The organization of frontostriatal brain wiring in non-affective early psychosis compared with healthy subjects using a novel diffusion imaging fiber cluster analysis.

BACKGROUND: Alterations in brain connectivity may underlie neuropsychiatric conditions such as schizophrenia. We here assessed the degree of convergence of frontostriatal fiber projections in 56 young adult healthy controls (HCs) and 108 matched Early Psychosis-Non-Affective patients (EP-NAs) using our novel fiber cluster analysis of whole brain diffusion magnetic resonance imaging tractography. METHODS: Using whole brain tractography and our fiber clustering methodology on harmonized diffusion magnetic resonance imaging data from the Human Connectome Project for Early Psychosis we identified 17 white matter fiber clusters that connect frontal cortex (FCtx) and caudate (Cd) per hemisphere in each group. To quantify the degree of convergence and, hence, topographical relationship of these fiber clusters, we measured the inter-cluster mean distances between the endpoints of the fiber clusters at the level of the FCtx and of the Cd, respectively. RESULTS: We found (1) in both groups, bilaterally, a non-linear relationship, yielding convex curves, between FCtx and Cd distances for FCtx-Cd connecting fiber clusters, driven by a cluster projecting from inferior frontal gyrus; however, in the right hemisphere, the convex curve was more flattened in EP-NAs; (2) that cluster pairs in the right (p = 0.03), but not left (p = 0.13), hemisphere were significantly more convergent in HCs vs EP-NAs; (3) in both groups, bilaterally, similar clusters projected significantly convergently to the Cd; and, (4) a significant group by fiber cluster pair interaction for 2 right hemisphere fiber clusters (numbers 5, 11; p = .00023; p = .00023) originating in selective PFC subregions. CONCLUSIONS: In both groups, we found the FCtx-Cd wiring pattern deviated from a strictly topographic relationship and that similar clusters projected significantly more convergently to the Cd. Interestingly, we also found a significantly more convergent pattern of connectivity in HCs in the right hemisphere and that 2 clusters from PFC subregions in the right hemisphere significantly differed in their pattern of connectivity between groups.

Complexity in the timing of the first postnatal ecdysis in snakes.

Lepidosaurian reptiles, particularly snakes, periodically shed the outer epidermal layers of their skin (ecdysis) to restore or enhance vital functions such as regulating water and gaseous exchange, growth, and protection against insult, infection or physical injury. Although many studies have focused on the nature and mechanisms of skin shedding, little attention has been paid to the timing of the first ecdysis in neonates following birth or hatching. A recent study investigated patterns of the time to first postnatal ecdysis in snakes based on a large dataset taken from the literature. The analysis demonstrated patterns in the time to first postnatal ecdysis related to phylogeny as well as several life history traits. While this assessment provides important advances in our knowledge of this topic, data on known biophysical drivers of ecdysis - temperature and humidity - were largely unavailable and were not evaluated. The first postnatal ecdysis of neonatal snakes can be viewed as an adaptive adjustment to the transition from the aqueous environment of the embryo to the aerial environment of the newborn. Hence, the timing of the first postnatal ecdysis is logically influenced by the aerial environment into which a newborn snake or hatchling finds itself. Therefore, in this Commentary, we first emphasize the putative plasticity of ecdysis with respect to epidermal lipids that structure the water permeability barrier and are established or renewed during ecdysis to reduce transepidermal evaporative water loss. We then discuss the likely importance of biophysical variables as influential covariates that need future investigation as potential co-determinants of the timing of first postnatal ecdysis.

Projecting kelp (Ecklonia radiata) gametophyte thermal adaptation and persistence under climate change.

