Phenotype-based targeted treatment of SGLT2 inhibitors and GLP-1 receptor agonists in type 2 diabetes.

AIMS/HYPOTHESIS: A precision medicine approach in type 2 diabetes could enhance targeting specific glucose-lowering therapies to individual patients most likely to benefit. We aimed to use the recently developed Bayesian causal forest (BCF) method to develop and validate an individualised treatment selection algorithm for two major type 2 diabetes drug classes, sodium-glucose cotransporter 2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP1-RA). METHODS: We designed a predictive algorithm using BCF to estimate individual-level conditional average treatment effects for 12-month glycaemic outcome (HbA1c) between SGLT2i and GLP1-RA, based on routine clinical features of 46,394 people with type 2 diabetes in primary care in England (Clinical Practice Research Datalink; 27,319 for model development, 19,075 for hold-out validation), with additional external validation in 2252 people with type 2 diabetes from Scotland (SCI-Diabetes [Tayside & Fife]). Differences in glycaemic outcome with GLP1-RA by sex seen in clinical data were replicated in clinical trial data (HARMONY programme: liraglutide [n=389] and albiglutide [n=1682]). As secondary outcomes, we evaluated the impacts of targeting therapy based on glycaemic response on weight change, tolerability and longer-term risk of new-onset microvascular complications, macrovascular complications and adverse kidney events. RESULTS: Model development identified marked heterogeneity in glycaemic response, with 4787 (17.5%) of the development cohort having a predicted HbA1c benefit >3 mmol/mol (>0.3%) with SGLT2i over GLP1-RA and 5551 (20.3%) having a predicted HbA1c benefit >3 mmol/mol with GLP1-RA over SGLT2i. Calibration was good in hold-back validation, and external validation in an independent Scottish dataset identified clear differences in glycaemic outcomes between those predicted to benefit from each therapy. Sex, with women markedly more responsive to GLP1-RA, was identified as a major treatment effect modifier in both the UK observational datasets and in clinical trial data: HARMONY-7 liraglutide (GLP1-RA): 4.4 mmol/mol (95% credible interval [95% CrI] 2.2, 6.3) (0.4% [95% CrI 0.2, 0.6]) greater response in women than men. Targeting the two therapies based on predicted glycaemic response was also associated with improvements in short-term tolerability and long-term risk of new-onset microvascular complications. CONCLUSIONS/INTERPRETATION: Precision medicine approaches can facilitate effective individualised treatment choice between SGLT2i and GLP1-RA therapies, and the use of routinely collected clinical features for treatment selection could support low-cost deployment in many countries.

Analysis of type 2 diabetes heterogeneity with a tree-like representation: insights from the prospective German Diabetes Study and the LURIC cohort.

