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Context: Cryptosporidium parvum infection, a common cause of diarrhea in persons infected with the human immunodeficiency virus (HIV), is difficult to treat or prevent.Objective: To evaluate relative rates of cryptosporidiosis in HIV-infected patients who were either receiving or not receiving chemoprophylaxis or treatment for Mycobacterium avium complex.Design: Analysis of prospectively collected data from HIV-infected patients' visits to their physicians since 1992.Setting: Ten (8 private, 2 publicly funded) HIV clinics in 9 US cities.Patients: A total of 1019 HIV-infected patients with CD4+ cell counts less than 0.075 x 10(9)/L.Main Outcome Measures: Incidence of clinical cryptosporidiosis during treatment with clarithromycin, rifabutin, and azithromycin.Results: Five of the 312 patients reportedly taking clarithromycin developed cryptosporidiosis vs 30 of the 707 patients not taking clarithromycin (relative hazard [RH], 0.25 [95% confidence interval (CI), 0.10-0.67]; P=.004). Two of the 214 patients taking rifabutin developed cryptosporidiosis vs 33 of the 805 not taking rifabutin (RH, 0.15 [95% CI, 0.04-0.62]; P=.01). Prophylactic efficacy of either drug was 75% or greater. No protective effect was seen in the 54 patients reportedly taking azithromycin (RH, 1.48 [95% CI, 0.44-5.04]; P=.46).Conclusions: Clarithromycin and rifabutin were highly protective against development of cryptosporidiosis in immune-suppressed HIV-infected persons in this analysis; further study is warranted. [ABSTRACT FROM AUTHOR]

Younger and older adults read a series of expository passages for immediate recall by self-pacing the presentation sector-by-sector on a computer screen. Regression analysis of sector reading times (RT) was used to estimate the time allocated by individuals to word-level (i.e., syllable length and mean word frequency), text-level (i.e., number of propositions, number of new concepts introduced, and total Yngve depth), and discourse-level (i.e., serial position) features. Age differences were found in the pattern of reading time allocation that engendered high levels of recall. Specifically, younger adults who achieved high recall were more responsive to word frequency and the introduction of new concepts. By contrast, high recall among the old was related to a greater degree of on-line contextual facilitation (i.e., a steeper serial position effect). These data suggest that there is an age difference in how the allocation of resources at encoding optimizes subsequent memory performance. [ABSTRACT FROM AUTHOR]

We performed transcriptomic analyses on freshly frozen (n=21) and paraffin-embedded (n=35) gastrointestinal (GI) biopsies from children with and without acute acute GI graft-versus-host disease (GvHD) to study differential gene expressions. We identified 164 significant genes, 141 upregulated and 23 downregulated, in acute GvHD from freshy frozen biopsies. CHI3L1 was the top differentially expressed gene in acute GvHD, involved in macrophage recruitment and bacterial adhesion. Mitochondrial genes were among the top downregulated genes. Immune deconvolution identified a macrophage cellular signature. Weighted gene co-expression network analysis showed enrichment of genes in the ERK1/2 cascade. Transcriptome data from 206 ulcerative colitis (UC) patients were included to uncover genes and pathways shared between GvHD and UC. Comparison with the UC transcriptome showed both shared and distinct pathways. Both UC and GvHD transcriptomes shared an innate antimicrobial signature and FCγ1RA/CD64 was upregulated in both acute GvHD (log-fold increase 1.7, P=0.001) and UC. Upregulation of the ERK1/2 cascade pathway was specific to GvHD. We performed additional experiments to confirm transcriptomics. Firstly, we examined phosphorylation of ERK (pERK) by immunohistochemistry on GI biopsies (acute GvHD n=10, no GvHD n=10). pERK staining was increased in acute GvHD biopsies compared to biopsies without acute GvHD (P=0.001). Secondly, plasma CD64, measured by enzyme-linked immunsorbant assay (n=85) was elevated in acute GI GvHD (P<0.001) compared with those without and was elevated in GVHD compared with inflammatory bowel disease (n=47) (P<0.001), confirming the upregulated expression seen in the transcriptome.

