Early intervention and disease modification in atopic dermatitis-the current state of the field and barriers to progress.

Atopic dermatitis (AD) is a highly prevalent chronic inflammatory skin disease representing a major source of global disability burden. Disease-modifying therapies are showing promise in chronic inflammatory disorders such as rheumatoid arthritis and Crohn's disease with method and timing of initial treatment impacting long-term disease outcomes. Whether disease-modifying therapies, specifically those used as an early interventional approach, impacts disease course and comorbidity development in AD is not well-understood. We reviewed the progress in disease modification strategies, emphasizing early intervention approaches in common (or proto-typical) inflammatory diseases. Although more common in other fields, disease modification approaches are becoming increasingly investigated in dermatology, though studies in AD are lacking. Despite significant limitations in ongoing and completed studies, early data are promising and suggest that both the choice and timing of early intervention approach can affect long-term disease course and comorbidity development. To best improve AD patient outcomes, more research is needed to further explore the impact of early disease-modifying therapies. Future studies should focus on identifying the most effective approaches and extend the early results to a more inclusive set of comorbidities and longer-term outcomes.

The Eczema Area and Severity Index: An update of progress and challenges in its measurement of atopic dermatitis after 20 years of use.

The Eczema Area and Severity Index is an investigator-assessed instrument reporting clinical signs of atopic dermatitis. The instrument is extensively validated in both adult and paediatric populations and recommended as a core outcome measure to assess clinical signs by the Harmonising Outcome Measures for Eczema initiative in clinical trials and was recently recommended as an option to measure signs in clinical practice. Here, we review the validation of the instrument using standard assessment criteria, explore controversies and challenges to its universal applicability and highlight future electronic adaptations. We find that the instrument demonstrates adequate performance in the measurement properties recommended by the COnsensus-based Standards for the selection of health Measurement INstruments initiative for instruments reporting clinical signs, is clinically interpretable, and is suitable for all atopic dermatitis severities. Some validation gaps remain. Information reporting on its performance in diverse populations, with emphasis on deeply pigmented skin, is promising though limited. Technological adaptations are demonstrating promising initial validation results and may facilitate remote and/or automated assessments assisting clinical care and decentralized clinical trials in the future. We find no strong evidence limiting its use in trials or clinical practice although questions pertaining to the effect of investigator training remain. We recommend that the Eczema Area and Severity Index be used in all interventional atopic dermatitis trials and be considered alongside other recommended clinical practice severity instruments.

Providers' perspectives on the reproductive decision-making of BRCA-positive women.

BACKGROUND: Reproductive decision-making is difficult for BRCA-positive women. Our objective was to assess the complexities of decision-making and identify decisional supports for patients and providers when discussing reproductive options prior to risk-reducing salpingo-oophorectomy (RRSO). METHODS: This study was of qualitive design, using data collection via semi-structured interviews conducted from November 2018 to October 2020. Individuals were included if they were identified to provide care to BRCA-positive women. In total, 19 providers were approached and 15 consented to participate. Providers were recruited from three clinics in Toronto, Ontario located at academic centers: [1] A familial ovarian cancer clinic, [2] A familial breast cancer clinic and [3] A fertility clinic, all of which treat carriers of the BRCA1/BRCA2 genetic mutation. The interview guide was developed according to the Ottawa Decision Support Framework and included questions regarding reproductive options available to patients, factors that impact the decision-making process and the role of decisional support. Interviews were transcribed and transcripts were analyzed thematically using NVIVO 12. RESULTS: Providers identified three major decisions that reproductive-aged women face when a BRCA mutation is discovered: [1] "Do I want children?"; [2] "Do I want to take the chance of passing on this the mutation?"; and [3] "Do I want to carry a child?" Inherent decision challenges that are faced by both providers and patients included difficult decision type, competing options, scientifically uncertain outcomes, and challenging decision timing. Modifiable decisional needs included: inadequate knowledge, unrealistic expectations, unclear values and inadequate support or resources. Identified clinical gaps included counselling time constraints, lack of reliable sources of background information for patients or providers and need for time-sensitive, geographically accessible, and centralized care. CONCLUSION: Our study identified a need for a patient information resource that can be immediately provided to patients who carry a BRCA genetic mutation. Other suggestions for clinical practice include more time during consultation appointments, adequate follow-up, value-centric counseling, access to psychosocial support, and a specialized decisional coach.

