Assessing progression of health technology assessment implementation in Asia: a balanced scorecard for cross comparison of selected countries in Asia.

OBJECTIVE: To provide an update on the use of health technology assessment (HTA) in Asia and lessons for countries seeking to advance HTA. METHODS: Build upon the research by Chootipongchaivat and the World Health Organization identifying eighteen "factors conducive to the development of HTA in Asia." These factors were used to create a balanced scorecard to assess the progress of HTA, measuring progress against each factor in China, India, Indonesia, Malaysia, Philippines, South Korea, Taiwan, Thailand, and Vietnam. A scoring system was used wherein: 1, No progress; 2, milestone at early stages, ad hoc HTA use; 3, progress on milestone but limited impact; 4, significant progress but limited remit; and 5, significant progress on milestone, routine HTA informs decisions. Total scores indicated progress of HTA while milestone scores provided contextual insights within countries. Literature reviews and expert interviews were used to complete scorecards. RESULTS: South Korea and Thailand scored highest with seventy-three and seventy-one points, respectively, while Vietnam scored lowest at 28.5. Advanced HTA programs have independent HTA agencies with a broad remit, explicit process and methods, network of researchers, and routine use of HTA. Taiwan and Malaysia fall in a middle tier, with established HTA programs with limited remit. The final tier with China, India, Indonesia, Philippines, and Vietnam, emerging HTA processes. CONCLUSIONS: Universal Health Coverage goals have catalyzed expansion of HTA. Political will, technical expertise, and sustained financing remain challenges for sustainable HTA programs. Legislation supporting HTA is helpful but political will is key. Recommendations for regional collaboration are provided.

Sphingosine kinases protect murine embryonic stem cells from sphingosine-induced cell cycle arrest.

Sphingosine-1-phosphate (S1P) is a bioactive lipid molecule regulating organogenesis, angiogenesis, cell proliferation, and apoptosis. S1P is generated by sphingosine kinases (SPHK1 and SPHK2) through the phosphorylation of ceramide-derived sphingosine. Phenotypes caused by manipulating S1P metabolic enzymes and receptors suggested several possible functions for S1P in embryonic stem cells (ESCs), yet the mechanisms by which S1P and related sphingolipids act in ESCs are controversial. We designed a rigorous test to evaluate the requirement of S1P in murine ESCs by knocking out both Sphk1 and Sphk2 to create cells incapable of generating S1P. To accomplish this, we created lines mutant for Sphk2 and conditionally mutant (floxed) for Sphk1, allowing evaluation of ESCs that transition to double-null state. The Sphk1/2-null ESCs lack S1P and accumulate the precursor sphingosine. The double-mutant cells fail to grow due to a marked cell cycle arrest at G2/M. Mutant cells activate expression of telomere elongation factor genes Zscan4, Tcstv1, and Tcstv3 and display longer telomeric repeats. Adding exogenous S1P to the medium had no impact, but the cell cycle arrest is partially alleviated by the expression of a ceramide synthase 2, which converts excess sphingosine into ceramide. The results indicate that sphingosine kinase activity is essential in mouse ESCs for limiting the accumulation of sphingosine that otherwise drives cell cycle arrest.

Exploring facilitators and barriers to introducing health technology assessment: a systematic review.

OBJECTIVE: This study aims to identify and codify the facilitators and barriers to help implementing partners institutionalize health technology assessment (HTA) successfully and navigate complex systems for health-related policy making. METHODS: We searched for peer-reviewed and gray literature articles examining HTA programs globally using six databases. Keywords used as a guide for capturing articles included "health technology assessment," "barrier," and "facilitator" and their synonyms. Search results were scrutinized for duplicates and screened through a review of titles and abstracts. A full-text review was conducted exploring articles' coverage of twenty-seven evaluation criteria across four primary areas of interest: barriers/facilitators, motivations, guidelines, and institutional frameworks. RESULTS: A total of 18,599 records were identified for duplication check, title, and abstract review. A total of 1,594 articles underwent full-text review, leading to a final synthesis of 262 studies. We found that ninety-seven articles discussed barriers/facilitators, with fifty-three of those discussing local capacity and unavailable human resources. Out of the sixty-six articles discussing motivations, forty-two cited the interest in supporting the decision-making process for, and promoting, appropriate resource allocation. Of the sixty-one articles that discussed guidelines and institutional framework, twenty-one articles described HTA as an independent national unit, and sixteen described their HTA unit as a unit within the Ministry of Health (MOH). CONCLUSIONS: This systematic review unpacks the dynamic and relevant contexts for understanding the HTA institutionalization process to help policy makers and practitioners achieve tangible progress in confronting the most critical issues facing priority setting and HTA institutionalization.