BACKGROUND AND AIMS: Kelp forests underpin temperate marine ecosystems but are declining due to ocean warming, causing loss of associated ecosystem services. Projections suggest significant future decline but often only consider the persistence of adult sporophytes. Kelps have a biphasic life cycle, and the haploid gametophyte can be more thermally tolerant than the sporophyte. Therefore, projections may be altered when considering the thermal tolerance of gametophytes. METHODS: We undertook thermal tolerance experiments to quantify the effect of temperature on gametophyte survival, relative growth rate (RGR) and sex ratio for three genetically distinct populations of Ecklonia radiata gametophytes from comparatively high, mid- and low latitudes (43°, 33° and 30°S). We then used these data to project the likely consequences of climate-induced thermal change on gametophyte persistence and performance across its eastern Australian range, using generalized additive and linear models. KEY RESULTS: All populations were adapted to local temperatures and their thermal maximum was 2-3 °C above current maximum in situ temperatures. The lowest latitude population was most thermally tolerant (~70 % survival up to 27 °C), while survival and RGR decreased beyond 25.5 and 20.5 °C for the mid- and low-latitude populations, respectively. Sex ratios were skewed towards females with increased temperature in the low- and high-latitude populations. Spatially explicit model projections under future ocean warming (2050-centred) revealed a minimal decline in survival (0-30 %) across populations, relative to present-day predictions. RGRs were also projected to decline minimally (0-2 % d-1). CONCLUSIONS: Our results contrast with projections for the sporophyte stage of E. radiata, which suggest a 257-km range contraction concurrent with loss of the low-latitude population by 2100. Thermal adaptation in E. radiata gametophytes suggests this life stage is likely resilient to future ocean warming and is unlikely to be a bottleneck for the future persistence of kelp.

From Sin to Sexual Self-Awareness: Black Women's Reflection on Lifetime Masturbation.

To date, there has been very little empirical research on Black women's masturbation practices and views on masturbation. This study fills the gap by exploring the messages Black women received about masturbation and self-pleasure and the sources of these messages using valence theory. Data were collected in 2021 from 242 Black women who participated in a survey during phase one of the triphasic Big Sex Study. Thematic analysis was used to analyze this short-form qualitative data. Results indicated a range of responses, with mixed messages reported more than negative, positive, and neutral messages. The three primary sources of messages were religion, family, and friends. There were several themes across the valence of messages including the development of positive messages, sexual self-awareness, masturbation as sin, health benefits and consequences, relationship difficulties, devaluation, and masturbation as dirty and gross. These results provide a basis for sexuality professionals to improve sociocultural knowledge about masturbation beliefs, practices, and message sources among Black women.

Adherence to Daily Oral TDF/FTC for PrEP in Community Health Center Populations: The Sustainable Health Center Implementation PrEP Pilot (SHIPP) Study.

The prevention effectiveness of oral preexposure prophylaxis (PrEP) is highly dependent on medication adherence but no validated longer term PrEP adherence measures are readily available for use by primary care clinicians caring for diverse populations. We compared two self-report measures (number of doses missed in past 7 days and day-by-day past week pill taking) to results of tenofovir concentrations in dried blood spot (DBS) samples at quarterly visits over the first 12 months of PrEP use. 1420 men and women in five US community health centers enrolled in a medication adherence substudy. For 3, 6, 9 and 12 months, the respective percentages of persons with self-report vs DBS levels consistent having taken all 7 doses in the week prior were 71% (51%), 70% (47%), 71% (46%) and 69% (44%). Conversely, the percentage of participants reporting taking 0-1 doses in the week prior by self-report vs DBS drug levels at 3, 6, 9 and 12 months consistent with this level of nonadherence of 6% (9%), 5% (10%), 8% (9%), and 9% (15%). The estimated risk of low adherence (estimated 0-1 doses in the week prior) was higher for participants of Black (RR 1.60, CI 1.09-2.34) or "Other" race (RR 1.62, CI 0.99-2.65) compared with participants of White race; being a transgender female (RR 2.31, CI 1.33-4.02) compared to men who have sex with men; or enrollment at a study site with less experience in the provision of PrEP. The estimated risk of low adherence by DBS was lower for participants with a higher number of sex partners in the past 3 months and those having a bachelor's degree or higher. More work is needed to provide clinicians with measures to assess medication adherence in diverse US populations being prescribed PrEP to support its effective use in reducing HIV acquisition in individuals and at the community level.

