effectiveness and attractiveness of two approaches to steroidal contraception. The use of a bioerodible polymeric carrier for predictable systemic steroidal administration has removed the largest hurdle to the development of a subcutaneous contraceptive implant. A polymeric progesterone delivery system has provided a method for localizing hormonal contraception in the uterine cavity. Extensions of these technologies may provide two useful tools in limiting fertility in an already overcrowded world.

Intrauterine contraception information for the patient.

PIP: To determine what a patient package insert (PPI) for an intrauterine contraceptive should contain, a survey was conducted using a group of 348 women randomly selected from the clinical population of 3 researchers in the Progestasert system trials in Palo Alto and San Jose, California and in New York City. The women were randomly assigned into 2 groups: A (175 women) and B (173 women). Demographic characteristics of both groups were similar (90% Caucasian; 21-37 years of age and with at least some college education). Questionnaires were mailed and $5 was offered for returned questionnaires. Group A received a PPI similar to that proposed in The Federal Register of 7/1/75 while group B received a PPI prepared by ALZA. In data analysis, statistics were used in a descriptive rather than mathematical sense. Of the 301 questionnaires mailed, 256 or 85% responded (134 in group A and 122 in group B). 95% and 98% in groups A and B, respectively, agreed that brochures are important sources of information (Table 1); 98 and 100% agreed that all system users should receive the PPI. Both groups were unanimous also, in agreeing that brochures should be read prior to insertion of device. Readers of the company-prepared brochure found its informational content more complete than the FDA-prepared version. The findings suggest that brochures should contain information on how the contraceptive works; who may use it; how it is used; its appearance; potential adverse effects; and other pertinent information.^ieng

[Impact of preoperative breast magnetic resonance imaging on surgical management: experience of two university hospitals]. / Impact de l'IRM mammaire préopératoire sur la prise en charge chirurgicale des cancers du sein: expérience de deux centres hospitaliers universitaires.

OBJECTIVES: Breast magnetic resonance imaging (MRI) has attained a solid position in the diagnosis of breast cancer but its benefit is still to be confirmed in the preoperative staging. The authors assessed the impact of preoperative breast MRI on surgical management of breast cancer in two university hospitals. PATIENTS AND METHODS: This retrospective review was realized in two university hospitals and concerned all patients with breast carcinoma who had a surgical first therapy. We selected 89 patients who underwent preoperative breast MRI in the period between January 2008 and December 2009. RESULTS: The sensitivity of breast MRI for detecting breast tumor was 95%. Fourteen percent of patients had a multifocal disease, 10% a multicentric disease and 2% a synchronous bilateral cancer. The correlation of radiological tumor size with histopathological size was r=0.68 in IRM compared to r=0.45 in conventional imaging (P<0.001). Nineteen additional biopsies were performed and 9.9% of false-positive findings were detected. Retrospectively, planned surgical management was altered in 9% of patients, resulted from use of breast MRI. Six patients had conversion of planned breast conservation to mastectomy and two patients underwent contralateral lumpectomy after discover synchronous bilateral cancer. DISCUSSION AND CONCLUSION: Breast MRI was very sensitive for the detection of breast carcinoma and improved local staging in almost 9% of patients. But, low specificity of this imaging requires a systematically validation of additional lesions by biopsy before surgical planning.

Evaluation and impact of residual disease in locally advanced cervical cancer after concurrent chemoradiation therapy: results of a multicenter study.

BACKGROUND: The aim of this study was to evaluate the diagnosis and impact of residual disease (RD) after concurrent chemoradiation therapy (CRT) in locally advanced cervical cancer (FIGO IB2-IVA). METHODS: This retrospective multicenter study included 159 patients who were treated with completion surgery after CRT between 2006 and 2012. Magnetic resonance imaging (MRI) was performed 4-6 weeks after CRT and compared to pathological evidence of residual disease. Kaplan-Meier survival curves were plotted and univariate/multivariate analyses were performed to assess the association between RD and the outcome. RESULTS: Residual disease was present in 45.3% of the patients and detected by MRI in 57.1%. The MRI had a 29.2% false positive rate and an 11.1% false negative rate. The overall survival (OS) rates at 3 and 5 years were 78.6% (CI 95% [71%-86.9%]) and 76.5% (CI 95% [68.2%-85.7%]), respectively. The disease free survival (DFS) rates at 3 and 5 years were 73.4% (CI 95% [65.6%-82%]) and 71.1% (CI 95% [62.7%-80.1%]), respectively. RD greater than 10 mm decreased DFS (HR = 4.84, p = 0.03), whereas RD between 1 and 10 mm (HR = 0.31, p = 0.58) and less than 1 mm (HR = 0.37, p = 0.54) had no impact on DFS. The OS was not changed by RD. DISCUSSION: The MRI accuracy value is not sufficient to select patients who might benefit from completion surgery. Residual disease over 10 mm decreased DFS but did not impact OS.