The long-term outcomes of adults with Fanconi anaemia (FA) have improved with advances in haematopoietic stem cell transplantation (HSCT) and more detailed follow-up and screening guidelines. The phenotype of those who survive to adulthood may differ from the typical presentation of FA. We collected retrospective clinical data on adults with FA who received their care at the Cincinnati Children's Hospital Medical Center. In our final cohort of 52 patients, there were 29 females and 23 males, with median (range) age of 21 (18-37) years. Overall, 42 patients (81%) were alive at last follow-up. In all, 36 adults (69%) had undergone HSCT, including eight who had developed myelodysplasia or acute myeloid leukaemia. Eight (15%) developed squamous cell carcinoma. Endocrine complications were common, including hypothyroidism (42%), diabetes (10%), low body mass index (31%) and low bone mineral density (51%). The majority of adults with FA were employed (52%) or full-time students (13%). A significant subset of patients with FA are surviving into adulthood without requiring HSCT. Endocrine abnormalities and the development of solid tumours complicate adulthood. With improved survival outcomes following HSCT and more aggressive malignancy screening protocols, ongoing longitudinal analysis will be important to further characterise this cohort and the phenotype of untransplanted adults with FA., (© 2022 The Authors. British Journal of Haematology published by British Society for Haematology and John Wiley & Sons Ltd.)

TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A -related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the β-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is ∼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca , an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara -/- ; tspearb -/- double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants., Competing Interests: The authors declare no competing interests., (© 2023 The Author(s).)

Vulvovaginitis is one of the most common gynecological complaints presenting in the pediatric and adolescent female. The common causes of vulvovaginitis in the pediatric patient differ than that considered in adolescent females. When a child present with vulvar itching, burning and irritation the most common etiology is non-specific and hygiene measures are recommended. However these symptoms can mimic more serious etiologies including infection, labial adhesion, lichen sclerosis, pinworms and foreign body must be considered. Yeast infection is rare in the pediatric population but common in the adolescent. In the adolescent patient infections are more common. Yeast and bacterial vaginosis are commonly seen but due to the higher rate of sexual activity in this population sexually transmitted infections must also be considered., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Study Objective: The goal was to develop a multispecialty committee to address deficiencies in pediatric and adolescent gynecology (PAG) resident education through curricular development under the auspices of the North American Society for Pediatric and Adolescent Gynecology. DESIGN, SETTING, PARTICIPANTS, INTERVENTIONS, AND MAIN OUTCOME MEASURES: A multispecialty North American committee was organized to develop short as well as long curricula in PAG through a combination of conference calls and face-to-face meetings. Content was guided by objectives of national accrediting organizations. The curricula used print as well as interactive electronic resources., Results: After publication of the short and long curricula, a dissemination strategy was developed to present the information at national meetings. A curricular study was performed after introduction of the curriculum to evaluate its efficacy. Long-term plans for further curricular components and expansion of educational tools are ongoing., Conclusion: We gathered a diverse multispecialty group of doctors to collaborate on a unified educational goal. This committee developed and disseminated resident PAG curricula using a variety of learning tools. This curricular development and implementation can occur with a minimal financial burden., (Copyright © 2017 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Study Objective: To describe how pediatric and adolescent patients present to the gynecologist when they have tethered cord syndrome (TCS)., Design: We conducted a retrospective chart review on all patients suspected by the gynecologist of having TCS., Setting: Single pediatric and adolescent gynecology clinic in a mid-sized city in the midwest., Participants: Thirty-two patients, first seen between 2005 and 2012, suspected of having TCS and for whom follow-up information was available., Interventions and Main Outcome Measures: Patient characteristics, including patient history, gynecologic clinical indicators, clinical outcomes, indications for surgery, and postoperative resolution of symptoms, were reviewed., Results: The initial review of systems indicated stress urinary incontinence, back pain, and constipation as common markers in the 32 patients who were suspected of having TCS. All 32 patients underwent lumbar magnetic resonance imaging without contrast and evaluation by neurosurgery. Of the 32 patients with suspected TCS, 18 were later confirmed and 14 were shown to not have TCS. Of the 18 patients with sufficient information to justify a detethering procedure, 14 patients were followed and 93% (13 patients) had complete resolution of symptoms. Final diagnosis in the non-TCS group varied, including vulvovaginitis, enuresis, chronic constipation, and lichen sclerosis. Symptoms improved with the treatment of each primary condition., Conclusions: TCS symptoms overlap with gynecologic conditions; therefore, patients with TCS may present initially to the gynecologist. In pediatric/adolescent patients, TCS should be considered when stress urinary incontinence, back pain, and constipation are discovered in the review of systems. Because possible irreversible ischemic and neurologic changes are believed to be involved, early diagnosis and surgery are crucial for resolution. Providers should be aware of TCS in these pediatric and adolescent settings, because quick assessment may result in complete resolution of a chronic progressive disease., (Copyright © 2015 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Purpose of Review: To provide clinicians with a review of recent research and clinically applicable tools regarding teen pregnancy., Recent Findings: Teen pregnancy rates have declined but still remain a significant problem in the USA. Teen pregnancy prevention was identified by Centers for Disease Control and Prevention as one of its top six priorities, which is increasing research and intervention data. Long-acting contraceptive methods are acceptable to teens and have been shown to reduce teen birth rates. Pregnant teens need special attention to counseling on pregnancy options and reducing risk during pregnancy with regular prenatal care. Postpartum teens should be encouraged and supported to breastfeed, monitored for depression, and have access to reliable contraception to avoid repeat undesired pregnancy., Summary: This review highlights important issues for all providers caring for female adolescents and those who may encounter teen pregnancy. Foremost prevention of teen pregnancy by comprehensive sexual education and access to contraception is the priority. Educating patients and healthcare providers about safety and efficacy of long-acting reversible contraception is a good step to reducing undesired teen pregnancies. Rates of postpartum depression are greater in adolescents than in adults, and adolescent mothers need to be screened and monitored for depression. Strategies to avoid another undesired pregnancy shortly after delivery should be implemented.