BACKGROUND: Heterogeneity in type 2 diabetes can be represented by a tree-like graph structure by use of reversed graph-embedded dimensionality reduction. We aimed to examine whether this approach can be used to stratify key pathophysiological components and diabetes-related complications during longitudinal follow-up of individuals with recent-onset type 2 diabetes. METHODS: For this cohort analysis, 927 participants aged 18-69 years from the German Diabetes Study (GDS) with recent-onset type 2 diabetes were mapped onto a previously developed two-dimensional tree based on nine simple clinical and laboratory variables, residualised for age and sex. Insulin sensitivity was assessed by a hyperinsulinaemic-euglycaemic clamp, insulin secretion was assessed by intravenous glucose tolerance test, hepatic lipid content was assessed by 1 H magnetic resonance spectroscopy, serum interleukin (IL)-6 and IL-18 were assessed by ELISA, and peripheral and autonomic neuropathy were assessed by functional and clinical measures. Participants were followed up for up to 16 years. We also investigated heart failure and all-cause mortality in 794 individuals with type 2 diabetes undergoing invasive coronary diagnostics from the Ludwigshafen Risk and Cardiovascular Health (LURIC) cohort. FINDINGS: There were gradients of clamp-measured insulin sensitivity (both dimensions: p<0·0001) and insulin secretion (pdim1<0·0001, pdim2=0·00097) across the tree. Individuals in the region with the lowest insulin sensitivity had the highest hepatic lipid content (n=205, pdim1<0·0001, pdim2=0·037), pro-inflammatory biomarkers (IL-6: n=348, pdim1<0·0001, pdim2=0·013; IL-18: n=350, pdim1<0·0001, pdim2=0·38), and elevated cardiovascular risk (nevents=143, pdim1=0·14, pdim2<0·00081), whereas individuals positioned in the branch with the lowest insulin secretion were more prone to require insulin therapy (nevents=85, pdim1=0·032, pdim2=0·12) and had the highest risk of diabetic sensorimotor polyneuropathy (nevents=184, pdim1=0·012, pdim2=0·044) and cardiac autonomic neuropathy (nevents=118, pdim1=0·0094, pdim2=0·06). In the LURIC cohort, all-cause mortality was highest in the tree branch showing insulin resistance (nevents=488, pdim1=0·12, pdim2=0·0032). Significant gradients differentiated individuals having heart failure with preserved ejection fraction from those who had heart failure with reduced ejection fraction. INTERPRETATION: These data define the pathophysiological underpinnings of the tree structure, which has the potential to stratify diabetes-related complications on the basis of routinely available variables and thereby expand the toolbox of precision diabetes diagnosis. FUNDING: German Diabetes Center, German Federal Ministry of Health, Ministry of Culture and Science of the state of North Rhine-Westphalia, German Federal Ministry of Education and Research, German Diabetes Association, German Center for Diabetes Research, European Community, German Research Foundation, and Schmutzler Stiftung.

In vivo quantification of programmed death-ligand-1 expression heterogeneity in tumors using fluorescence lifetime imaging.

Cancer patient selection for immunotherapy is often based on programmed death-ligand-1 (PD-L1) expression as a biomarker. PD-L1 expression is currently quantified using immunohistochemistry, which can only provide snapshots of PD-L1 expression status in microscopic regions of ex vivo specimens. In vivo imaging using targeted agents can capture dynamic variations of PD-L1 expression in entire tumors within and across multiple subjects. Towards this goal, several PD-L1 targeted molecular imaging probes have been evaluated in murine models and humans. However, clinical translation of these probes has been limited due to a significant non-specific accumulation of the imaging probes and the inability of conventional imaging modalities to provide quantitative readouts that can be compared across multiple subjects. Here we report that in vivo time-domain (TD) fluorescence imaging can provide quantitative estimates of baseline tumor PD-L1 heterogeneity across untreated mice and variations in PD-L1 expression across mice undergoing clinically relevant anti-PD1 treatment. This approach relies on a significantly longer fluorescence lifetime (FLT) of PD-L1 specific anti-PD-L1 antibody tagged to IRDye 800CW (αPDL1-800) compared to nonspecific αPDL1-800. Leveraging this unique FLT contrast, we show that PD-L1 expression can be quantified across mice both in superficial breast tumors using planar FLT imaging, and in deep-seated liver tumors (>5 mm depth) using the asymptotic TD algorithm for fluorescence tomography. Our results suggest that FLT contrast can accelerate the preclinical investigation and clinical translation of novel molecular imaging probes by providing robust quantitative readouts of receptor expression that can be readily compared across subjects.

Fluorescence lifetime of injected indocyanine green as a universal marker of solid tumours in patients.

The surgical resection of solid tumours can be enhanced by fluorescence-guided imaging. However, variable tumour uptake and incomplete clearance of fluorescent dyes reduces the accuracy of distinguishing tumour from normal tissue via conventional fluorescence intensity-based imaging. Here we show that, after systemic injection of the near-infrared dye indocyanine green in patients with various types of solid tumour, the fluorescence lifetime (FLT) of tumour tissue is longer than the FLT of non-cancerous tissue. This tumour-specific shift in FLT can be used to distinguish tumours from normal tissue with an accuracy of over 97% across tumour types, and can be visualized at the cellular level using microscopy and in larger specimens through wide-field imaging. Unlike fluorescence intensity, which depends on imaging-system parameters, tissue depth and the amount of dye taken up by tumours, FLT is a photophysical property that is largely independent of these factors. FLT imaging with indocyanine green may improve the accuracy of cancer surgeries.

