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Background Melanoma-associated antigen H1 (MAGEH1) is a protein that belongs to melanoma-associated antigen (MAGE) superfamily. Growth arrest and DNA damage 45G (GADD45G) is a member of the DNA damage-inducible gene family which responds to environmental stresses. We have previously shown that GADD45G is a protein that promotes apoptosis of renal tubular cells in response to a nephrotoxic injury. In this study, we show evidence that MAGEH1 interacts with GADD45G and is involved in the induction of nephrotoxin-induced apoptosis of renal tubular cells. Methods Primary human renal tubular epithelial (HRE) cells and human kidney 2 (HK-2) cells were used in this study. To produce stable cell lines in which MAGEH1 expression was silenced, HRE cells were transduced with a lentiviral vector encoding a single guide RNA construct targeting the MAGEH1 gene. To knockdown GADD45G expression in HRE cells, a vector containing short hairpin RNA (shRNA) was used. We used short interfering RNAs (siRNA) to achieve transient silencing of genes in HK-2 cells. Recombinant adenoviruses were synthesized to overexpress MAGEH1 and GADD45G proteins. Human protein microarray was used to identify proteins that binds to GADD45G. Co-immunoprecipitation assays were then performed to confirm microarray results. Cell death was induced by cyclosporine A (CsA). Real-time quantitative PCR assay was used to evaluate gene expression levels. The degree of apoptosis and necrosis of cultured cells was evaluated by flow cytometry. Expression levels of caspases were examined using western blot analysis. Results We found that GADD45G bound to one protein spotted in the protein microarray, which was subsequently identified as MAGEH1. We confirmed the interaction between GADD45G and MAGEH1 protein using the co-immunoprecipitation assay. MAGEH1 gene expression was not altered by CsA-induced cytotoxic injury, whereas GADD45G gene expression was increased significantly upon CsA treatment. MAGEH1 expression was significantly downregulated in GADD45G knockdown HRE stable cells suggesting that MAGEH1 expression may be dependent on GADD45G expression. CsA-induced apoptosis was significantly reduced in MAGEH1 knockdown HRE stable cells which led to an increased survival of these cells. Similar results were observed in GADD45G knockdown HRE stable cells. Accordingly, CsA-induced apoptosis was significantly decreased in MAGEH1 siRNA and GADD45G siRNA transfected HK-2 cells. CsA-induced activation of caspase-7 and caspase-9 was inhibited in MAGEH1 knockdown HRE stable cells, and similarly in GADD45G knockdown HRE stable cells. Conclusions To the best of our knowledge, this is the first study to show that MAGEH1 interacts with GADD45G and that MAGEH1 is involved in caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

IntroductionPsychological factors such as anxiety and confidence that students have in the patient care situation are important in that this affects the actual clinical performance. Students who are just starting clinical practice have a lack of clinical knowledge, skill proficiency, and patient communication skills, so they experience anxiety and lack of confidence in clinical setting. Practice in a safe environment, such as simulation education, can help students perform more settled and competently in patient care. The purpose of this study was to analyze the effect of high-fidelity simulation experience on anxiety and confidence in medical students.Materials and methodsThis study enrolled 37 5th-year students at Ajou University School of Medicine in 2020. Two simulation trainings were implemented, and a survey was conducted to measure students' level of anxiety and confidence before and after each simulation. Based on the research data, a paired t-test was conducted to compare these variables before and after the simulation, and whether this was their first or second simulation experience.ResultsStudents had a significantly lower level of anxiety and a significantly higher level of confidence after the simulation than before. In addition, after one simulation experience, students had less anxiety and more confidence before the second simulation compared to those without simulation experience.ConclusionsWe confirmed that medical students need to be repeatedly exposed to simulation education experiences in order to have a sense of psychological stability and to competently deliver medical treatment in a clinical setting. There is a practical limitation in that medical students do not have enough opportunities to meet the patients during clinical practice in hospitals. Therefore, in order to produce excellent doctors, students should have the expanded opportunities to experience simulation education so they can experience real-world medical conditions.