The presence of antibiotic-resistant Staphylococcus spp. and Escherichia coli in smallholder pig farms in Uganda.

BACKGROUND: The development of antimicrobial resistance is of global concern, and is commonly monitored by the analysis of certain bacteria. The aim of the present study was to study the antibiotic susceptibility in isolates of Staphylococcus spp. and Escherichia (E.) coli obtained from healthy pigs originating from nineteen herds enrolled in a study on herd health management in Lira district, northern Uganda. Skin and nasal swabs were analyzed for the presence of Staphylococcus spp., and selectively cultivated to investigate the presence of methicillin-resistant Staphylococcus (S.) aureus (MRSA), and rectal swabs were analyzed for the presence of E. coli. Antibiotic susceptibility was tested by broth micro-dilution. Information on the antibiotic usage and treatment regimens during the previous year was gathered using structured interviews and longitudinal data. RESULTS: In Staphylococcus spp., resistance to penicillin (10/19 isolates; 53%), fusidic acid (42%) and tetracycline (37%) were most commonly found. In E. coli, resistance to sulfamethoxazole (46/52 isolates; 88%), tetracycline (54%) and trimethoprim (17%) was most frequent. Methicillin-resistant S. aureus was found in one sample (1/50; 2%). Multi-drug resistant isolates of Staphylococcus spp. and E. coli were found in 54 and 47% of the herds, respectively. At the herd level, no associations could be made between antibiotic resistance and herd size or treatment regimens for either of the bacteria. CONCLUSION: In conclusion, resistance to important antibiotics frequently used in animals in Uganda was common, and the presence of MRSA was demonstrated, in Ugandan pig herds.

Medical and gynecological comorbidities in adult women with Turner syndrome: our multidisciplinary clinic experience.

Objective: Women with Turner syndrome (TS) are at increased risk for chronic health conditions. Reports describing the presence of comorbidities in older adult women with TS are limited. This study aimed to examine the prevalence of endocrine, gynecological, and other chronic medical conditions in a cohort of adult TS patients.Methods: A retrospective chart review was conducted on patients seen between 1 February 2015 and 1 July 2018 in a multidisciplinary TS clinic at a university-based ambulatory hospital in Toronto, Canada. All women seen at the TS clinic with a diagnosis of TS aged >18 years were included. The prevalence of diseases was determined overall and stratified by age (<40 and ≥40 years). Statistical comparisons were done using the chi-square test. The main study outcomes included the presence of comorbidities.Results: Of 122 adult women with TS, 24.5% had hypothyroidism, 16% had dysglycemia, and 27.9% had decreased bone mass. Hypothyroidism and dysglycemia were more common among older women (respectively age ≥40 years vs. age <40 years: 36.7% vs. 17.8%, p = 0.018; and 24.5% vs. 5.5%, p = 0.023). Gynecological conditions were identified in 35% of patients and were more common among older women (42.8% age ≥40 years vs. 13.7% age <40 years, p = 0.003). Overall, 41% had hearing impairment, 36.1% had cardiac abnormalities, 14.8% had hypertension, 18.8% had renal abnormalities, and 9% had celiac disease.Conclusions: The results of this study indicate a high prevalence of medical conditions in women with TS, especially those ≥40 years of age. Our study underscores the importance of multidisciplinary adult TS clinics for ongoing screening and management of comorbidities.

Vulvovaginal graft-versus-host disease: a review.

Hematopoietic cell transplantation (HCT) is associated with well-described gynecologic sequelae, including vulvovaginal graft-versus-host disease (GVHD). Vulvovaginal GVHD is a common complication of allogeneic HCT, but has been under-reported in the literature. Guidelines have been published only recently to recommend common terminology, treatment, and surveillance. This review summarizes the presentation, management, and surveillance aspects of vulvovaginal GVHD. We recommend a standardized referral between women undergoing HCT and an experienced gynecologist capable of managing this disease and treating sexual side effects.

Exposure-safety and efficacy response relationships and population pharmacokinetics of eslicarbazepine acetate.