Activation-Induced Cytidine Deaminase Regulates Fibroblast Growth Factor/Extracellular Signal-Regulated Kinases Signaling to Achieve the Naïve Pluripotent State During Reprogramming.

Induced pluripotent stem cells (iPSCs) derived by in vitro reprogramming of somatic cells retain the capacity to self-renew and to differentiate into many cell types. Pluripotency encompasses multiple states, with naïve iPSCs considered as ground state, possessing high levels of self-renewal capacity and maximum potential without lineage restriction. We showed previously that activation-induced cytidine deaminase (AICDA) facilitates stabilization of pluripotency during reprogramming. Here, we report that Acida-/- iPSCs, even when successfully reprogrammed, fail to achieve the naïve pluripotent state and remain primed for differentiation because of a failure to suppress fibroblast growth factor (FGF)/extracellular signal-regulated kinases (ERK) signaling. Although the mutant cells display marked genomic hypermethylation, suppression of FGF/ERK signaling by AICDA is independent of deaminase activity. Thus, our study identifies AICDA as a novel regulator of naïve pluripotency through its activity on FGF/ERK signaling. Stem Cells 2019;37:1003-1017.

Correction to: Mass testing and treatment for malaria followed by weekly fever screening, testing and treatment in Northern Senegal: feasibility, cost and impact.

An amendment to this paper has been published and can be accessed via the original article.

AID stabilizes stem-cell phenotype by removing epigenetic memory of pluripotency genes.

The activation-induced cytidine deaminase (AID; also known as AICDA) enzyme is required for somatic hypermutation and class switch recombination at the immunoglobulin locus. In germinal-centre B cells, AID is highly expressed, and has an inherent mutator activity that helps generate antibody diversity. However, AID may also regulate gene expression epigenetically by directly deaminating 5-methylcytosine in concert with base-excision repair to exchange cytosine. This pathway promotes gene demethylation, thereby removing epigenetic memory. For example, AID promotes active demethylation of the genome in primordial germ cells. However, different studies have suggested either a requirement or a lack of function for AID in promoting pluripotency in somatic nuclei after fusion with embryonic stem cells. Here we tested directly whether AID regulates epigenetic memory by comparing the relative ability of cells lacking AID to reprogram from a differentiated murine cell type to an induced pluripotent stem cell. We show that Aid-null cells are transiently hyper-responsive to the reprogramming process. Although they initiate expression of pluripotency genes, they fail to stabilize in the pluripotent state. The genome of Aid-null cells remains hypermethylated in reprogramming cells, and hypermethylated genes associated with pluripotency fail to be stably upregulated, including many MYC target genes. Recent studies identified a late step of reprogramming associated with methylation status, and implicated a secondary set of pluripotency network components. AID regulates this late step, removing epigenetic memory to stabilize the pluripotent state.

The challenges of introducing routine G6PD testing into radical cure: a workshop report.

The only currently available drug that effectively removes malaria hypnozoites from the human host is primaquine. The use of 8-aminoquinolines is hampered by haemolytic side effects in glucose-6-phosphate dehydrogenase (G6PD) deficient individuals. Recently a number of qualitative and a quantitative rapid diagnostic test (RDT) format have been developed that provide an alternative to the current standard G6PD activity assays. The WHO has recently recommended routine testing of G6PD status prior to primaquine radical cure whenever possible. A workshop was held in the Philippines in early 2015 to discuss key challenges and knowledge gaps that hinder the introduction of routine G6PD testing. Two point-of-care (PoC) test formats for the measurement of G6PD activity are currently available: qualitative tests comparable to malaria RDT as well as biosensors that provide a quantitative reading. Qualitative G6PD PoC tests provide a binomial test result, are easy to use and some products are comparable in price to the widely used fluorescent spot test. Qualitative test results can accurately classify hemizygous males, heterozygous females, but may misclassify females with intermediate G6PD activity. Biosensors provide a more complex quantitative readout and are better suited to identify heterozygous females. While associated with higher costs per sample tested biosensors have the potential for broader use in other scenarios where knowledge of G6PD activity is relevant as well. The introduction of routine G6PD testing is associated with additional costs on top of routine treatment that will vary by setting and will need to be assessed prior to test introduction. Reliable G6PD PoC tests have the potential to play an essential role in future malaria elimination programmes, however require an improved understanding on how to best integrate routine G6PD testing into different health settings.