Intraoperative molecular imaging: 3rd biennial clinical trials update.

Significance: This third biennial intraoperative molecular imaging (IMI) conference shows how optical contrast agents have been applied to develop clinically significant endpoints that improve precision cancer surgery. Aim: National and international experts on IMI presented ongoing clinical trials in cancer surgery and preclinical work. Previously known dyes (with broader applications), new dyes, novel nonfluorescence-based imaging techniques, pediatric dyes, and normal tissue dyes were discussed. Approach: Principal investigators presenting at the Perelman School of Medicine Abramson Cancer Center's third clinical trials update on IMI were selected to discuss their clinical trials and endpoints. Results: Dyes that are FDA-approved or currently under clinical investigation in phase 1, 2, and 3 trials were discussed. Sections on how to move benchwork research to the bedside were also included. There was also a dedicated section for pediatric dyes and nonfluorescence-based dyes that have been newly developed. Conclusions: IMI is a valuable adjunct in precision cancer surgery and has broad applications in multiple subspecialties. It has been reliably used to alter the surgical course of patients and in clinical decision making. There remain gaps in the utilization of IMI in certain subspecialties and potential for developing newer and improved dyes and imaging techniques.

Near-infrared fluorescence lifetime imaging of amyloid-ß aggregates and tau fibrils through the intact skull of mice.

Non-invasive methods for the in vivo detection of hallmarks of Alzheimer's disease can facilitate the study of the progression of the disease in mouse models and may enable its earlier diagnosis in humans. Here we show that the zwitterionic heptamethine fluorophore ZW800-1C, which has peak excitation and emission wavelengths in the near-infrared optical window, binds in vivo and at high contrast to amyloid-ß deposits and to neurofibrillary tangles, and allows for the microscopic imaging of amyloid-ß and tau aggregates through the intact skull of mice. In transgenic mouse models of Alzheimer's disease, we compare the performance of ZW800-1C with that of the two spectrally similar heptamethine fluorophores ZW800-1A and indocyanine green, and show that ZW800-1C undergoes a longer fluorescence-lifetime shift when bound to amyloid-ß and tau aggregates than when circulating in blood vessels. ZW800-1C may prove advantageous for tracking the proteinic aggregates in rodent models of amyloid-ß and tau pathologies.

Comparison of fluorescence lifetime and multispectral imaging for quantitative multiplexing in biological tissue.

Fluorescence lifetime (FLT) multiplexing and multispectral imaging (MSI) are both frequently employed for in vitro and ex vivo biological studies. In vivo applications of MSI for deep seated fluorophores require consideration of diffusive light propagation in biological tissue. We have previously shown that a well-known redshift of fluorescence spectra in diffusive medium induces a fluorophore cross-talk, which cannot be accounted for even with known optical properties of the medium. In contrast, FLT measurements remain largely unaffected by light propagation in tissue, enabling zero cross-talk and accurate relative quantification. While a fully quantitative estimation of fluorophore concentrations requires depth resolved tomographic imaging, this is often not possible due to the difficulty of estimating tissue optical properties and modelling light propagation in complex tissue geometries. Here, we experimentally investigate the performance of planar (non-tomographic) MSI and FLT multiplexing for the quantitative recovery of multiple near-infrared fluorophores embedded in 4-8 mm thick tissue. We show that FLT multiplexing provides a superior quantification accuracy (error < 10%) compared to MSI (error = 20-107%) in tissue. The error rates for MSI increased with tissue thickness and can be directly attributed to the spectral redshift induced cross-talk between emission spectra. Our data indicate that planar FLT multiplexing can provide high quantification accuracy in thick biological tissue without a need for optical property estimation, thereby offering an important validation tool for rapid quantification of fluorophore concentrations in bulk tissue.

A nanoparticle probe for the imaging of autophagic flux in live mice via magnetic resonance and near-infrared fluorescence.