Introduction: Influenza is a common and potentially serious disease in children. This retrospective cohort study examined the incidence of complications and associated risk factors in this population, and the effects of antiviral treatment., Methods: Data for children aged ≤17 years with a clinical diagnosis of influenza (ICD-9-CM codes 487.xx or 488.xx) during the 2006-2010 influenza seasons (including the 2009-2010 pandemic season) were obtained from US insurance claims databases. Unconditional logistic regression was used to evaluate the effect of antiviral treatment on the incidence of complications and healthcare resource utilization during the 30 days post the index influenza diagnosis. A sub-analysis in children aged <1 year was performed., Results: Antiviral treatment was used in 315,128 (39.53%) of 797,284 cases. The risk of complications was higher in children with pre-existing conditions, e.g., asthma (odds ratio [OR] = 1.86) or cystic fibrosis (OR = 1.67) than otherwise healthy children. Antiviral treatment reduced the 30-day risk of complications, hospitalization, emergency department visits, and ≥2 outpatient visits versus no treatment (ORs = 0.76, 0.69, 0.76, and 0.81, respectively); 30-day risks were further reduced by early treatment (within 2 days of diagnosis). The sub-analysis included 19,666 children aged <1 year; 7.38% received antiviral treatment during the pre-pandemic seasons and 33.00% during the pandemic season. Findings were similar to the main analyses; however, healthcare resource utilization was only significantly reduced by early treatment., Conclusions: Antiviral treatment is associated with reduced risk of complications and healthcare resource utilization in children of all ages with influenza, especially when initiated early.