It can be difficult for anesthesiologists to determine the optimal dose of propofol for end-stage kidney disease (ESKD) patients due to changes in drug disposition. The purpose of this study was to evaluate the potency of propofol for inducing loss of consciousness in ESKD patients. Patients with normal kidney function (Control group, n = 15), those with ESKD (ESKD group, n = 15), and those with ESKD undergoing cervical epidural anesthesia (ESKD-CEB group, n = 15) were administered propofol by target-controlled infusion (TCI) using the Schneider model. The effect-site concentration (Ce) of propofol started at 0.5 μg/ml and increased in increments of 0.5 μg/ml until the patient did not respond to verbal commands. The relationship between the probability (P) of loss of consciousness and the Ce of propofol was analyzed in each group using logistic regression. The Ce values of propofol at the time of loss of consciousness were 4.3 ± 0.9, 3.7 ± 0.9, and 3.3 ± 1.0 μg/ml for the Control, ESKD, and ESKD-CEB* groups, respectively (*significant difference vs. control, P < 0.05). The estimated Ce50 values for lost ability to respond to verbal command were 4.56, 3.75, and 3.21 μg/ml for the Control, ESKD, and ESKD-CEB groups, respectively. In conclusion, when inducing anesthesia in ESKD patients, we recommend using an initial dose similar to that of patients with normal kidney function, or rather starting with a lower dose.

There have been no studies on the characteristics of parenteral nutrition (PN) supply for adult inpatients in South Korea. The aim of this retrospective multicenter cross sectional study was to investigate the current practice and characteristics of PN support in hospitalized adult patients in South Korea for the first time. This study was conducted retrospectively for the adult patients who were hospitalized and received PN in nine hospitals on August 1st, 2017 to October 30th, 2017. We evaluated the type of PN formulation, PN administration period, administration route, calories supplied, amount of protein supplied, and laboratory results. Among the 11,580 inpatient admissions on that day, 1,439 patients received PN (12.4%). The majority of enrolled patients (96.5%) used the commercial PN, of which 86.2% were multi-chamber. 71.2% of them received PN peripherally. The average in hospital PN duration was 17.8 ± 52.6 days. Patients received only 65.4 ± 25.4% calories of their target calories. The in-hospital mortality of enrolled patients was 22%. In South Korea, commercial PN was usually administered to hospitalized adult patients and in-hospital mortality in adult patients using PN was higher in South Korea compared to other countries. This study provides the characteristics and the PN support status of hospitalized adult patients receiving PN in South Korea.

PURPOSE:To assess the in vivo whole-brain relationship between uptake of [18F]THK-5351 on PET and cortical atrophy on structural MRI according to the presence and severity of Alzheimer's disease (AD). MATERIALS AND METHODS:Sixty-five participants (21 normal controls, 32 mild cognitive impairment [MCI] subjects, and 12 AD patients) were enrolled from a prospective multicenter clinical trial (NCT02656498). Structural MRI and [18F]THK-5351 PET were performed within a 2-month interval. Cortical volume and standardized uptake value ratios (SUVR) were calculated from MRI and PET images, respectively, for 35 FreeSurfer-derived cortical regions. Pearson's correlation coefficients between SUVR and cortical volume were calculated for the same regions, and correlated regions were compared according to disease severity and β-amyloid PET positivity. RESULTS:No significantly correlated regions were found in the normal controls. Negative correlations between SUVR and cortical volume were found in the MCI and AD groups, mainly in limbic locations in MCI and isocortical locations in AD. The AD group exhibited stronger correlations (r = -0.576-0.781) than the MCI group (r = 0.368-0.571). Hippocampal atrophy did not show any correlation with SUVR in the β-amyloid PET-negative group, but negatively correlated with SUVR (r = -0.494, P = .012) in the β-amyloid PET-positive group. CONCLUSIONS:Regional THK-5351 uptake correlated more strongly with cortical atrophy in AD compared with MCI, thereby demonstrating a close relationship between the neuro-pathologic process and cortical atrophy. Hippocampal atrophy was associated with both β-amyloid and THK-5351 uptake, possibly reflecting an interaction between β-amyloid and tau deposition in the neurodegeneration process.