Thirst and drinking in North American watersnakes (Nerodia spp.).

We quantified drinking behavior in three species of North American watersnakes: Nerodia clarkii, which is a marine or brackish water amphibious species, and Nerodiafasciata and Nerodiataxispilota, both freshwater amphibious species. All three species have relatively small and similar thresholds of dehydration (TH, approximately -4% loss of body mass) that elicit thirst and drinking of fresh water. These species have higher thirst sensitivity than several species of hydrophiine and laticaudine sea snakes, which are characterized by much lower TH (greater dehydration, -9% to <-20%). Nerodia clarkii, which is often found in coastal oceanic water, refused to drink seawater, but drank fresh water when dehydrated. In separate trials involving dehydration of N. clarkii and N. fasciata that were concurrently fed fish at regular intervals, snakes eventually refused to eat at TH of approximately -12% of original body mass, but resumed eating after they were allowed to drink fresh water and rehydrate. The drinking behaviors of Nerodia corroborate previous data on the importance of fresh water for drinking, and they complement growing evidence that dietary water does not itself mitigate dehydration in snakes. These new data increase understanding of water relationships in the context of evolutionary transitions from land to sea, and they emphasize the importance of fresh water resources in the conservation of coastal and marine species of reptiles.

Bronchoalveolar lavage fluid IMMY Sona Aspergillus lateral-flow assay for the diagnosis of invasive pulmonary aspergillosis: a prospective, real life evaluation.

Prompt and reliable diagnosis of invasive pulmonary aspergillosis (IPA) is essential for early initiation of antifungal therapy. We evaluated bronchoalveolar lavage (BAL) fluid IMMY Sona Aspergillus lateral-flow assay (IMMY LFA) in 92 individuals with suspected pulmonary infection. Sensitivity and specificity (vs. host factor but no IPA) of BAL IMMY LFA for diagnosis of IPA in individuals with any European Organisation for Research and Treatment of Cancer-defied "host factor" were 67% and 85%, respectively. Performance appeared better in individuals with renal transplantation (100%, 100%), compared to those with hematological malignancy and/or allogenic stem cell transplantation (70%, 78%). We found BAL IMMY LFA to be a convenient and useful addition to our diagnostic armory for IPA. LAY ABSTRACT: We evaluated a new test for diagnosing invasive pulmonary aspergillosis from bronchoscopy samples. We tested 92 people and found that it was 67% sensitive and 85% specific (compared to diagnosis according to a set of internationally recognised criteria). We found this test convenient and useful.

Surgical management of complex ileocolonic Crohn's disease: a survey of IBD colorectal surgeons to assess variability in operative strategy.

INTRODUCTION: To explore the reported variability in the surgical management of ileocolonic Crohn' s disease and identify areas of standard practice, we present this study which aims to assess how different colorectal surgeons with a subspecialty interest in inflammatory bowel disease (IBD) surgery may act in different clinical scenarios of ileocolonic Crohn's disease. METHODS: Anonymous videos demonstrating the small bowel walkthrough and anonymised patients' clinical data, imaging and pathological findings were distributed to the surgeons using an electronic tool. Surgeons answered on operative strategy, bowel resections, management of small bowel mesentery, type of anastomosis and use of stomas. RESULTS: Eight small bowel walkthrough videos were registered and 12 assessors completed the survey with a questionnaire completion rate of 87.5%. There was 87.7% agreement in the need to perform an ileocolonic resection. However, the agreement for the need to perform associated surgical procedures such as strictureplasties or further bowel resections was only 57.4%. When an anastomosis was fashioned, the side to side configuration was the most commonly used. The preferred management of the mesentery was dissection close to the bowel. CONCLUSIONS: The decision on the main procedure to be performed had a high agreement amongst the different assessors, but the treatment of multifocal disease was highly controversial, with low agreement on the need for associated procedures to treat internal fistulae and the use of strictureplasties. At the same time, there was significant heterogeneity in the decision on when to anastomose and when to fashion an ileostomy.