OBJECTIVES: Eslicarbazepine acetate (ESL) is a once-daily (QD) oral antiepileptic drug (AED) for focal-onset seizures (FOS). Pharmacokinetic (PK) and pharmacodynamic (PD) models were developed to assess dose selection, identify significant AED drug interactions, and quantitate relationships between exposure and safety and efficacy outcomes from Phase 3 trials of adjunctive ESL. METHODS: Eslicarbazepine (the primary active metabolite of ESL) population PK was evaluated using data from 1351 subjects enrolled in 14 studies (11 Phase 1 and three Phase 3 studies) after multiple oral doses ranging from 400 to 1200 mg. Population PK and PD models related individual eslicarbazepine exposures to safety outcomes and efficacy responses. RESULTS: Eslicarbazepine PK was described by a one-compartment model with linear absorption and elimination. The probability of a treatment-emergent adverse event (TEAE; dizziness, headache, or somnolence) was higher with an initial dose of ESL 800 mg than with an initial dose of ESL 400 mg QD. Body weight, sex, region, and baseline use of carbamazepine (CBZ) or lamotrigine were also found to influence the probability of TEAEs. Eslicarbazepine exposure influenced serum sodium concentration, standardized seizure frequency, and probability of response; better efficacy outcomes were predicted in patients not from Western Europe (WE; vs WE patients) and those not taking CBZ (vs taking CBZ) at baseline. CONCLUSIONS: Pharmacokinetic and PK/PD modeling were implemented during the development of ESL for adjunctive treatment of FOS in adults. This quantitative approach supported decision-making during the development of ESL, and contributed to dosing recommendations and labeling information related to drug interactions.

Correction to: Inflammatory markers before and after farrowing in healthy sows and in sows affected with postpartum dysgalactia syndrome.

The original article [1] contains an error whereby the caption in Figure 8 is incorrect; the correct caption can be seen ahead alongside its respective image.

Presence of Salmonella spp., Yersinia enterocolitica, Yersinia pseudotuberculosis and Escherichia coli O157:H7 in wild boars.

The European wild boar populations are growing and spreading to new areas, which might constitute a threat to public health, since wild boar can harbour pathogens with the potential to cause serious illness in humans. Tonsils, ileocaecal lymph nodes and faecal samples were collected from 88 Swedish wild boars and analysed for the presence of the zoonotic pathogens Salmonella spp., Yersinia enterocolitica, Y. pseudotuberculosis and enterohaemorrhagic Escherichia coli O157:H7 (EHEC). A combination of cultivation and polymerase chain reaction (PCR) analysis was used and overall, 20% of sampled individuals tested positive for Y. enterocolitica, 20% for Y. pseudotuberculosis and 10% for Salmonella spp. A total of 41% of sampled individuals tested positive for one or more of these three pathogens. No EHEC were detected. Samples PCR-positive for Salmonella spp. were cultivated further and six isolates were obtained, belonging to Salmonella enterica subspecies enterica and subspecies diarizone. The pathogens were most commonly detected in tonsil samples.

Aberrant dendritic cell function conditions Th2-cell polarization in allergic rhinitis.

BACKGROUND: Myeloid (m) and plasmacytoid (p) dendritic cells (DCs) regulate immune responses to allergens, whereas it remains unclear whether abnormal DC function characterizes patients with airway allergy and whether putative dysfunction exists only in target organs. To evaluate DC function from patients with allergic rhinitis (AR), we assessed nasal, cutaneous as well as blood DCs after in vivo and in vitro allergen challenge, respectively. METHODS: DCs were immunostained in nasal and skin tissues, and cytokine expression was assessed by dual immunofluorescence. Cytokine production and regulation of cocultured peripheral CD4+ T cells were assayed by ELISA. RESULTS: In AR patients, local allergen challenge resulted in increases in pDC and mDC numbers at 8 h in the nasal mucosa and at 8-48 h in the skin. Defects in IL-10 and IFN-α were observed in both organs from AR. Blood mDCs from AR exhibited reduced IL-10 and IL-12 expression. The capacity of activated pDCs from AR to produce IFN-α and to trigger IL-10 by allogeneic CD4(+) T cells was diminished, whereas mDCs from these patients supported Th2- and Th17-cell differentiation. CONCLUSION: In allergic rhinitis, DCs are altered not only locally but also in the systemic circulation. mDCs and pDCs increased in airway and skin tissues exposed to the allergen and displayed reduced production of IL-10 and 'type 1 signals' (IL-12, IFN-α) both locally and in blood. Functional studies showed that this results in preferential Th2/Th17-cell polarization and impaired generation by blood DCs of IL-10+ T cells, linking systemic DC dysfunction and biased T-cell responses.