Autophagy-the lysosomal degradation of cytoplasmic components via their sequestration into double-membraned autophagosomes-has not been detected non-invasively. Here we show that the flux of autophagosomes can be measured via magnetic resonance imaging or serial near-infrared fluorescence imaging of intravenously injected iron oxide nanoparticles decorated with cathepsin-cleavable arginine-rich peptides functionalized with the near-infrared fluorochrome Cy5.5 (the peptides facilitate the uptake of the nanoparticles by early autophagosomes, and are then cleaved by cathepsins in lysosomes). In the heart tissue of live mice, the nanoparticles enabled quantitative measurements of changes in autophagic flux, upregulated genetically, by ischaemia-reperfusion injury or via starvation, or inhibited via the administration of a chemotherapeutic or the antibiotic bafilomycin. In mice receiving doxorubicin, pre-starvation improved cardiac function and overall survival, suggesting that bursts of increased autophagic flux may have cardioprotective effects during chemotherapy. Autophagy-detecting nanoparticle probes may facilitate the further understanding of the roles of autophagy in disease.

First Clinical Results of Fluorescence Lifetime-enhanced Tumor Imaging Using Receptor-targeted Fluorescent Probes.

PURPOSE: Fluorescence molecular imaging, using cancer-targeted near infrared (NIR) fluorescent probes, offers the promise of accurate tumor delineation during surgeries and the detection of cancer specific molecular expression in vivo. However, nonspecific probe accumulation in normal tissue results in poor tumor fluorescence contrast, precluding widespread clinical adoption of novel imaging agents. Here we present the first clinical evidence that fluorescence lifetime (FLT) imaging can provide tumor specificity at the cellular level in patients systemically injected with panitumumab-IRDye800CW, an EGFR-targeted NIR fluorescent probe. EXPERIMENTAL DESIGN: We performed wide-field and microscopic FLT imaging of resection specimens from patients injected with panitumumab-IRDye800CW under an FDA directed clinical trial. RESULTS: We show that the FLT within EGFR-overexpressing cancer cells is significantly longer than the FLT of normal tissue, providing high sensitivity (>98%) and specificity (>98%) for tumor versus normal tissue classification, despite the presence of significant nonspecific probe accumulation. We further show microscopic evidence that the mean tissue FLT is spatially correlated (r > 0.85) with tumor-specific EGFR expression in tissue and is consistent across multiple patients. These tumor cell-specific FLT changes can be detected through thick biological tissue, allowing highly specific tumor detection and noninvasive monitoring of tumor EFGR expression in vivo. CONCLUSIONS: Our data indicate that FLT imaging is a promising approach for enhancing tumor contrast using an antibody-targeted NIR probe with a proven safety profile in humans, suggesting a strong potential for clinical applications in image guided surgery, cancer diagnostics, and staging.

Erratum: Comparison of fluorescence lifetime and multispectral imaging for quantitative multiplexing in biological tissue: erratum.

[This corrects the article on p. 3854 in vol. 13, PMID: 35991924.].

Fluorescent nanodiamond - hyaluronate conjugates for target-specific molecular imaging.

Despite wide investigation on molecular imaging contrast agents, there are still strong unmet medical needs to enhance their signal-to background ratio, brightness, photostability, and biocompatibility with multimodal imaging capability. Here, we assessed the feasibility of fluorescent nanodiamonds (FNDs) as carbon based photostable and biocompatible materials for molecular imaging applications. Because FNDs have negatively charged nitrogen vacancy (NV) centers, they can emit bright red light. FNDs were conjugated to hyaluronate (HA) for target-specific molecular imaging. HA is a biocompatible, biodegradable, and linear polysaccharide with abundant HA receptors in the liver, enabling liver targeted molecular imaging. In vitro cell viability tests revealed the biocompatibility of HA-FND conjugates and the competitive cellular uptake test confirmed their target-specific intracellular delivery to HepG2 cells with HA receptors. In addition, in vivo fluorescence lifetime (FLT) assessment revealed the imaging capability of FNDs and HA-FND conjugates. After that, we could confirm the statistically significant liver-targeted delivery of HA-FND conjugates by in vivo imaging system (IVIS) analysis and ex vivo biodistribution tests in various organs. The renal clearance test and histological analysis corroborated the in vivo biocompatibility and safety of HA-FND conjugates. All these results demonstrated the feasibility of HA-FND conjugates for further molecular imaging applications.