Video-laparoscopic assessment of the small bowel in Crohn's disease: a comparative study to evaluate surgeons' inter-observer variability.

BACKGROUND: Assessment of the entire small bowel is advocated during Crohn's disease (CD) surgery, as intraoperative detection of new lesions may lead to change in the planned procedure. The aim of this study was to evaluate the inter-observer variability in the assessment of extent and severity of CD at the small bowel laparoscopic "walkthrough". METHODS: A survey on laparoscopic assessment of the small bowel in patients with CD, including items adapted from the MREnterography or ultrasound in Crohn's disease (METRIC) study and from the classification of severity of mesenteric disease was developed by an invited committee of colorectal surgeons. Anonymous laparoscopic videos demonstrating the small bowel "walkthrough" in ileocolonic resection for primary and recurrent CD were distributed to the committee members together with the anonymous survey. The primary outcome was the rate of inter-observer variability on assessment of strictures, dilatations, complications and severity of mesenteric inflammation. RESULTS: 12 assessors completed the survey on 8 small bowel walkthrough videos. The evaluation of the small bowel thickening and of the mesenteric fat wrapping were the most reliable assessments with an overall agreement of 87.1% (k = 0.31; 95% CI - 0.22, 0.84) and 82.7% (k = 0.35; 95% CI - 0.04, 0.73), respectively. The presence of strictures and pre-stenotic dilatation demonstrated agreement of 75.2% (k = 0.06: 95% CI - 0.33, 0.45) and 71.2% (k = 0.33; 95% CI 0.15, 0.51), respectively. Evaluation of fistulae had an overall agreement of 75.3%, while there was a significant variation in the evaluation of mild, moderate and severe mesenteric disease with overall agreement ranging from 33.3 to 100%. CONCLUSION: Laparoscopic assessment of the small bowel thickening and of the presence of mesenteric fat wrapping is reliable for the intraoperative evaluation of CD with high inter-rater agreement. There is significant heterogeneity in the assessment of the severity of the mesenteric disease involvement.

The use of Endo-SPONGE® in rectal anastomotic leaks: a systematic review.

BACKGROUND: The aim of this study was to assess the efficacy of an endoluminal vacuum device (Endo-SPONGE®) in the treatment of rectal anastomotic leaks. METHODS: All studies looking at endoluminal vacuum therapy with Endo-SPONGE® in the treatment of rectal anastomotic leaks were included. A comprehensive search was conducted as per Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Primary outcome was defined as the rate of total anastomotic salvage, with secondary outcomes including rate of ileostomy closure, additional transrectal closures and functional outcomes RESULTS: Sixteen studies met the inclusion criteria. There was a significant publication bias (z = 3.53, p = 0.0004). Two hundred sixty-six patients were identified. The median treatment failure rate was 11.8% (range 0-44%), with random effects model of 0.17 (95% CI 0.11-0.22). There was improvement with early therapy start (OR 3.48) and negative correlation with neoadjuvant radiotherapy (OR 0.56). Fifty-one percent of all diverting stomas were closed at the end of treatment period and 12.8% of patients required an additional trans-rectal closure of the abscess cavity. CONCLUSIONS: Endo-SPONGE® seems to be a useful method of rectal anastomotic leak treatment in selected group of patients; however, the quality of available data is poor and it is impossible to draw a final conclusion. There is unexpected high rate of permanent ileostomy. There is a need for further assessment of this therapy with well-designed randomised or cohort studies.