BackgroundGrowth Arrest and DNA Damage 45γ (GADD45γ) is a member of the DNA damage-inducible gene family which responds to environmental stresses. Apoptosis is a critical mode of renal tubular cell death in nephrotoxin-induced acute kidney injury. In this study, we investigated the role of GADD45γ in renal tubular cell apoptosis induced by nephrotoxic drugs.MethodsPrimary human renal tubular epithelial (HRE) cells were used in this study. To derive stable cell lines in which GADD45γ expression was silenced, HRE cells were transduced with a plasmid encoding GADD45γ-specific shRNA. The recombinant adenovirus containing the GADD45γ gene was synthesized to overexpress GADD45γ protein. Cell death was induced by cisplatin and cyclosporine A (CsA). To prevent apoptotic cell death, pan-caspase inhibitor ZVAD-FMK was used. To prevent non-apoptotic cell death, necrostatin-1 and ferrostatin-1 were used. The degree of apoptosis and necrosis of cultured cells were evaluated by flow cytometry.ResultsExpression of the GADD45γ gene was significantly upregulated in response to treatment with CsA and cisplatin. Apoptosis and necrosis induced by these drugs were significantly reduced by silencing of GADD45γ, and significantly augmented by the overexpression of GADD45γ. The activation of caspase-3 and caspase-7 as well as caspase-9 induced by cisplatin or CsA was reduced by silencing of GADD45γ, and was augmented by the overexpression of GADD45γ, indicating that caspase activation is dependent on the expression of GADD45γ. ZVAD-FMK significantly inhibited apoptosis induced by cisplatin or CsA, indicating a role of caspases in mediating apoptotic cell death. ZVAD-FMK was effective to prevent necrosis as well, indicating that the observed necrosis was a secondary event following apoptosis at least in part.ConclusionsTo our knowledge, this is the first study to show that GADD45γ is required for the caspase-dependent apoptosis of renal tubular cells induced by nephrotoxic drugs.

To evaluate the patients' morphologic factors affecting radiation dose in pediatric chest CT.From November 2013 to May 2015, 315 pediatric chest CT scans were obtained using a CT scanner, and classified into 5 groups according to the patients' age. For each age group, the chest CT scans were divided into two subgroups. A cut-off value used was the 75th percentile of size-specific dose estimates (SSDE), age-specific diagnostic reference level (DRL): less than the 75th percentile of SSDE (Group A, n = 238) and greater than the 75th percentile of SSDE (Group B, n = 77). All CT scans were performed with the same protocol using automatic tube voltage selection and current modulation techniques. The morphologic factors of the patients including body mass index (BMI), arm angles, presence of medical devices in the scan field, and degree of off-centering within the CT gantry were compared between groups A and B.Group B showed narrower arm angles on scout and coronal reformatted images, higher frequency of the presence of devices and higher BMI than group A (P < 0.001, P < 0.001; P = 0.018, and P < 0.001, respectively). In multivariate analysis, narrower arm angles, the presence of devices on the scout images and higher BMI were independently associated with higher SSDE (P = 0.001, P = 0.037, and P < 0.001, respectively).During acquisition of the scout images, arms-down position and the presence of medical devices were associated with a high radiation dose above age-specific DRLs in pediatric chest CT, regardless of repositioning before the actual scanning. In addition, off-centering had no clinical impact on radiation dose in the routine practice.