The School for Science and Math at Vanderbilt (SSMV) is an innovative partnership program between a Research I private university and a large urban public school system. The SSMV was started in 2007 and currently has 101 students enrolled in the program, with a total of 60 students who have completed the 4-yr sequential program. Students attend the SSMV for one full day per week during the school year and 3-6 wk in the summers following their ninth- to 11th-grade years, with each grade of 26 students coming to the Vanderbilt campus on a separate day. The research-based curriculum focuses on guiding students through the process of learning to develop questions and hypotheses, designing projects and performing analyses, and communicating results of these projects. The SSMV program has elevated the learning outcomes of students as evidenced by increased achievement scores relative to a comparison group of students; has provided a rigorous research-based science, technology, engineering, and mathematics elective curriculum that culminates in a Summer research internship; has produced 27 Intel and Siemens semifinalists and regional finalists over the past 4 yr; and has supported the development of writing and communication skills resulting in regional and national oral presentations and publications in scientific journals., (© 2014 A. Eeds et al. CBE—Life Sciences Education © 2014 The American Society for Cell Biology. This article is distributed by The American Society for Cell Biology under license from the author(s). It is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License (http://creativecommons.org/licenses/by-nc-sa/3.0).)

The degree of exposure to Pediatric and Adolescent Gynecology (PAG) varies across academic programs in Obstetrics and Gynecology, Pediatrics, and Adolescent Medicine. Nevertheless, these programs are responsible to train residents and provide opportunities within their training programs to fulfill PAG learning objectives. To that end, North American Society for Pediatric and Adolescent Gynecology has taken a leadership role in PAG resident education by disseminating the Short Curriculum with specific learning objectives and list of essential resources where key concepts in PAG can be covered., (Copyright © 2014 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

Study Objective: The purpose of this study was to evaluate our adolescent patient population who had received a levonorgestrel intrauterine system (LNG-IUS) at or after the time of endometriosis diagnosis, and determine efficacy of the LNG-IUS in regards to pain and bleeding on follow-up exam., Design: Retrospective cohort study., Setting: Pediatric Adolescent Gynecology Clinic and Children's Hospital in a metropolitan area., Participants: Adolescent patients age 14-22 with pathology-proven endometriosis who had the LNG-IUS placed during the course of their treatment for this disease. Patients were divided into LNG-IUS placement at the time of surgical diagnosis versus placement some time after diagnosis., Main Outcome Measures: Pain and bleeding were assessed by follow-up exam. Pain was classified at each follow-up visit as either none, minimal, moderate, or severe. Bleeding was classified as none, irregular spotting, irregular bleeding, or daily bleeding., Results: The majority of patients (67%) required additional hormonal therapy for pain and bleeding suppression. Time to bleeding suppression and pain suppression was sooner in the group with interval time between surgical diagnosis and LNG-IUS placement, compared to LNG-IUS placement at the time of surgery (2.4 months vs 5.3 months until bleeding suppression, and 3.8 months vs 4.8 months until pain suppression), although statistical significance was not achieved., Conclusions: The LNG-IUS is an option for treatment of endometriosis in adolescents. As pain is the main problem associated with endometriosis, LNG-IUS placement is beneficial at the time of surgery when it is diagnosed. A prospective study is needed for further assessment of outcomes., (Copyright © 2013 North American Society for Pediatric and Adolescent Gynecology. Published by Elsevier Inc. All rights reserved.)

We build on previous work to show how serial diffusion-weighted MRI (DW-MRI) data can be used to estimate proliferation rates in a rat model of brain cancer. Thirteen rats were inoculated intracranially with 9L tumor cells; eight rats were treated with the chemotherapeutic drug 1,3-bis(2-chloroethyl)-1-nitrosourea and five rats were untreated controls. All animals underwent DW-MRI immediately before, one day and three days after treatment. Values of the apparent diffusion coefficient (ADC) were calculated from the DW-MRI data and then used to estimate the number of cells in each voxel and also for whole tumor regions of interest. The data from the first two imaging time points were then used to estimate the proliferation rate of each tumor. The proliferation rates were used to predict the number of tumor cells at day three, and this was correlated with the corresponding experimental data. The voxel-by-voxel analysis yielded Pearson’s correlation coefficients ranging from −0.06 to 0.65, whereas the region of interest analysis provided Pearson’s and concordance correlation coefficients of 0.88 and 0.80, respectively. Additionally, the ratio of positive to negative proliferation values was used to separate the treated and control animals (p <0.05) at an earlier point than the mean ADC values. These results further illustrate how quantitative measurements of tumor state obtained non-invasively by imaging can be incorporated into mathematical models that predict tumor growth.