Occurrence of pathogens in wild rodents caught on Swedish pig and chicken farms.

A total of 207 wild rodents were caught on nine pig farms, five chicken farms and five non-farm locations in Sweden and surveyed for a selection of bacteria, parasites and viruses. Lawsonia intracellularia and pathogenic Yersinia enterocolitica were only detected in rodents on pig farms (9% and 8% prevalence, respectively) which indicate that these agents are more likely to be transmitted to rodents from pigs or the environment on infected farms. Brachyspira hyodysenteriae (1%), Brachyspira intermedia (2%), Campylobacter jejuni (4%), Campylobacter upsaliensis (2%), leptospires (7%) and encephalomyocarditis virus (9%) were also detected from rodents not in contact with farm animals. Giardia and Cryptosporidium spp. were common, although no zoonotic types were verified, and Salmonella enterica was isolated from 1/11 mice on one farm but not detected by PCR from any of the rodents. Trichinella spp. and Toxoplasma gondii were not detected.

Niacin: vitamin and antidyslipidemic drug.

Niacin is defined collectively as nicotinamide and nicotinic acid, both of which fulfill the vitamin functions of niacin carried out by the bioactive forms NAD(P). In the last few decades numerous new enzymes that consume NAD(P) as substrates have been identified. The functions of these enzymes are emerging as exciting paradigm shifts, even though they are in early stages of discovery. The recent identification of the nicotinic acid receptor has allowed distinction of the drug-like roles of nicotinic acid from its vitamin functions, specifically in modulating blood lipid levels and undesirable side effects such as skin vasodilation and the more rare hepatic toxicities. This information has led to a new strategy for drug delivery for niacin, which, if successful, could have a major impact on human health through decreasing risk for cardiovascular disease. Understanding the many other effects of niacin has much broader potential for disease intervention and treatment in numerous diseases including cancer.

Folate in skin cancer prevention.

Skin, the largest, most exposed organ of the body, provides a protective interface between humans and the environment. One of its primary roles is protection against exposure to sunlight, a major source of skin damage where the UV radiation (UVR) component functions as a complete carcinogen. Melanin pigmentation and the evolution of dark skin is an adaptive protective mechanism against high levels of UVR exposure. Recently, the hypothesis that skin pigmentation balances folate preservation and Vitamin D production has emerged. Both micronutrients are essential for reproductive success. Photodegradation of bioactive folates suggests a mechanism for the increased tendency of populations of low melanin pigmentation residing in areas of high UV exposure to develop skin cancers. Folate is proposed as a cancer prevention target for its role in providing precursors for DNA repair and replication, as well as its ability to promote genomic integrity through the generation of methyl groups needed for control of gene expression. The cancer prevention potential of folate has been demonstrated by large-scale epidemiological and nutritional studies indicating that decreased folate status increases the risk of developing certain cancers. While folate deficiency has been extensively documented by analysis of human plasma, folate status within skin has not been widely investigated. Nevertheless, inefficient delivery of micronutrients to skin and photolysis of folate argue that documented folate deficiencies will be present if not exacerbated in skin. Our studies indicate a critical role for folate in skin and the potential to protect sun exposed skin by effective topical delivery as a strategy for cancer prevention.

Impact of a novel multilayer imager on metal artifacts in MV-CBCT.