Task-sharing interventions for improving control of diabetes in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Task-sharing interventions using non-physician health-care workers might be a potential diabetes management strategy in health systems that are constrained by physician shortages, such as those in low-income and middle-income countries (LMICs). METHODS: We did a systematic review and meta-analysis of task-sharing intervention strategies for managing type 2 diabetes in LMICs. We searched PubMed, Embase, and CINAHL from database inception to Sept 25, 2019, for studies that were randomised control trials or cluster randomised trials with task-shifted or task-shared interventions delivered to adults (≥18 years) by non-physician health workers versus usual care, done in LMICs with glycated haemoglobin (HbA1c) or fasting blood sugar (FBS) as outcome measures. The methodological quality of included studies was assessed using the Cochrane risk of bias tool. Random-effects model meta-analysis was used to estimate the population average pooled mean difference for HbA1c and FBS with 95% CIs. Our study protocol was registered in the PROSPERO database (CRD42018081015). FINDINGS: We found 4213 studies from the literature search, of which 46 (1·1%) were eligible for the narrative synthesis, including a total of 16 973 participants. 16 of these studies were excluded from the meta-analysis due to high risk of bias. 24 studies with a total of 5345 participants were included in the meta-analysis of HbA1c and 18 studies with a total of 3287 participants for FBS. Interventions led to an average reduction in HbA1c when tasks were delivered by nurses (averaged pooled mean difference -0·54% [95% CI -0·89 to -0·18]; I2=80%) and pharmacists (-0·91% [-1·15 to -0·68]; I2=58%), but not when they were delivered by dietitians (-0·50% [-1·10 to 0·09]; I2=54%) or community health workers (0·05% [0·03 to 0·07]; I2=0%). A reduction in average FBS was also observed when interventions were delivered by pharmacists (average pooled mean difference -36·26 mg/dL [-52·60 to -19·92]; I2=78%) but not nurses (-7·46 mg/dL [-18·44 to 3·52]; I2=79%) or community health workers (-5·41 [-12·74 to 1·92]; I2=71%). Only one study reported on FBS when tasks were delivered by dietitians, with a mean difference of -35·00 mg/dL (-65·96 to -4·04). INTERPRETATION: Task sharing interventions with non-physician healthcare workers show moderate effectiveness in diabetes management in LMIC settings. Although relatively high heterogeneity limits the interpretation of the overall findings, interventions led by pharmacists and nurses in LMICs with relatively high physician density are effective strategies in the management of diabetes. FUNDING: Wellcome Trust-Department of Biotechnology India Alliance.

Propagation of time-resolved fluorescence in a diffuse medium: complex analytical derivation.

The spatiotemporal evolution of fluorescence in an optically diffusive medium following ultrashort laser pulse excitation is evaluated using complex analytical methods. When expressed as a Fourier integral, the integrand of the time-resolved diffuse fluorescence with embedded fluorophores is shown to exhibit branch points and simple pole singularities in the lower-half complex-frequency plane. Applying Cauchy's integral theorem to solve the Fourier integral, we calculate the time-resolved signal for fluorescence lifetimes that are both shorter and longer compared to the intrinsic absorption timescale of the medium. These expressions are derived for sources and detectors that are in the form of localized points and wide-field harmonic spatial patterns. The accuracy of the expressions derived from complex analysis is validated against the numerically computed, full time-resolved fluorescence signal. The complex analysis shows that the branch points and simple poles contribute to two physically distinct terms in the net fluorescence signal. While the branch points result in a diffusive term that exhibits spatial broadening (corresponding to a narrowing with time in the spatial Fourier domain), the simple poles lead to fluorescence decay terms with spatial/spatial-frequency distributions that are independent of time. This distinct spatiotemporal behavior between the diffuse and fluorescence signals forms the basis for direct measurement of lifetimes shorter than the intrinsic optical diffusion timescales in a turbid medium.

In vivo deep-tissue microscopy with UCNP/Janus-dendrimers as imaging probes: resolution at depth and feasibility of ratiometric sensing.