Swyer syndrome is known as pure gonadal dysgenesis. Individuals with Swyer syndrome are phenotypically female with unambiguously female genital appearance at birth, and normal Mullerian structures. The condition usually first becomes apparent in adolescence with delayed puberty and amenorrhea due to the fact that the gonads have no hormonal or reproductive potential. These individuals are characterized by 46XY karyotype, primary amenorrhea, tall stature, female external genitalia and normal but hypoestrogenised vagina and cervix. A high incidence of gonadoblastoma and germ cell malignancies has been reported in dysgenetic gonads, and therefore, the current practice is to proceed to a gonadectomy once the diagnosis is made. Herein, we report a case of gonadoblastoma and dysgerminoma diagnosed on touch preparation in a dysgenetic gonad of a 16-year-old patient with Swyer syndrome., (Copyright © 2010 Wiley-Liss, Inc.)

In this paper we consider chemotherapy in a spatial model of tumor growth. The model, which is of reaction-diffusion type, takes into account the complex interactions between the tumor and surrounding stromal cells by including densities of endothelial cells and the extra-cellular matrix. When no treatment is applied the model reproduces the typical dynamics of early tumor growth. The initially avascular tumor reaches a diffusion limited size of the order of millimeters and initiates angiogenesis through the release of vascular endothelial growth factor (VEGF) secreted by hypoxic cells in the core of the tumor. This stimulates endothelial cells to migrate towards the tumor and establishes a nutrient supply sufficient for sustained invasion. To this model we apply cytostatic treatment in the form of a VEGF-inhibitor, which reduces the proliferation and chemotaxis of endothelial cells. This treatment has the capability to reduce tumor mass, but more importantly, we were able to determine that inhibition of endothelial cell proliferation is the more important of the two cellular functions targeted by the drug. Further, we considered the application of a cytotoxic drug that targets proliferating tumor cells. The drug was treated as a diffusible substance entering the tissue from the blood vessels. Our results show that depending on the characteristics of the drug it can either reduce the tumor mass significantly or in fact accelerate the growth rate of the tumor. This result seems to be due to complicated interplay between the stromal and tumor cell types and highlights the importance of considering chemotherapy in a spatial context.

Objective: The aim of this prospective study was to evaluate differences in contrast enhancement and contrast enhancement kinetics in benign versus malignant ovarian masses with pulse inversion harmonic transvaginal sonography., Methods: Seventeen consecutive patients with 23 morphologically abnormal ovarian masses (solid or cystic with papillary excrescences, focally thickened walls, or irregular solid areas) smaller than 10 cm received a microbubble contrast agent intravenously while undergoing pulse inversion harmonic transvaginal sonography. The following parameters were assessed in all tumors: detectable contrast enhancement, time to peak enhancement (wash-in), peak contrast enhancement, half wash-out time, and area under the enhancement curve. Tumor histologic analysis was used to distinguish benign from malignant ovarian tumors., Results: Fourteen benign masses and 9 malignancies were studied. There was a statistically significant difference in the peak enhancement (mean +/- SD, 23.3 +/- 2.8 versus 12.3 +/- 3.9 dB; P < .01), half wash-out time (139.9 +/- 43.6 versus 46.3 +/- 19.7 seconds; P < .01), and area under the enhancement curve (2012.9 +/- 532.9 versus 523.9 +/- 318 seconds(-1); P < .01) in malignant masses compared with benign disease. There was no statistically significant difference in the time to peak enhancement (26.1 +/- 6.3 versus 24.9 +/- 7.6 seconds; P = .07)., Conclusions: Overall, our data showed a significant difference in the contrast enhancement kinetic parameters between benign and malignant ovarian masses.