Although advanced magnetic resonance imaging (MRI) techniques provide useful information for the differential diagnosis of intra-axial mass-like lesions, the specific diagnostic role of multimodal MRI over conventional magnetic resonance imaging (CMRI) alone in the differential diagnosis of mass-like lesions from a large heterogeneous cohort has not been studied. In this study, we aimed to determine the added value of a joint approach of diffusion-weighted imaging (DWI) and dynamic-susceptibility-contrast perfusion imaging (DSC-PWI) for diagnosis of intra-axial mass-like lesions, comparing them with CMRI alone. Furthermore, we performed these evaluations in a manner simulating clinical practice. Our institutional review board approved this retrospective study and waived the requirement for informed consent. A total of 1038 patients with intra-axial mass-like lesions were retrospectively recruited according to their histological and clinico-radiological diagnoses made between January 2005 and December 2014. All patients underwent CMRI, DWI and DSC-PWI. The diagnostic accuracy and confidence in diagnosing each type of intra-axial mass-like lesions, and for differentiating the intra-axial brain tumors from non-neoplastic lesions, were compared according to the MRI protocols. The disease-specific sensitivity of joint approach differed according to specific disease entities in diagnosing each disease category. Joint approach provided the best diagnostic accuracy for discriminating intra-axial brain tumors from non-neoplastic lesions, with high diagnostic accuracy (95.3-96.7%), specificity (82-84.0%), positive-predictive-value (97.0-97.3%), and negative-predictive-value (84.8-92.7%), with the reader's confidence values being significantly improved over those on CMRI alone (all p-values < 0.001). In conclusion, joint approach of DWI, DSC-PWI to CMRI helps to differentiate non-neoplastic lesions from intra-axial brain tumors, and improves diagnostic confidence compared with CMRI alone. The benefit from the combined imaging differs for each disease category; thus joint approach needs to be customized according to clinical suspicion.

To determine if perfusion in surgical cavity wall enhancement (SCWE) obtained in early post-treatment MR imaging can stratify time-to-progression (TTP) in glioblastoma.This study enrolled 60 glioblastoma patients with more than 5-mm-thick SCWEs as detected on contrast-enhanced MR imaging after concurrent chemoradiation therapy. Two independent readers categorized the shape and perfusion state of SCWEs as nodular or non-nodular and as having positive or negative perfusion compared with the contralateral grey matter on arterial spin labeling (ASL). The perfusion fraction on ASL within the contrast-enhancing lesion was calculated. The independent predictability of TTP was analyzed using the Kaplan-Meier method and Cox proportional hazards modelling.The perfusion fraction was higher in the non-progression group, significantly for reader 2 (P = 0.03) and borderline significantly for reader 1 (P = 0.08). A positive perfusion state and (P = 0.02) a higher perfusion fraction of the SCWE were found to become an independent predictor of longer TTP (P = 0.001 for reader 1 and P < 0.001 for reader 2). The contrast enhancement pattern did not become a TTP predictor.Assessment of perfusion in early post-treatment MR imaging can stratify TTP in patients with glioblastoma for adjuvant temozolomide therapy. Positive perfusion in SCWEs can become a predictor of a longer TTP.

Distinguishing non-neoplastic pituitary stalk lesions (non-NPSLs) from neoplastic pituitary stalk lesions (NPSLs) is a major concern in guiding treatment for a thickened pituitary stalk. Our study aimed to aid provide preoperative diagnostic assistance by combining clinical and magnetic resonance imaging (MRI) findings to distinguish non-NPSLs from NPSLs.We recruited 158 patients with thickened pituitary stalk lesions visible on MRI. Laboratory findings included hypopituitarism, diabetes insipidus (DI), and hyperprolactinemia. MR images were assessed for anterior-posterior thickness (mm), diffuse pituitary stalk thickening, cystic changes, a high T1 signal, and glandular or extrasellar involvement. A diagnostic model was developed using a recursive partitioning logistic regression analysis. The model was validated in an independent dataset comprising 63 patients, and its diagnostic performance was compared with that of the original radiological reports.A univariate analysis found significant associations of DI (P = 0.006), absence of extrasellar involvement (P = 0.002), and lower stalk thickness (P = 0.031) with non-NPSLs. A diagnostic model was created using the following parameters (in order of priority): 1) lack of extrasellar involvement, 2) stalk thickness < 5.3 mm, and 3) presence of DI. The diagnostic performance (area under the curve; AUC) of this model in the independent set was 0.813, representing a significant improvement over the original radiological reports (AUC: 0.713, P = 0.029).The joint diagnostic approach based on clinical and imaging-based factors robustly distinguished non-NPSLs from NPSLs. This approach could guide treatment strategies and prevent unnecessary surgery in patients with non-NPSL.