Positron Emission Tomography Imaging of Macaques with Tuberculosis Identifies Temporal Changes in Granuloma Glucose Metabolism and Integrin α4ß1-Expressing Immune Cells.

Positron emission tomography and computed tomography imaging (PET/CT) is an increasingly valuable tool for diagnosing tuberculosis (TB). The glucose analog [18F]fluoro-2-deoxy-2-d-glucose ([18F]-FDG) is commonly used in PET/CT that is retained by metabolically active inflammatory cells in granulomas, but lacks specificity for particular cell types. A PET probe that could identify recruitment and differentiation of different cell populations in granulomas would be a useful research tool and could improve TB diagnosis and treatment. We used the Mycobacterium-antigen murine inflammation model and macaques with TB to identify [64Cu]-labeled CB-TE1A1P-PEG4-LLP2A ([64Cu]-LLP2A), a high affinity peptidomimetic ligand for very late Ag-4 (VLA-4; also called integrin α4ß1) binding cells in granulomas, and compared [64Cu]-LLP2A with [18F]-FDG over the course of infection. We found that [64Cu]-LLP2A retention was driven by macrophages and T cells, with less contribution from neutrophils and B cells. In macaques, granulomas had higher [64Cu]-LLP2A uptake than uninfected tissues, and immunohistochemical analysis of granulomas with known [64Cu]-LLP2A uptake identified significant correlations between LLP2A signal and macrophage and T cell numbers. The same cells coexpressed integrin α4 and ß1, further supporting that macrophages and T cells drive [64Cu]-LLP2A avidity in granulomas. Over the course of infection, granulomas and thoracic lymph nodes experienced dynamic changes in affinity for both probes, suggesting metabolic changes and cell differentiation or recruitment occurs throughout granuloma development. These results indicate [64Cu]-LLP2A is a PET probe for VLA-4, which when used in conjunction with [18F]-FDG, may be a useful tool for understanding granuloma biology in TB.

Conditioned Medium of Mesenchymal Stromal Cells: A New Class of Therapeutics.

Mesenchymal stromal cell (MSCs) represent a class of biologics with the prospects for employment as immunomodulatory, tissue-protective, and regenerative therapeutics. In parallel with cellular therapy, cell-free therapy based on MSC-secreted bioactive factors is being actively developed. MSCs secrete a variety of protein, peptide, RNA, and lipid mediators which can be concentrated, frozen, or even lyophilized without loss of activity, which gives them a certain advantage over cellular products requiring liquid nitrogen storage and infrastructure to revive frozen cells. This review (i) describes currently conducted clinical trials of cell-free products containing MSC secretome; (ii) summarizes main approaches to the generation and characterization of conditioned media concentrates and extracellular vesicle isolates; (iii) analyzes a variety of preclinical studies where effectiveness of secretome products has been shown; and (iv) summarizes current knowledge about secretome bioactive components obtained by analysis of in vivo models testing the therapeutic potential of the MSC secretome.

Circulating low-density lipoprotein ceramide concentrations increase in Holstein dairy cows transitioning from gestation to lactation.