Study Objective: To determine if screening for coagulation disorders was routinely performed during the evaluation of adolescents with abnormal uterine bleeding., Design: A retrospective chart review. Data were analyzed using the chi-square test. P < 0.05 was considered significant., Setting: Outpatient clinics of an academic center., Participants: Eligible charts of patients age eighteen years and under with abnormal uterine bleeding who were evaluated either by pediatric gynecologists, gynecologists, or pediatricians., Interventions: A chart review., Main Outcome Measures: Data on provider type, documented patient history and laboratory tests ordered., Results: In our review, 43% (n= 36) of patients were evaluated by gynecologists, 38% (n=32) by pediatricians and 19% (n=16) by pediatric gynecologists. The mean age of patients whose charts were reviewed was 15 years. Overall 36.6% (n=30) of providers indicated that they screened for a bleeding disorder by documenting at least one screening question in the patient's history. There was a significant difference among providers with 68.8% (n=11) of pediatric gynecologists documenting at least one screening question, compared to 31.4% (n=11) of gynecologists and 25.8% (n=8) of pediatricians (P < 0.05). Overall 14.6% (n=12) of subjects were screened for a coagulation disorder with laboratory testing., Conclusions: The majority of adolescents with abnormal uterine bleeding were not screened for bleeding disorders. The frequency of evaluation for blood dyscrasias varied by specialty.

Purpose: Most HIV-infected persons are now treated as ambulatory patients. Obtaining continually updated data about these patients' changing conditions, therapies, and reimbursement is essential to health care provision and planning. The systematic tracking of patient medical and laboratory information in an ongoing commercial data collection program (The Health Research Network) allows clinicians to better understand health outcomes, practice patterns, and epidemiologic trends for their patients., Methods: To evaluate trends in conditions and therapies of ambulatory HIV-infected patients, we analyzed such data electronically and prospectively collected in the HIV Outpatient Study (HOPS) from 1992 through 1996 from 1876 patients seen in 11,755 clinic visits to ten HIV clinical practices., Results: Patients were as likely to be diagnosed with Mycobacterium avium complex ([MAC] 5.4 cases per 100 person-years) or wasting syndrome (7.8 cases per 100 person-years), as Pneumocystis carinii pneumonia ([PCP]; 7.6 cases per 100 person-years) or Kaposi sarcoma ([KS]; 6.9 cases per 100 person-years). A nested analysis showed that HIV-infected cigarette smokers were at substantially greater risk of pneumonia (relative hazard [RH] = 2.3), bronchitis (RH = 1.7) and hairy leukoplakia (RH = 1.9) than nonsmokers. By 1996, 35 (56%) of 62 patients with PCP, 9 (30%) of 30 patients with other pneumonias, 28 (90%) of 31 patients with KS, 35 (73%) of 48 patients with MAC, and 24 (63%) of 38 patients with cytomegalovirus retinitis were treated without hospitalization., Conclusions: The HOPS provides continually updated information on the changing characteristics, conditions, and therapy of ambulatory HIV-infected patients.

Background and Methods: National surveillance data show recent, marked reductions in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS). To evaluate these declines, we analyzed data on 1255 patients, each of whom had at least one CD4+ count below 100 cells per cubic millimeter, who were seen at nine clinics specializing in the treatment of human immunodeficiency virus (HIV) infection in eight U.S. cities from January 1994 through June 1997., Results: Mortality among the patients declined from 29.4 per 100 person-years in the first quarter of 1995 to 8.8 per 100 in the second quarter of 1997. There were reductions in mortality regardless of sex, race, age, and risk factors for transmission of HIV. The incidence of any of three major opportunistic infections (Pneumocystis carinii pneumonia, Mycobacterium avium complex disease, and cytomegalovirus retinitis) declined from 21.9 per 100 person-years in 1994 to 3.7 per 100 person-years by mid-1997. In a failure-rate model, increases in the intensity of antiretroviral therapy (classified as none, monotherapy, combination therapy without a protease inhibitor, and combination therapy with a protease inhibitor) were associated with stepwise reductions in morbidity and mortality. Combination antiretroviral therapy was associated with the most benefit; the inclusion of protease inhibitors in such regimens conferred additional benefit. Patients with private insurance were more often prescribed protease inhibitors and had lower mortality rates than those insured by Medicare or Medicaid., Conclusions: The recent declines in morbidity and mortality due to AIDS are attributable to the use of more intensive antiretroviral therapies.