Intracranial abscess due to Mycobacterium avium complex in an immunocompetent host: a case report.

BACKGROUND: Mycobacterium avium complex (MAC) is a ubiquitous pathogen, widely distributed in the environment including water, soil and animals. It is an uncommonly encountered clinical pathogen; primarily causing pulmonary infections in patients with underlying lung disease or disseminated disease in immunocompromised hosts. Sporadically, extra-pulmonary infections have been documented including involvement of the liver, spleen, skin, soft tissue and lymph nodes. Central nervous system (CNS) infections due to MAC are exceedingly rare and carry a poor prognosis. Additionally, such infections are largely reported in patients infected with HIV. Herein we report the first case of intracranial abscess due to MAC in an immunocompetent man with a normal CD4 count and negative HIV status. CASE PRESENTATION: A previously healthy 40-year-old male presented to us with progressively worsening CNS symptoms. The patient's presentation was uncharacteristic of MAC infection in immunocompetent hosts, as he developed subacute, progressive symptoms that included severe frontal headaches, left eyelid swelling, blurry vision, and diplopia, without any pulmonary or systemic manifestations. Neuroimaging revealed multiple ring-enhancing lesions, which required neurosurgical intervention. MAC was the only pathogen that grew from intraoperative tissue cultures. The patient was subsequently treated with a 12-month regimen consisting of Clarithromycin, Ethambutol, and Rifampin, with successful clinical resolution. CONCLUSION: Our findings indicate that it is important to consider rare infections such as MAC in immunocompetent patients, regardless of atypical symptoms. Despite the severity of this infection, with timely diagnosis effective treatment is available.

Silencing of UCHL1 by CpG promoter hyper-methylation is associated with metastatic gastroenteropancreatic well-differentiated neuroendocrine (carcinoid) tumors.

BACKGROUND: Well-differentiated gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are rare tumors with varying metastatic potential. The underlying molecular basis for metastasis by GEP-NETs remains undefined. METHODS: Quantitative PCR and immunohistochemistry (IHC) staining for ubiquitin carboxyl-terminal esterase L1 (UCHL1) gene and protein expression was performed on a group of localized and metastatic well-differentiated GEP-NET samples acquired from a prospectively maintained tissue bank. The ability of extent of UCHL1 IHC staining to differentiate localized and metastatic tumors was compared with Ki-67 index. RESULTS: Among 46 total samples, UCHL1 expression at both the gene and protein level was significantly greater among localized GEP-NETs compared with metastatic tumors and metastases (p < 0.001). Hypermethylation of the UCHL1 promoter was commonly observed among metastatic primary tumors and metastases (those with the lowest UCHL1 expression) but not among localized tumors (p < 0.001). Poor staining (<50 %) for UCHL1 was observed in 27 % of localized tumors compared with 87 % of metastatic tumors (p = 0.001). The presence of <50 % staining for UCHL1 was 88 % sensitive and 73 % specific for identifying metastatic disease. In contrast, there was no association between Ki-67 index and metastatic disease. In multivariable analysis, only UCHL1 staining <50 % [odds ratio (OR) 24.5, p = 0.035] and vascular invasion (OR 38.4, p = 0.03) were independent risk factors for metastatic disease at the time of initial surgery. CONCLUSIONS: Loss of UCHL1 expression by CpG promoter hypermethylation is associated with metastatic GEP-NETs. Extent of UCHL1 staining should be explored as a potentially clinically useful adjunct to Ki-67 index in evaluating GEP-NETs for aggressive features.

Dual role of lipids for genome stability and pluripotency facilitates full potency of mouse embryonic stem cells.

While Mek1/2 and Gsk3ß inhibition ("2i") supports the maintenance of murine embryonic stem cells (ESCs) in a homogenous naïve state, prolonged culture in 2i results in aneuploidy and DNA hypomethylation that impairs developmental potential. Additionally, 2i fails to support derivation and culture of fully potent female ESCs. Here we find that mouse ESCs cultured in 2i/LIF supplemented with lipid-rich albumin (AlbuMAX) undergo pluripotency transition yet maintain genomic stability and full potency over long-term culture. Mechanistically, lipids in AlbuMAX impact intracellular metabolism including nucleotide biosynthesis, lipid biogenesis, and TCA cycle intermediates, with enhanced expression of DNMT3s that prevent DNA hypomethylation. Lipids induce a formative-like pluripotent state through direct stimulation of Erk2 phosphorylation, which also alleviates X chromosome loss in female ESCs. Importantly, both male and female "all-ESC" mice can be generated from de novo derived ESCs using AlbuMAX-based media. Our findings underscore the importance of lipids to pluripotency and link nutrient cues to genome integrity in early development.