Objective. Megavoltage cone-beam computed tomography (MV-CBCT) imaging offers several advantages including reduced metal artifacts and accurate electron density mapping for adaptive or emergent situations. However, MV-CBCT imaging is limited by the poor efficiency of current detectors. Here we examine a new MV imager and compare CBCT reconstructions under clinically relevant scenarios.Approach. A multilayer imager (MLI), consisting of four vertically stacked standard flat-panel imagers, was mounted to a clinical linear accelerator. A custom anthropomorphic pelvis phantom with replaceable femoral heads was imaged using MV-CBCT and kilovoltage CBCT (kV-CBCT). Bone, aluminum, and titanium were used as femoral head inserts. 8 MU 2.5 MV scans were acquired for all four layers and (as reference) the top layer. Prostate and bladder were contoured on a reference CT and transferred to the other scans after rigid registration, from which the structural similarity index measure (SSIM) was calculated. Prostate and bladder were also contoured on CBCT scans without guidance, and Dice coefficients were compared to CT contours.Main results. kV-CBCT demonstrated the highest SSIMs with bone inserts (prostate: 0.86, bladder: 0.94) and lowest with titanium inserts (0.32, 0.37). Four-layer MV-CBCT SSIMs were preserved with bone (0.75, 0.80) as compared to titanium (0.67, 0.74), outperforming kV-CBCT when metal is present. One-layer MV-CBCT consistently underperformed four-layer results across all phantom configurations. Unilateral titanium inserts and bilateral aluminum insert results fell between the bone and bilateral titanium results. Dice coefficients trended similarly, with four-layer MV-CBCT reducing metal artifact impact relative to KV-CBCT to provide better soft-tissue identification.Significance. MV-CBCT with a four-layer MLI showed improvement over single-layer MV scans, approaching kV-CBCT quality for soft-tissue contrast. In the presence of artifact-producing metal implants, four-layer MV-CBCT scans outperformed kV-CBCT by eliminating artifacts and single-layer MV-CBCT by reducing noise. MV-CBCT with a novel multi-layer imager may be a valuable alternative to kV-CBCT, particularly in the presence of metal.

Implementation of the HOME core outcome set for clinical trials of atopic eczema-barriers and opportunities: the HOME IX meeting report.

The Harmonising Outcome Measures for Eczema (HOME) initiative established a core outcome set (COS) for atopic eczema (AE) clinical trials in 2019. This set encompasses four core outcome domains and corresponding measurement instruments: clinical signs (EASI), patient-reported symptoms (POEM and NRS 11 point for worst itch over the last 24 h), quality of life (DLQI/CDLQI/IDQoLI), and long-term control (Recap or ADCT). Following its roadmap, the HOME initiative is now focused on supporting implementation of the COS. To identify barriers and facilitators to implementation of the COS, and to guide the effort to promote COS uptake, a virtual consensus meeting was held over 2 days (September 25-26, 2021) attended by 55 participants (26 healthcare professionals, 16 methodologists, 5 patients, 4 industry representatives, and 4 students). Implementation themes were identified by a pre-meeting survey distributed to HOME members, presentations, and whole-group discussion. Participants were divided into five multi-professional small groups which ranked their top 3 most important themes, followed by whole-group discussion and anonymous consensus voting (consensus criteria: < 30% disagreement). Three most important implementation themes were identified and agreed upon: (1) awareness and stakeholder engagement, (2) universal applicability of the COS, and (3) ensuring minimum administrative burden. Working groups to address these issues are now a priority for the HOME initiative. The results from this meeting will inform the development of a HOME Implementation Roadmap in an effort to support other COS groups planning for effective implementation of their core sets.

Reduced T-bet in addition to enhanced STAT6 and GATA3 expressing T cells contribute to human allergen-induced late responses.

BACKGROUND: T-bet and GATA-3 are transcriptional factors involved in Th1 and Th2 cell differentiation, although their concomitant roles at protein levels in target organs during human allergic disease have not been assessed. OBJECTIVES: We investigated the expression of T-bet and GATA-3 in nasal and cutaneous models of Th2 (grass-pollen allergen) and a cutaneous model of Th1 (PPD) responses in man. METHODS: Nasal biopsies were obtained at 8 h and skin biopsies at 8 and 48 h after allergen and PPD challenges, respectively, from 10 allergic rhinitics and 6 non-atopic controls. T cells were assessed using immunofluorescence microscopy. RESULTS: There were increases in CD3(+)STAT6(+)cells (P = 0.01 for nose and skin) and CD3(+)GATA3(+)cells (P = 0.03 for skin) in response to allergen compared with diluent in allergics. When compared with non-atopics after allergen challenge the difference between the two groups was also significant for CD3(+)STAT6(+) (P = 0.001 and 0.03) and for CD3(+)GATA3(+)cells (P = 0.04 and 0.001) for nose and skin respectively. Following PPD challenge CD3(+)STAT4(+)cells and CD3(+)T-bet(+)cells increased in both groups compared with diluent (P = 0.02 and 0.03 for both TFs), whereas only CD3(+)T-bet(+) cells were significantly greater in non-atopics compared with allergics (P = 0.04). The ratio of GATA3(+):T-bet(+) T cells in allergen-induced responses was significantly greater in the allergics (P = 0.008 and 0.01 nose and skin respectively), whereas the ratio of T-bet:GATA3(+)T cells was significantly higher in the non-atopics during PPD-induced responses (P = 0.003). CONCLUSIONS AND CLINICAL RELEVANCE: Dysregulation of Th1 transcription may contribute to heightened expression of STAT6 and GATA3 leading to exaggerated Th2-driven manifestations of allergic disease.