Objective: To evaluate the efficacy and safety of oral famciclovir in the suppression of genital herpes., Methods: In this randomized, double-blind, placebo-controlled trial that was performed at 11 university and 9 private ambulatory care referral centers, 375 women who were 18 years of age or older and had a history of 6 or more episodes of genital herpes during 12 of the last 24 months in the absence of suppressive therapy were treated for 4 months with oral famciclovir, 125 mg once daily or twice daily, 250 mg once daily or twice daily, 500 mg once daily, or placebo. The primary outcome measures included the time to first clinically and virologically confirmed recurrences, and safety as measured by clinical laboratory tests and adverse experiences., Results: The median time to first recurrence was 82 days in the placebo group, 114 days in those receiving famciclovir, 125 mg once daily, and more than 120 days in the other treatment groups. When compared with placebo recipients, the time to the first clinical recurrence was significantly prolonged in subjects who received famciclovir, 125 mg twice daily (hazard ratio, 1.8; 95% confidence interval, 1.0-3.0; P = .03), and in those who received famciclovir, 250 mg twice daily (hazard ratio, 3.6; 95% confidence interval, 1.9-6.9; P < .001). Treatment was well tolerated, and there was no evidence of emergence of resistance during or after suppressive famciclovir therapy., Conclusions: Oral famciclovir, 250 mg, given twice daily for 4 months is an effective, well-tolerated treatment for the suppression of genital herpes in women with frequent recurrences, but single daily doses produced less complete suppression of genital herpes.

Background: We compared two combinations of nucleosides with zidovudine alone in patients with advanced human immunodeficiency virus (HIV) infection., Methods: A total of 1102 patients with the acquired immunodeficiency syndrome or fewer than 200 CD4 cells per cubic millimeter were randomly assigned to receive zidovudine alone or zidovudine combined with either didanosine or zalcitabine. Disease progression, survival, toxic effects, and the CD4 cell response were assessed., Results: After a median follow-up of 35 months, disease progression or death occurred in 62 percent of the 363 patients assigned to zidovudine plus didanosine, 63 percent of the 367 assigned to zidovudine plus zalcitabine, and 66 percent of the 372 assigned to zidovudine only (P=0.24). As compared with zidovudine therapy, treatment with zidovudine plus didanosine was associated with a relative risk of disease progression or death of 0.86 (95 percent confidence interval, 0.71 to 1.03), and treatment with zidovudine plus zalcitabine was associated with a relative risk of 0.92 (95 percent confidence interval, 0.76 to 1.10). Survival was similar in the three groups. In a subgroup analysis, combination therapy delayed disease progression or death in patients who had previously received zidovudine for 12 months or less. Therapy with zidovudine plus didanosine resulted in more gastrointestinal adverse effects, and treatment with zidovudine plus zalcitabine, more neuropathy. The mean increases in CD4 cell counts at two months were higher with combination therapy than with zidovudine alone., Conclusions: In patients with advanced HIV infection, combination therapy with zidovudine and either didanosine or zalcitabine is not superior to zidovudine therapy alone. However, these combinations may be more effective than zidovudine monotherapy in patients with little or no previous zidovudine treatment.

The HIV wasting syndrome and other HIV-associated weight loss is a major problem in HIV-infected patients. The available data strongly suggest that wasting is associated with decreased survival. It may also further impair immune function. A variety of etiologies probably contribute to this wasting, including hypermetabolism, alterations in metabolism, lessened oral intake, malabsorption, cytokine effects, and endocrine dysfunction. The relative contributions of each of these etiologies to wasting probably varies considerably from patient to patient. Successful treatment calls for identification of possible etiologies of wasting in the individual patient with AIDS. Further treatment may include treating underlying conditions and controlling such symptoms as diarrhea, nausea, or fever. Nutritional support, including both parenteral and enteral nutrition, has shown some promise of efficacy, and a variety of drugs appears to be helpful. Future treatment to reverse wasting may include the use of several of these agents in combination. Currently, there is much that clinicians can do to evaluate and treat the HIV wasting syndrome, with significant potential benefits to their patients.