Progenitor cell origin plays a role in fate choices of mature B cells.

B cells, the Ab-producing cells of the immune system, develop from hematopoietic stem cells (HSCs) through well-defined stages during which Ig genes are rearranged to generate a clonal BCR. Signaling through the BCR plays a role in the subsequent cell fate decisions leading to the generation of three distinct types of B cells: B1, marginal zone, and follicular B cells. Common lymphoid progenitors (CLPs) are descended from HSCs, and although recent observations suggest that CLPs may not be physiological T cell precursors, it is generally accepted that CLPs are obligate progenitors for B cells. In addition, a CLP-like progenitor of unknown significance that lacks expression of c-kit (kit(-)CLP) was recently identified in the mouse model. In this study, we show that CLPs, kit(-)CLPs and a population within the lin(-)Sca1(+)kit(+)flt3(-) HSC compartment generate mature B cell types in different proportions: CLPs and kit(-)CLPs show a stronger marginal zone/follicular ratio than lin(-)Sca1(+)kit(+)flt3(-) cells, whereas kit(-)CLPs show a stronger B1 bias than any other progenitor population. Furthermore, expression of Sca1 on B cells depends on their progenitor origin as B cells derived from CLPs and kit(-)CLPs express more Sca1 than those derived from lin(-)Sca1(+)kit(+)flt3(-) cells. These observations indicate a role for progenitor origin in B cell fate choices and suggest the existence of CLP-independent B cell development.

QSER1 protects DNA methylation valleys from de novo methylation.

DNA methylation is essential to mammalian development, and dysregulation can cause serious pathological conditions. Key enzymes responsible for deposition and removal of DNA methylation are known, but how they cooperate to regulate the methylation landscape remains a central question. Using a knockin DNA methylation reporter, we performed a genome-wide CRISPR-Cas9 screen in human embryonic stem cells to discover DNA methylation regulators. The top screen hit was an uncharacterized gene, QSER1, which proved to be a key guardian of bivalent promoters and poised enhancers of developmental genes, especially those residing in DNA methylation valleys (or canyons). We further demonstrate genetic and biochemical interactions of QSER1 and TET1, supporting their cooperation to safeguard transcriptional and developmental programs from DNMT3-mediated de novo methylation.

Lin-Sca1+kit- bone marrow cells contain early lymphoid-committed precursors that are distinct from common lymphoid progenitors.

The significance of a population in mouse bone marrow of lineage-negative (Lin(-)), Sca1-positive, c-kit-negative (LSK(-)) cells, which is reported to be devoid of long-term repopulation capacity or myeloid potential, is unknown. In this study, we show that the LSK(-) population is composed of several subsets defined by the expression of flt3, CD25, and IL-7Ralpha. The first subset was CD25(-) and more than 90% expressed either flt3, IL-7Ralpha, or both. The CD25(-)LSK(-) population had T cell, B cell, and NK cell potential in vivo, and most of this activity was localized in the flt3(+) subset, irrespective of the expression of IL-7Ralpha. Although lymphoid potential of flt3(+)LSK(-) cells in vivo was 3-fold lower than that of lin(-)Sca1(low)kit(low)IL7Ralpha(+) common lymphoid progenitors (CLPs), their cloning efficiency in vitro was 10-fold lower than that of CLPs. Furthermore, although the myeloid potential of flt3(+)LSK(-) cells was 10-fold lower than that of CLPs in the absence of M-CSF, the relative myeloid potential of both populations was similar in its presence. These observations suggest differential growth factor requirements of both populations. The second subset of LSK(-) cells was homogeneously CD25(+)flt3(-)IL7Ralpha(+) and could be generated from both CD25(-)LSK(-) cells and from CLPs, but did not engraft in immunodeficient Rag1(-/-) or Rag1(-/-)gamma(c)(-/-) hosts. This population, of which the significance is unclear, was increased in Rag1(-/-) mice and in old mice. Thus, the LSK(-) population is phenotypically and functionally heterogeneous and contains early lymphoid-committed precursors. Our findings imply that the early stages of lymphoid commitment are more complex than was thus far assumed.