To determine whether multiple repeated administrations of gadolinium-based macrocyclic ionic MR contrast agent (MICA) are associated with intracranial gadolinium deposition and identify the predisposing factors for deposition in various clinical situations.In this institutional review board-approved retrospective study, 385 consecutive patients who underwent MICA-enhanced MR imaging were enrolled. The dentate nucleus-to-pons (DN/P) and globus pallidus-to-thalamus (GP/Th) signal intensity (SI) ratios on unenhanced T1-weighted images were recorded by 2 independent readers and averaged. The mean DN/P and GP/Th SI ratio difference between the last and the first examinations were tested using the one-sample t-test. Student's t-test and stepwise regression analysis were used to identify the predisposing factors for deposition based on the number of administrations, time interval, hepatic and renal function, magnetic field strength, and chemo- or radiation therapy.The mean DN/P SI ratio difference was not different from zero (P = .697), even in patients with ≥20 administrations (n = 33). Only patients with abnormal renal function showed an increase in the mean DN/P SI ratio difference (P = .019). The mean DN/P SI ratio difference was not associated with any predisposing factors. However, the mean GP/Th SI ratio difference showed decrease (P < .001), which was associated with age (P = .007), number of administrations (P = .01) and number of radiation therapy sessions (P = .022) on multivariate analysis.Multiple repeated administrations of MICA were not associated with increased T1 signal intensity in deep brain nuclei suggestive of Gd deposition in patients with normal renal function.

Carfilzomib (CFZ) is a peptide epoxyketone proteasome inhibitor approved for the treatment of multiple myeloma (MM). Despite the remarkable efficacy of CFZ against MM, the clinical trials in patients with solid cancers yielded rather disappointing results with minimal clinical benefits. Rapid degradation of CFZ in vivo and its poor penetration to tumor sites are considered to be major factors limiting its efficacy against solid cancers. We previously reported that polymer micelles (PMs) composed of biodegradable block copolymers poly(ethylene glycol) (PEG) and poly(caprolactone) (PCL) can improve the metabolic stability of CFZ in vitro. Here, we prepared the CFZ-loaded PM, PEG-PCL-deoxycholic acid (CFZ-PM) and assessed its in vivo anticancer efficacy and pharmacokinetic profiles. Despite in vitro metabolic protection of CFZ, CFZ-PM did not display in vivo anticancer efficacy in mice bearing human lung cancer xenograft (H460) superior to that of the clinically used cyclodextrin-based CFZ (CFZ-CD) formulation. The plasma pharmacokinetic profiles of CFZ-PM were also comparable to those of CFZ-CD and the residual tumors that persisted in xenograft mice receiving CFZ-PM displayed an incomplete proteasome inhibition. In summary, our results showed that despite its favorable in vitro performances, the current CFZ-PM formulation did not improve in vivo anticancer efficacy and accessibility of active CFZ to solid cancer tissues over CFZ-CD. Careful consideration of the current results and potential confounding factors may provide valuable insights into the future efforts to validate the potential of CFZ-based therapy for solid cancer and to develop effective CFZ delivery strategies that can be used to treat solid cancers.

