A Cathepsin-Targeted Quenched Activity-Based Probe Facilitates Enhanced Detection of Human Tumors during Resection.

PURPOSE: Fluorescence-guided surgery using tumor-targeted contrast agents has been developed to improve the completeness of oncologic resections. Quenched activity-based probes that fluoresce after covalently binding to tumor-specific enzymes have been proposed to improve specificity, but none have been tested in humans. Here, we report the successful clinical translation of a cathepsin activity-based probe (VGT-309) for fluorescence-guided surgery. EXPERIMENTAL DESIGN: We optimized the specificity, dosing, and timing of VGT-309 in preclinical models of lung cancer. To evaluate clinical feasibility, we conducted a canine study of VGT-309 during pulmonary tumor resection. We then conducted a randomized, double-blind, dose-escalation study in healthy human volunteers receiving VGT-309 to evaluate safety. Finally, we tested VGT-309 in humans undergoing lung cancer surgery. RESULTS: In preclinical models, we found highly specific tumor cell labeling that was blocked by a broad spectrum cathepsin inhibitor. When evaluating VGT-309 for guidance during resection of canine tumors, we found that the probe selectively labeled tumors and demonstrated high tumor-to-background ratio (TBR; range: 2.15-3.71). In the Phase I human study, we found that VGT-309 was safe at all doses studied. In the ongoing Phase II trial, we report two cases in which VGT-309 localized visually occult, non-palpable tumors (TBRs = 2.83 and 7.18) in real time to illustrate its successful clinical translation and potential to improve surgical management. CONCLUSIONS: This first-in-human study demonstrates the safety and feasibility of VGT-309 to label human pulmonary tumors during resection. These results may be generalizable to other cancers due to cathepsin overexpression in many solid tumors.

Quality of patient-reported outcome reporting in trials of diabetes in pregnancy: A systematic review.

AIMS: Patient-reported outcomes (PROs) are reports of the patient's health status that come directly from the patient without interpretation by the clinician or anyone else. They are increasingly used in randomised controlled trials (RCTs). In this systematic review we identified RCTs conducted in women with diabetes in pregnancy which included PROs in their primary or secondary outcomes. We then evaluated the quality of PRO reporting against an internationally accepted reporting framework (Consolidated Standards of Reporting Trials (CONSORT-PRO) guidelines). METHODS: We searched online databases for studies published 2013-2021 using a combination of keywords. Two authors reviewed all abstracts independently. Data on study characteristics and the quality of PRO reporting were extracted from relevant studies. We conducted a multiple regression analysis to identify factors associated with high quality reporting. RESULTS: We identified 7122 citations. Thirty-five articles were included for review. Only 17% of RCTs included a PRO as a primary or secondary outcome. Out of a maximum score of 100 the median score was 46, indicating sub-optimal reporting. A multiple regression analysis did not reveal any factors associated with high quality reporting. CONCLUSIONS: Researchers should be mindful of the importance of PRO inclusion and reporting and include reliable PROs in trials.

Gleason grade accuracy of transperineal and transrectal prostate biopsies in MRI-naïve patients.

PURPOSE: Accurate assessment of Gleason grade is essential to guiding prostate cancer management. Not all healthcare systems have universal access to prostate MRI. We investigated whether transperineal (TP) prostate biopsies provide more accurate Gleason grading than transrectal (TR) biopsies in MRI-naïve patients. METHODS: Consecutive patients undergoing TP and TR systematic prostate needle biopsies from 2011 to 2018 were analysed. Patients who underwent radical prostatectomy (RP) within 180 days of biopsies were included. Patients undergoing MRI prior to biopsies were excluded. Pathological concordance, incidence of Gleason upgrading, and correlation coefficients among biopsies and RP Gleason grade were compared. A sub-analysis for concordance in anterior prostate tumours was conducted. RESULTS: 262 patients were included (112 TP; 150 TR), the median age was 63 years, and median time from biopsy to RP was 68 days. Concordance with RP histology for TP was 65% compared to 49% for TR (p = 0.011). Biopsy technique predicted RP concordance independent of the number of cores. Gleason upgrading occurred following 24% of TP versus 33% of TR biopsies. In anterior and apical tumours, upgrading occurred in 19% of TP biopsies and 38% of TR biopsies (p = 0.027). CONCLUSION: This study suggests TP approach to prostate biopsies result in improved histological grade accuracy in men whom MRI is not available, even after controlling for number of cores. TP approach also resulted in less upgrading for lesions in the anterior and apical prostate compared to TR.

A core outcome set for the treatment of pregnant women with pregestational diabetes: an international consensus study.