A correlation study between meteorological parameters and COVID-19 pandemic in Mumbai, India.

BACKGROUND AND AIMS: Meteorological parameters play a major role in the transmission of infectious diseases such as COVID-19. In this study, we aim to analyze the correlation between meteorological parameters and COVID-19 pandemic in the financial capital of India, Mumbai. METHODS: In this research, we collected data from April 27 till July 25, 2020 (90 days). A Spearman rank correlation test along with two-tailed p test and an Artificial Neural Network (ANN) technique have been used to predict the associations of COVID-19 with meteorological parameters. RESULTS: A significant correlation of COVID-19 was found with temperature (Tmin), dew point (DPmax), relative humidity (RHmax, RHavg, RHmin) and surface pressure (Pmax, Pavg, Pmin). The parameters which showed significant correlation were then taken for the modeling and prediction of COVID-19 infections using Artificial Neural Network technique. CONCLUSIONS: It was found that the relative humidity and pressure parameters had the most influencing effect out of all other significant parameters (obtained from Spearman's method) on the active number of COVID-19 cases. The finding in this study might be useful for the public, local authorities, and the Ministry of Health, Govt. of India to combat COVID-19.

A human embryonic stem cell reporter line for monitoring chemical-induced cardiotoxicity.

AIMS: Human embryonic stem cells (hESCs) can be used to generate scalable numbers of cardiomyocytes (CMs) for studying cardiac biology, disease modelling, drug screens, and potentially for regenerative therapies. A fluorescence-based reporter line will significantly enhance our capacities to visualize the derivation, survival, and function of hESC-derived CMs. Our goal was to develop a reporter cell line for real-time monitoring of live hESC-derived CMs. METHODS AND RESULTS: We used CRISPR/Cas9 to knock a mCherry reporter gene into the MYH6 locus of hESC lines, H1 and H9, enabling real-time monitoring of the generation of CMs. MYH6:mCherry+ cells express atrial or ventricular markers and display a range of cardiomyocyte action potential morphologies. At 20 days of differentiation, MYH6:mCherry+ cells show features characteristic of human CMs and can be used successfully to monitor drug-induced cardiotoxicity and oleic acid-induced cardiac arrhythmia. CONCLUSION: We created two MYH6:mCherry hESC reporter lines and documented the application of these lines for disease modelling relevant to cardiomyocyte biology.

Modeling polymorphic ventricular tachycardia at rest using patient-specific induced pluripotent stem cell-derived cardiomyocytes.

BACKGROUND: While mutations in the cardiac type 2 ryanodine receptor (RyR2) have been linked to exercise-induced or catecholaminergic polymorphic ventricular tachycardia (CPVT), its association with polymorphic ventricular tachycardia (PMVT) occurring at rest is unclear. We aimed at constructing a patient-specific human-induced pluripotent stem cell (hiPSC) model of PMVT occurring at rest linked to a single point mutation in RyR2. METHODS: Blood samples were obtained from a patient with PMVT at rest due to a heterozygous RyR2-H29D mutation. Patient-specific hiPSCs were generated from the blood samples, and the hiPSC-derived cardiomyocytes (CMs) were generated via directed differentiation. Using CRIPSR/Cas9 technology, isogenic controls were generated by correcting the RyR2-H29D mutation. Using patch-clamp, fluorescent confocal microscopy and video-image-based analysis, the molecular and functional properties of RyR2-H29D hiPSCCMs and control hiPSCCMs were compared. FINDINGS: RyR2-H29D hiPSCCMs exhibit intracellular sarcoplasmic reticulum (SR) Ca2+ leak through RyR2 under physiological pacing. RyR2-H29D enhances the contribution of inositol 1,4,5-trisphosphate receptors to excitation-contraction coupling (ECC) that exacerbates abnormal Ca2+ release in RyR2-H29D hiPSCCMs. RyR2-H29D hiPSCCMs exhibit shorter action potentials, delayed afterdepolarizations, arrhythmias and aberrant contractile properties compared to isogenic controls. The RyR2-H29D mutation causes post-translational remodeling that is fully reversed with isogenic controls. INTERPRETATION: To conclude, in a model based on a RyR2 point mutation that is associated with short-coupled PMVT at rest, RyR2-H29D hiPSCCMs exhibited aberrant intracellular Ca2+ homeostasis, shortened action potentials, arrhythmias and abnormal contractile properties. FUNDING: French Muscular Dystrophy Association (AFM; project 16,073, MNM2 2012 and 20,225), "Fondation de la Recherche Médicale" (FRM; SPF20130526710), "Institut National pour la Santé et la Recherche Médicale" (INSERM), National Institutes of Health (ARM; R01 HL145473) and New York State Department of Health (NYSTEM C029156).