Latent 2', 5'-oligoadenylate (2-5A) synthetase activity, bioactive 2-5A and RNase L activity were measured in extracts of peripheral blood mononuclear cells (PMBC) before and during a randomized, multicenter, placebo-controlled, double-blind study of poly(I)-poly(C12U) in individuals with chronic fatigue syndrome (CFS) as defined by the Centers for Disease Control and Prevention. The mean values for bioactive 2-5A and RNase L activity were significantly elevated at baseline compared to controls (p < .0001 and p = .001, respectively). In individuals that presented with elevated RNase L activity at baseline, therapy with poly(I)-poly(C12U) resulted in a significant decrease in both bioactive 2-5A and RNase L activity (p = .09 and p = .005, respectively). Decrease in RNase L activity in individuals treated with poly(I)-poly(C12U) correlated with cognitive improvement (p = .007). Poly(I)-poly(C12U) therapy resulted in a significant decrease in bioactive 2-5A and RNase L activity in agreement with clinical and neuropsychological improvements (Strayer DR, et al., Clin. Infectious Dis. 18:588-595, 1994). The results described show that poly(I)-poly(C12U) is a biologically active drug in CFS.

We compared endocrine function in patients with the HIV wasting syndrome with other HIV-positive patients without wasting to determine associations between endocrine dysfunction and wasting. Sixty-six HIV-seropositive patients were evaluated by thyroid, gonadal, and adrenal function tests. Fourteen of these patients met the clinical definition of wasting. Total and free testosterone levels were significantly lower in patients with wasting compared with patients without wasting with both similar and higher mean CD4 counts. Prolactin levels were significantly higher, and cortisol levels were higher with borderline significance in patients with wasting compared with patients with similar CD4 counts without wasting. These findings suggest that endocrine function in the HIV wasting syndrome differs from that of HIV-infected patients without wasting, which may have implications about the pathogenesis and treatment of the HIV wasting syndrome.

Chronic fatigue syndrome (CFS) is a physically debilitating illness associated with immunologic abnormalities, viral reactivation, and impairment of cognition. In a randomized, multicenter, placebo-controlled, double-blind study of 92 patients meeting the CFS case definition of the Centers for Disease Control and Prevention, the response of several laboratory and clinical variables to an antiviral and immunomodulatory drug, poly(I).poly(C12U), was determined. Measures of clinical response included Karnofsky performance score, a cognition scale derived from a self-administered instrument assessing symptomatology (SCL-90-R), an activities of daily living scale, and exercise treadmill performance. After 24 weeks, patients receiving poly(I).poly(C12U) had higher scores for both global performance and perceived cognition than did patients receiving placebo. In particular, patients given poly(I).poly(C12U) had increased Karnofsky performance scores (P < .03), exhibited a greater ability to do work during exercise treadmill testing (P = .01), displayed an enhanced capacity to perform the activities of daily living (P < .04), had a reduced cognitive deficit (P = .05), and required less use of other medications (P < .05).

Objective: We measured micronutrient values in patients with the HIV wasting syndrome and in other HIV-seropositive patients to determine whether specific micronutrient deficiencies were associated with the wasting syndrome., Methods: Serum from 47 HIV-seropositive patients was evaluated for concentrations of vitamin A, B6, B12, C, D, E, folate, the mineral zinc, carotene and glutathione. Comparisons were made between groups stratified by CD4 cell count and wasting/non-wasting status., Results: Mean serum levels were significantly lower for vitamin A (P = 0.04), folate (P = 0.04) and carotene (P = 0.06) in patients with the HIV wasting syndrome than in non-wasting patients with comparable CD4 cell counts. Values of vitamins A, B6, C, D, carotene and glutathione were below the normal range in over 10% of HIV-seropositive patients in this study., Conclusion: Decreased micronutrient concentrations are common in HIV-infected patients and occur more frequently in patients with the wasting syndrome. Clinicians may wish to evaluate HIV-seropositive patients with wasting for individual micronutrient deficiencies, although they should note that particular deficiencies may be only part of the larger picture of malabsorption and undernutrition.