The purpose of this study was to evaluate the accuracy of diffusion-weighted imaging (DWI) and dynamic contrast-enhanced (DCE) perfusion MR imaging for distinguishing tumor recurrence from post-treatment effect as alternatives to dynamic-susceptibility contrast-enhanced (DSC) perfusion MR imaging when the DSC image is uninterpretable.This retrospective study was approved by our institutional review board. Seventy one post-treatment glioblastoma patients who showed enlarged contrast-enhancing lesions on follow-up MR images after concurrent chemoradiotherapy and uninterpretable DSC images for corresponding enhancing lesions, underwent additional DWI and DCE MR imaging. The primary outcome was the frequency of interpretable DWI and DCE MR cases in these 71 patients. The secondary outcome was the area under the receiver operating characteristic curve (AUC) of DWI and DCE imaging parameters for distinguishing tumor recurrence from post-treatment effect in selected patients with interpretable DWI and DCE images. The imaging parameters were quantified as 10% cumulative histogram cutoff of apparent diffusion coefficient (ADC10) and 90% cumulative histogram cutoff of initial area under the time signal intensity curve (IAUC90). The AUCs were cross-validated by using leave-one-out method.Of the 71 patients, the uninterpretable DSC images were associated with treatment-related hemorrhage within the corresponding enhancing lesions (n = 54, 76.1%) and a near skull base location (n = 17, 23.9%). The frequencies of interpretable DWI and DCE image were 51 (71.8%) and 59 (83.1%) of the 71 cases with uninterpretable DSC images, respectively. Of the 45 selected patients with interpretable DWI and DCE images, the combination of DWI with DCE imaging showed a superior diagnostic performance than DWI or DCE imaging alone for differentiating tumor recurrence from post-treatment effect (cross-validated AUC: 0.78 versus 0.55 and 0.73 for reader 1; cross-validated AUC: 0.78 versus 0.53 and 0.75 for reader 2, respectively). Cross-validated accuracy of the single and combined imaging parameters also showed the highest for the combination of DWI with DCE MR imaging (72.9% for reader 1; 72.5% for reader 2) and the lowest for DWI alone (54.0% for reader 1; 56.4% for reader 2). Inter-reader agreement for DCE imaging was higher than that for DWI (intraclass correlation coefficient: 0.95 versus 0.87).DCE MR imaging could be a superior and more reproducible imaging biomarker than DWI for differentiating tumor recurrence from post-treatment effect in patients with post-treatment glioblastoma when DSC MR images are not interpretable.

The proteasome is a key regulator of cellular protein homeostasis and is a clinically validated anticancer target. The immunoproteasome, a subtype of proteasome expressed mainly in hematopoietic cells, was initially recognized for its role in antigen presentation during the immune response. Recently, the immunoproteasome has been implicated in several disease conditions including cancer and autoimmune disorders, but many of the factors contributing to these pathological processes remain unknown. In particular, the codon 60 polymorphism of the PSMB9 gene encoding the β1i immunoproteasome catalytic subunit has been investigated in the context of a variety of diseases. Despite this, previous studies have so far reported inconsistent findings regarding the impact of this polymorphism on proteasome activity. Thus, we set out to investigate the impact of the PSMB9 codon 60 polymorphism on the expression and activity of the β1i immunoproteasome subunit in a panel of human cancer cell lines. The β1i-selective fluorogenic substrate Acetyl-Pro-Ala-Leu-7-amino-4-methylcoumarin was used to specifically measure β1i catalytic activity. Our results indicate that the codon 60 Arg/His polymorphism does not significantly alter the expression and activity of β1i among the cell lines tested. Additionally, we also examined the expression of β1i in clinical samples from colon and pancreatic cancer patients. Our immunohistochemical analyses showed that ≈ 70% of clinical colon cancer samples and ≈ 53% of pancreatic cancer samples have detectable β1i expression. Taken together, our results indicate that the β1i subunit of the immunoproteasome is frequently expressed in colon and pancreatic cancers but that the codon 60 genetic variants of β1i display similar catalytic activities and are unlikely to contribute to the significant inter-cell-line and inter-individual variabilities in the immunoproteasome activity.