Predicting benefit from fulvestrant in pretreated metastatic breast cancer patients.

Fulvestrant use in pretreated metastatic breast cancer patients is associated with variable response rates. This study aimed to characterize these responses and to develop a prediction model to identify those patients who could potentially derive the most clinical benefit. A nationwide review of patients enrolled in a Canadian compassionate use program from 1999 to 2006 was performed. Prior therapy with tamoxifen, steroidal, and nonsteroidal aromatase inhibitors was mandatory. The dependent variable in the analysis was the proportion of patients requiring chemotherapy at 3 months following the start of fulvestrant. General Linear Mixed modeling was used to identify factors significantly associated with this dependant variable and to subsequently develop the prediction model. Three hundred and five women received at least one dose of fulvestrant; 207 went on to receive chemotherapy (68%). Median duration of fulvestrant treatment was 4.1 months (range 0.8-63.1). Factors predictive of being chemotherapy free at 3 months included older age, no prior adjuvant hormonal therapy, and the absence of lung or brain metastases at the start of therapy. A receiver operating characteristic (ROC) curve analysis had an area under the curve of 0.70 (95% CI 0.60-0.80). This model was able to identify risk information that could be helpful in assessing which patients would most likely benefit from fulvestrant as an intervention with the objective being a delay in chemotherapy.

Survival outcomes for patients with metastatic triple-negative breast cancer: implications for clinical practice and trial design.

BACKGROUND: Clinical experience suggests that many women with triple-negative metastatic breast cancer (MBC) relapse quickly. This has implications for clinical practice and trial design. We evaluated the duration of first-, second-, and third-line chemotherapy as a surrogate for duration of treatment response. PATIENTS AND METHODS: We performed a retrospective multicenter chart review of patients with triple-negative MBC receiving palliative chemotherapy. Primary outcome was duration of palliative chemotherapy, and secondary outcome was to identify prognostic variables. RESULTS: A total of 111 patients were analyzed. Median age at diagnosis was 51 years (range, 26-82 years). Fourteen percent of patients presented with MBC. Twenty-seven percent received neoadjuvant chemotherapy, and 48% received adjuvant chemotherapy. Median distant disease-free interval (DDFI) was 18 months (range, 0-172 months). At presentation of MBC, 68% had visceral and 71% had multiple sites of disease. Median survival with MBC was 13.3 months (range, 0.8-99.8 months). Median duration of first-line palliative therapy was 11.9 weeks (range, 0-73.1 weeks). Eighty-seven patients (78%) went on to receive second-line therapy with a median duration of 9 weeks (range, 0-120.9 weeks), and 55 (49%) received third-line therapy with a median duration of 4 weeks (range, 0-59 weeks). Multivariate analysis revealed that age < 50 years, ALP > 120 U/L, history of previous chemotherapy, DDFI < 12 months, and visceral presentation were all independently associated with a poor prognosis. CONCLUSION: Despite the poorer overall prognosis of patients with triple-negative disease, there remains considerable heterogeneity in individual outcomes. Many women with recurrent triple-negative disease will progress quickly on first-, second-, and third-line palliative treatment. Future clinical trials in this population must take into account their shorter time to progression when determining optimal trial design.

Autopsy findings of miliary tuberculosis in a renal transplant recipient.

Miliary tuberculosis is a lethal form of disseminated tuberculosis (TB), deriving its name from the millet-seed-sized granulomas in multiple organs. As TB still remains a leading cause of morbidity and mortality in India, its disseminated forms need to be diagnosed early to ensure more aggressive treatment at the earliest possible time. However, a considerable number of cases are missed ante-mortem. We discuss the case of a 32-year-old immunocompromised, non-HIV patient with an ante-mortem diagnosis of pulmonary TB. However, multiple organ involvement by Mycobacterium tuberculosis was demonstrated on autopsy. This case highlights the role of autopsy as a research and learning tool, and prudential clinico-pathologic correlation, which will improve clinical outcomes in the future.