Modelling environmentally mediated spread of livestock-associated methicillin-resistant Staphylococcus aureus in a pig herd.

Infectious disease models are a useful tool to support within-herd disease control strategies. This study presents a stochastic compartment model with environmentally mediated transmission to represent the spread of livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) in a farrow-to-finish pig herd. The aims of the study were to (1) construct a model of the spread of LA-MRSA that included spread of LA-MRSA through the environment; (2) parameterise the model to fit previously published observational data in order to obtain realistic LA-MRSA transmission rates; (3) and to investigate how changes in the mixing of animals in the farrowing and finishing units may affect the prevalence of LA-MRSA in a herd. The results showed that indirect transmission allowed LA-MRSA to persist in the herd without the assumption of persistently shedding individuals. Reducing the mixing of pigs upon entry to the finishing unit was also shown to lower the LA-MRSA prevalence in the unit if the initial LA-MRSA level in the unit was low, but at high prevalence, no effect of mixing was identified. In the farrowing unit, changing the proportion of piglets that were cross-fostered did not affect the within-herd LA-MRSA prevalence. The study demonstrates that there are several important knowledge gaps regarding the shedding and transmission of LA-MRSA in different animal age groups and further experimental studies are needed. This work also provides a new, robust and flexible model framework for the investigation of control and mitigation strategies for LA-MRSA and other infections in a pig herd.

Tumor immunogenicity is determined by the mechanism of cell death via induction of heat shock protein expression.

In situ killing of tumor cells using suicide gene transfer to generate death by a non-apoptotic pathway was associated with high immunogenicity and induction of heat shock protein (hsp) expression. In contrast, a syngeneic colorectal tumor line, CMT93, killed predominantly by apoptosis, showed low levels of hsp expression and less immunogenicity. When apoptosis was inhibited in CMT93 cells by overexpression of bcl-2, hsp was also induced. Furthermore, when cDNA encoding hsp70 was stably transfected into B16 and CMT93 cells, its expression significantly enhanced the immunogenicity of both tumors. Increased levels of hsp, induced by non-apoptotic cell killing, may provide an immunostimulatory signal in vivo which helps break tolerance to tumor antigens. These findings have important implications for the development of novel anti-cancer therapies aimed at promoting patients' immune responses to their own tumors.

Restoration of cytomegalovirus-specific CD4+ T-lymphocyte responses after ganciclovir and highly active antiretroviral therapy in individuals infected with HIV-1.

Recent studies of subjects infected with human immunodeficiency virus (HIV-1) have produced conflicting results about the extent of reconstitution possible in the CD4+ lymphocyte repertoire after highly active antiretroviral therapy (HAART). The effect of HAART on the incidence of opportunistic infections will probably depend on reconstitution of antigen-specific CD4+ lymphocyte responses to important pathogens, including cytomegalovirus (CMV), the leading cause of blindness in AIDS. Several studies have demonstrated an important role for CD4+ lymphocytes in controlling CMV replication in vitro and in clinical studies. It is now possible to quantitate antigen-specific CD4+ lymphocyte responses by flow cytometry. Using this method, we studied CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 with and without a history of active CMV-associated end organ disease (EOD), and in those with quiescent CMV EOD after ganciclovir therapy and HAART. The presence of active CMV-associated EOD strongly correlated with loss of CMV-specific lymphocyte responses (P = 0.0004). In contrast, patients with no history of CMV-associated EOD and most patients with quiescent EOD after HAART demonstrated strong CMV-specific CD4+ lymphocyte responses. These data indicate that the loss of CMV-specific CD4+ lymphocyte responses in individuals infected with HIV-1 who have active CMV EOD may be restored after ganciclovir therapy and HAART, which provides evidence for functional immune reconstitution to an important pathogen.