To compare the clinical outcomes and cost-effectiveness of routine HIV screening in Portugal to the current practice of targeted and on-demand screening.We used Portuguese national clinical and economic data to conduct a model-based assessment.We compared current HIV detection practices to strategies of increasingly frequent routine HIV screening in Portuguese adults aged 18-69. We considered several subpopulations and geographic regions with varying levels of undetected HIV prevalence and incidence. Baseline inputs for the national case included undiagnosed HIV prevalence 0.16%, annual incidence 0.03%, mean population age 43 years, mean CD4 count at care initiation 292 cells/μL, 63% HIV test acceptance, 78% linkage to care, and HIV rapid test cost €6 under the proposed routine screening program. Outcomes included quality-adjusted survival, secondary HIV transmission, cost, and incremental cost-effectiveness.One-time national HIV screening increased HIV-infected survival from 164.09 quality-adjusted life months (QALMs) to 166.83 QALMs compared to current practice and had an incremental cost-effectiveness ratio (ICER) of €28,000 per quality-adjusted life year (QALY). Screening more frequently in higher-risk groups was cost-effective: for example screening annually in men who have sex with men or screening every three years in regions with higher incidence and prevalence produced ICERs of €21,000/QALY and €34,000/QALY, respectively.One-time HIV screening in the Portuguese national population will increase survival and is cost-effective by international standards. More frequent screening in higher-risk regions and subpopulations is also justified. Given Portugal's challenging economic priorities, we recommend prioritizing screening in higher-risk populations and geographic settings.

The World Health Organization (WHO) has called for the "virtual elimination" of pediatric HIV: a mother-to-child HIV transmission (MTCT) risk of less than 5%. We investigated uptake of prevention of MTCT (PMTCT) services, infant feeding recommendations, and specific drug regimens necessary to achieve this goal in Zimbabwe.We used a computer model to simulate a cohort of HIV-infected, pregnant/breastfeeding women (mean age, 24 y; mean CD4, 451/µl; breastfeeding duration, 12 mo). Three PMTCT regimens were evaluated: (1) single-dose nevirapine (sdNVP), (2) WHO 2010 guidelines' "Option A" (zidovudine in pregnancy, infant nevirapine throughout breastfeeding for women without advanced disease, lifelong combination antiretroviral therapy for women with advanced disease), and (3) WHO "Option B" (pregnancy/breastfeeding-limited combination antiretroviral drug regimens without advanced disease; lifelong antiretroviral therapy with advanced disease). We examined four levels of PMTCT uptake (proportion of pregnant women accessing and adhering to PMTCT services): reported rates in 2008 and 2009 (36% and 56%, respectively) and target goals in 2008 and 2009 (80% and 95%, respectively). The primary model outcome was MTCT risk at weaning. The 2008 sdNVP-based National PMTCT Program led to a projected 12-mo MTCT risk of 20.3%. Improved uptake in 2009 reduced projected risk to 18.0%. If sdNVP were replaced by more effective regimens, with 2009 (56%) uptake, estimated MTCT risk would be 14.4% (Option A) or 13.4% (Option B). Even with 95% uptake of Option A or B, projected transmission risks (6.1%-7.7%) would exceed the WHO goal of less than 5%. Only if the lowest published transmission risks were used for each drug regimen, or breastfeeding duration were shortened, would MTCT risks at 95% uptake fall below 5%.Implementation of the WHO PMTCT guidelines must be accompanied by efforts to improve access to PMTCT services, retain women in care, and support medication adherence throughout pregnancy and breastfeeding, to approach the "virtual elimination" of pediatric HIV in Zimbabwe. Please see later in the article for the Editors' Summary.