Low-density lipoprotein (LDL) ceramide causes insulin resistance in obese diabetic nonruminants. Because previous work suggests that liver-derived ceramide may impair insulin action in postpartum cows, our objectives were to characterize peripartal changes in lipoprotein ceramides. We further studied the effects of prepartum adiposity on lipoprotein ceramide levels. Twenty-eight pregnant Holstein cows (parity = 3.65 ± 1.62) with lean (body condition score, BCS = 2.97 ± 0.16; body weight, BW = 630 ± 55.2 kg; n = 15) or overweight (BCS = 3.93 ± 0.27; BW = 766 ± 46.1 kg; n = 13) body condition 28 d before expected parturition were evaluated. Sampling occurred on d -20.5 ± 1.74, -13.8 ± 1.71, -7.84 ± 4.07, -6.71 ± 1.00, -3.92 ± 0.64, and -1.28 ± 0.61 (before parturition); daily until d 8 postpartum; and on d 10, 12, 14, 21, and 28. Adipose tissue and liver were biopsied on d -7.84 ± 4.07 and 10. Postpartum insulin sensitivity was assessed using the hyperinsulinemic-euglycemic clamp. Lipoprotein fractions were isolated using liquid chromatography. Sphingolipids were quantified using mass spectrometry. Data were analyzed using a mixed model with repeated measures. Overweight cows had a higher BCS and BW at enrollment relative to lean cows, but BCS and BW were similar postpartum. Overweight cows lost more body condition (0.97 ± 0.36 vs. 0.55 ± 0.16 BCS units) and BW (291 ± 67.3 vs. 202 ± 54.5 kg) during transition relative to lean cows. Adipocyte volume and counts declined from prepartum to postpartum (50.4 and 13.7%, respectively), and adipocyte volume was greater (48.2%) in overweight cows prepartum relative to lean cows. Although DMI was comparable between BCS groups, milk yield tended to be greater in overweight cows. Plasma free fatty acid and ß-hydroxybutyrate and liver lipid levels were 40, 16, and 37% greater, respectively, in overweight cows compared with lean cows. Glucose infusion rate during the hyperinsulinemic-euglycemic clamp tended to be lower in overweight cows. Ceramide levels within triacylglycerol-rich lipoprotein fractions declined postpartum, whereas LDL ceramide increased postpartum. Overweight cows had lower triacylglycerol-rich lipoprotein C16:0-ceramide levels relative to lean cows. Prepartum LDL C24:0-ceramide levels were greater in overweight cows relative to lean cows. Independent of prepartum adiposity, we concluded that serum LDL ceramide levels are elevated in early-lactation cows experiencing adipose tissue free fatty acid mobilization and hepatic steatosis.

Which patients are not included in the English Cancer Waiting Times monitoring dataset, 2009-2013? Implications for use of the data in research.

BACKGROUND: Cancer waiting time targets are routinely monitored in England, but the Cancer Waiting Times monitoring dataset (CWT) does not include all eligible patients, introducing scope for bias. METHODS: Data from adults diagnosed in England (2009-2013) with colorectal, lung, or ovarian cancer were linked from CWT to cancer registry, mortality, and Hospital Episode Statistics data. We present demographic characteristics and net survival for patients who were and were not included in CWT. RESULTS: A CWT record was found for 82% of colorectal, 76% of lung, and 77% of ovarian cancer patients. Patients not recorded in CWT were more likely to be in the youngest or oldest age groups, have more comorbidities, have been diagnosed through emergency presentation, have late or missing stage, and have much poorer survival. CONCLUSIONS: Researchers and policy-makers should be aware of the limitations in the completeness and representativeness of CWT, and draw conclusions with appropriate caution.

PET CT Identifies Reactivation Risk in Cynomolgus Macaques with Latent M. tuberculosis.

Mycobacterium tuberculosis infection presents across a spectrum in humans, from latent infection to active tuberculosis. Among those with latent tuberculosis, it is now recognized that there is also a spectrum of infection and this likely contributes to the variable risk of reactivation tuberculosis. Here, functional imaging with 18F-fluorodeoxygluose positron emission tomography and computed tomography (PET CT) of cynomolgus macaques with latent M. tuberculosis infection was used to characterize the features of reactivation after tumor necrosis factor (TNF) neutralization and determine which imaging characteristics before TNF neutralization distinguish reactivation risk. PET CT was performed on latently infected macaques (n = 26) before and during the course of TNF neutralization and a separate set of latently infected controls (n = 25). Reactivation occurred in 50% of the latently infected animals receiving TNF neutralizing antibody defined as development of at least one new granuloma in adjacent or distant locations including extrapulmonary sites. Increased lung inflammation measured by PET and the presence of extrapulmonary involvement before TNF neutralization predicted reactivation with 92% sensitivity and specificity. To define the biologic features associated with risk of reactivation, we used these PET CT parameters to identify latently infected animals at high risk for reactivation. High risk animals had higher cumulative lung bacterial burden and higher maximum lesional bacterial burdens, and more T cells producing IL-2, IL-10 and IL-17 in lung granulomas as compared to low risk macaques. In total, these data support that risk of reactivation is associated with lung inflammation and higher bacterial burden in macaques with latent Mtb infection.