Lanthanide-based upconverting nanoparticles (UCNPs) are known for their remarkable ability to convert near-infrared energy into higher energy light, offering an attractive platform for construction of biological imaging probes. Here we focus on in vivo high-resolution microscopy - an application for which the opportunity to carry out excitation at low photon fluxes in non-linear regime makes UCNPs stand out among all multiphoton probes. To create biocompatible nanoparticles we employed Janus-type dendrimers as surface ligands, featuring multiple carboxylates on one 'face' of the molecule, polyethylene glycol (PEG) residues on another and Eriochrome Cyanine R dye as the core. The UCNP/Janus-dendrimers showed outstanding performance as vascular markers, allowing for depth-resolved mapping of individual capillaries in the mouse brain down to a remarkable depth of ∼1000 µm under continuous wave (CW) excitation with powers not exceeding 20 mW. Using a posteriori deconvolution, high-resolution images could be obtained even at high scanning speeds in spite of the blurring caused by the long luminescence lifetimes of the lanthanide ions. Secondly, the new UCNP/dendrimers allowed us to evaluate the feasibility of quantitative analyte imaging in vivo using a popular ratiometric UCNP-to-ligand excitation energy transfer (EET) scheme. Our results show that the ratio of UCNP emission bands, which for quantitative sensing should respond selectively to the analyte of interest, is also strongly affected by optical heterogeneities of the medium. On the other hand, the luminescence decay times of UCNPs, which are independent of the medium properties, are modulated via EET only insignificantly. As such, quantitative analyte sensing in biological tissues with UCNP-based probes still remains a challenge.

Efficacy of Modern Diabetes Treatments DPP-4i, SGLT-2i, and GLP-1RA in White and Asian Patients With Diabetes: A Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The pathophysiology of type 2 diabetes differs markedly by ethnicity. PURPOSE: A systematic review and meta-analysis was conducted to assess the impact of ethnicity on the glucose-lowering efficacy of the newer oral agents, sodium-glucose cotransporter 2 inhibitors (SGLT-2i), glucagon-like peptide 1 receptor agonists (GLP-1RA), and dipeptidyl peptidase 4 inhibitors (DPP-4i), using evidence from randomized clinical trials (RCTs). DATA SOURCES: A literature search was conducted in PubMed of all randomized, placebo-controlled trials of DPP-4i, SGLT-2i, and GLP-1RA. The search strategy was developed based on Medical Subject Headings (MeSH) terms and keywords. STUDY SELECTION: A total of 64 studies that qualified for meta-analysis after full-text review based on predefined inclusion and exclusion criteria-RCTs with at least 50 patients in each arm, >70% of population from Asian or white group, duration ≥24 weeks, and publication up to March 2019-were selected for systematic review and meta-analysis. DATA EXTRACTION: Data extraction was done for aggregated study-level data by two independent researchers. Absolute changes in HbA1c (%) from baseline to 24 weeks between the drug and placebo were considered as the primary end point of the study. DATA SYNTHESIS: Change in HbA1c was evaluated by computing mean differences and 95% CIs between treatment and placebo arms. LIMITATIONS: The study is based on summarized data and could not be separated based on East Asians and South Asians. CONCLUSIONS: The glucose-lowering efficacy of SGLT-2i, and to a lesser extent DPP-4i, was greater in studies of predominantly Asian ethnicity compared with studies of predominantly white ethnicity. There was no difference seen by ethnicity for GLP-1RA.

Fluorescence Lifetime-Based Tumor Contrast Enhancement Using an EGFR Antibody-Labeled Near-Infrared Fluorophore.