IntAct: intra-operative fluorescence angiography to prevent anastomotic leak in rectal cancer surgery: a randomized controlled trial.

AIM: Anastomotic leak (AL) is a major complication of rectal cancer surgery. Despite advances in surgical practice, the rates of AL have remained static, at around 10-15%. The aetiology of AL is multifactorial, but one of the most crucial risk factors, which is mostly under the control of the surgeon, is blood supply to the anastomosis. The MRC/NIHR IntAct study will determine whether assessment of anastomotic perfusion using a fluorescent dye (indocyanine green) and near-infrared laparoscopy can minimize the rate of AL leak compared with conventional white-light laparoscopy. Two mechanistic sub-studies will explore the role of the rectal microbiome in AL and the predictive value of CT angiography/perfusion studies. METHOD: IntAct is a prospective, unblinded, parallel-group, multicentre, European, randomized controlled trial comparing surgery with intra-operative fluorescence angiography (IFA) against standard care (surgery with no IFA). The primary end-point is rate of clinical AL at 90 days following surgery. Secondary end-points include all AL (clinical and radiological), change in planned anastomosis, complications and re-interventions, use of stoma, cost-effectiveness of the intervention and quality of life. Patients should have a diagnosis of adenocarcinoma of the rectum suitable for potentially curative surgery by anterior resection. Over 3 years, 880 patients from 25 European centres will be recruited and followed up for 90 days. DISCUSSION: IntAct will rigorously evaluate the use of IFA in rectal cancer surgery and explore the role of the microbiome in AL and the predictive value of preoperative CT angiography/perfusion scanning.

Variability in tuberculosis granuloma T cell responses exists, but a balance of pro- and anti-inflammatory cytokines is associated with sterilization.

Lung granulomas are the pathologic hallmark of tuberculosis (TB). T cells are a major cellular component of TB lung granulomas and are known to play an important role in containment of Mycobacterium tuberculosis (Mtb) infection. We used cynomolgus macaques, a non-human primate model that recapitulates human TB with clinically active disease, latent infection or early infection, to understand functional characteristics and dynamics of T cells in individual granulomas. We sought to correlate T cell cytokine response and bacterial burden of each granuloma, as well as granuloma and systemic responses in individual animals. Our results support that each granuloma within an individual host is independent with respect to total cell numbers, proportion of T cells, pattern of cytokine response, and bacterial burden. The spectrum of these components overlaps greatly amongst animals with different clinical status, indicating that a diversity of granulomas exists within an individual host. On average only about 8% of T cells from granulomas respond with cytokine production after stimulation with Mtb specific antigens, and few "multi-functional" T cells were observed. However, granulomas were found to be "multi-functional" with respect to the combinations of functional T cells that were identified among lesions from individual animals. Although the responses generally overlapped, sterile granulomas had modestly higher frequencies of T cells making IL-17, TNF and any of T-1 (IFN-γ, IL-2, or TNF) and/or T-17 (IL-17) cytokines than non-sterile granulomas. An inverse correlation was observed between bacterial burden with TNF and T-1/T-17 responses in individual granulomas, and a combinatorial analysis of pair-wise cytokine responses indicated that granulomas with T cells producing both pro- and anti-inflammatory cytokines (e.g. IL-10 and IL-17) were associated with clearance of Mtb. Preliminary evaluation suggests that systemic responses in the blood do not accurately reflect local T cell responses within granulomas.