PURPOSE: Imaging techniques for highly specific detection of cancer cells in vivo can have applications ranging from preclinical drug discovery studies to clinical cancer diagnosis and surgical therapy. Although fluorescence imaging using cancer-targeted antibodies has shown promise, nonspecific probe accumulation in tissue results in significant background fluorescence, reducing detection sensitivity using traditional intensity-based continuous-wave (CW) fluorescence imaging. Here we demonstrate that fluorescence lifetime (FLT) imaging can provide significant tumor contrast enhancement over CW intensity in preclinical models of human breast cancer. EXPERIMENTAL DESIGN: Mice bearing MDA-MB-231 tumors were injected with anti-EGFR antibody conjugated to the fluorescent dye IRDye 800CW (anti-EGFR-800). Time domain fluorescence imaging was performed in vivo and in situ up to 48 hours after dye injection. RESULTS: Mice injected with anti-EGFR-800 showed a significantly longer FLT (0.7 ± 0.03 ns) compared with the FLT of nonspecific probe uptake in liver (0.63 ± 0.05 ns), providing a dramatic improvement in sensitivity and specificity compared with CW intensity. IgG antibody-conjugated IRDye 800CW did not show an increased FLT compared with normal tissue, suggesting that the FLT increase of anti-EGFR-800 in tumors was associated with receptor expression. Using serial surgery, we show that FLT allows the detection of smaller residual tumors in the surgical bed than possible using CW intensity. CONCLUSIONS: Our data suggest that FLT can significantly enhance tumor contrast using fluorescently labeled antibodies, thereby accelerating the efficient clinical application of these probes for margin assessment in image-guided surgery and for highly specific detection of tumor receptors in vivo.

Task sharing with non-physician health-care workers for management of blood pressure in low-income and middle-income countries: a systematic review and meta-analysis.

BACKGROUND: Task sharing for the management of hypertension could be useful for understaffed and resource-poor health systems. We assessed the effectiveness of task-sharing interventions in improving blood pressure control among adults in low-income and middle-income countries. METHODS: We searched the Cochrane Library, PubMed, Embase, and CINAHL for studies published up to December 2018. We included intervention studies involving a task-sharing strategy for management of blood pressure and other cardiovascular risk factors. We extracted data on population, interventions, blood pressure, and task sharing groups. We did a meta-analysis of randomised controlled trials. FINDINGS: We found 3012 references, of which 54 met the inclusion criteria initially. Another nine studies were included following an updated search. There were 43 trials and 20 before-and-after studies. We included 31 studies in our meta-analysis. Systolic blood pressure was decreased through task sharing in different groups of health-care workers: the mean difference was -5·34 mm Hg (95% CI -9·00 to -1·67, I2=84%) for task sharing with nurses, -8·12 mm Hg (-10·23 to -6·01, I2=57%) for pharmacists, -4·67 mm Hg (-7·09 to -2·24, I2=0%) for dietitians, -3·67 mm Hg (-4·58 to -2·77, I2=24%) for community health workers, and -4·85 mm Hg (-6·12 to -3·57, I2=76%) overall. We found a similar reduction in diastolic blood pressure (overall mean difference -2·92 mm Hg, -3·75 to -2·09, I2=80%). The overall quality of evidence based on GRADE criteria was moderate for systolic blood pressure, but low for diastolic blood pressure. INTERPRETATION: Task-sharing interventions are effective in reducing blood pressure. Long-term studies are needed to understand their potential impact on cardiovascular outcomes and mortality. FUNDING: Wellcome Trust/DBT India Alliance.

Measuring childhood socioeconomic position in health research: Development and validation of childhood socioeconomic position questionnaire using mixed method approach.

Background: There is no single best indicator to assess the childhood socioeconomic position (CSEP) in public health research. The aim of the study is to develop and validate a new questionnaire, with adequate psychometric properties, to measure the childhood SEP of the young adults. Methods: The first phase consisted of a qualitative phase to identify the variables to measure childhood SEP through the in-depth interviews among 15 young adults (18-45 years) of rural Kerala. The second phase was a quantitative phase to validate the questionnaire through a cross sectional survey among 200 young adults of Kerala. We did content validity, reliability tests and construct validity by using exploratory factor analysis of the questionnaire to demonstrate its psychometric properties. Results: The qualitative analysis reported 26 variables spread across 5 domains to measure the CSEP. Finally, the questionnaire has 11 questions with 3 domains named as value added through paternity, maternal occupation-related factors and parental education. The questionnaire has good reliability (Cronbach's α=0.88) also. Conclusion: We have developed a reliable and valid questionnaire to measure the childhood SEP of younger adults and can be used in various public health research.