OBJECTIVE: To develop a core outcome set (COS) for randomised controlled trials (RCTs) evaluating the effectiveness of interventions for the treatment of pregnant women with pregestational diabetes mellitus (PGDM). DESIGN: A consensus developmental study. SETTING: International. POPULATION: Two hundred and five stakeholders completed the first round. METHODS: The study consisted of three components. (1) A systematic review of the literature to produce a list of outcomes reported in RCTs assessing the effectiveness of interventions for the treatment of pregnant women with PGDM. (2) A three-round, online eDelphi survey to prioritise these outcomes by international stakeholders (including healthcare professionals, researchers and women with PGDM). (3) A consensus meeting where stakeholders from each group decided on the final COS. MAIN OUTCOME MEASURES: All outcomes were extracted from the literature. RESULTS: We extracted 131 unique outcomes from 67 records meeting the full inclusion criteria. Of the 205 stakeholders who completed the first round, 174/205 (85%) and 165/174 (95%) completed rounds 2 and 3, respectively. Participants at the subsequent consensus meeting chose 19 outcomes for inclusion into the COS: trimester-specific haemoglobin A1c, maternal weight gain during pregnancy, severe maternal hypoglycaemia, diabetic ketoacidosis, miscarriage, pregnancy-induced hypertension, pre-eclampsia, maternal death, birthweight, large for gestational age, small for gestational age, gestational age at birth, preterm birth, mode of birth, shoulder dystocia, neonatal hypoglycaemia, congenital malformations, stillbirth and neonatal death. CONCLUSIONS: This COS will enable better comparison between RCTs to produce robust evidence synthesis, improve trial reporting and optimise research efficiency in studies assessing treatment of pregnant women with PGDM. TWEETABLE ABSTRACT: 165 key stakeholders have developed #Treatment #CoreOutcomes in pregnant women with #diabetes existing before pregnancy.

A systematic review on outcome reporting in randomised controlled trials assessing treatment interventions in pregnant women with pregestational diabetes.

BACKGROUND: Pregestational diabetes mellitus (PGDM) is associated with adverse pregnancy outcomes. Studies assessing interventions to improve maternal and infant outcomes have increased exponentially over recent years. Several outcomes in this field of maternal diabetes are rare, making it difficult to synthesise evidence. OBJECTIVES: To collect outcomes reported in studies assessing treatment interventions in pregnant women with PGDM. SEARCH STRATEGY: CENTRAL, Web of Science, Medline, CINAHL, Embase and ClinicalTrials.gov from their inception until 27 January 2020. SELECTION CRITERIA: Any randomised controlled trial assessing treatment interventions in pregnant women with PGDM reported in English. DATA COLLECTION AND ANALYSIS: Two independent reviewers assessed the suitability of articles and retrieved the data. Outcomes extracted from the literature were broadly categorised into maternal, fetal/infant or other outcomes by the study advisory group. MAIN RESULTS: Sixty-seven of the 1475 studies identified fulfilled the inclusion criteria. The median number of outcomes reported per study was 15 (range 1-46). The majority of studies were from North America and Europe. Insulin and metformin were the most commonly investigated pharmacological interventions. Glucose monitoring was the most assessed technological intervention. In all, 131 unique outcomes were extracted: maternal (n = 69), fetal/infant (n = 61) and other (n = 1). CONCLUSIONS: Outcome reporting in treatment interventions trials of pregnant women with PGDM is varied, making it difficult to synthesise evidence, especially for rare outcomes. Systems are needed to standardise outcome reporting in future clinical trials and so facilitate evidence synthesis in this area of maternal diabetes. REGISTRATION: The systematic review was registered prospectively with the International Prospective Register of Systematic Reviews (PROSPERO) database (Registration number CRD42020173549). TWEETABLE ABSTRACT: Outcome reporting is heterogeneous in intervention trials of pregnant women with diabetes existing before pregnancy.

Diabetes care and pregnancy outcomes for women with pregestational diabetes in Ireland.

AIMS: Pre-gestational diabetes mellitus (PGDM) is associated with adverse outcomes. We aimed to examine pregnancies affected by PGDM; report on these pregnancy outcomes and compare outcomes for patients with type 1 versus type 2 diabetes mellitus; compare our findings to published Irish and United Kingdom (UK) data and identify potential areas for improvement. METHODS: Between 2016 and 2018 information on 679 pregnancies from 415 women with type 1 Diabetes Mellitus and 244 women with type 2 diabetes was analysed. Data was collected on maternal characteristics; pregnancy preparation; glycaemic control; pregnancy related complications; foetal and maternal outcomes; unscheduled hospitalisations; congenital anomalies and perinatal deaths. RESULTS: Only 15.9% of women were adequately prepared for pregnancy. Significant deficits were identified in availability and attendance at pre-pregnancy clinic, use of folic acid, attaining appropriate glycaemic targets and appropriate retinal screening. The majority of pregnancies (n = 567, 83.5%) resulted in a live birth but the large number of infants born large for gestational age (LGA) (n = 280, 49.4%), born prematurely <37 weeks and requiring neonatal intensive care unit (NICU) admission continue to be significant issues. CONCLUSIONS: This retrospective cohort study identifies multiple targets for improvements in the provision of care to women with pre-gestational DM which are likely to translate into better pregnancy outcomes.

Mass and the Dangers of Syncope.

Introduction Syncope is defined as a transient, self-limited loss of consciousness with an inability to maintain postural tone that is followed by spontaneous recovery. We revisit situational syncope focusing on one situation, Mass. Methods We interrogated our electronic syncope database for key terms associated with situational syncope. From the most commonly encountered situation, Mass, we interrogated the results of tilt testing performed to identify evidence of orthostatic hypotension. Results There were 110 cases of situational syncope identified with 56.3% (n=62) taking place at mass. All had tilt table testing performed and 15.4% (n=17) had evidence of orthostatic hypotension. Conclusion The multiple sudden changes in position during mass from sitting to kneeling to standing can precipitate an episode of orthostatic hypotension. Consideration should be given as to whether it is safe for older mass goers to be subjected to such significant orthostatic stress.

An Irish National Diabetes in Pregnancy Audit: aiming for best outcomes for women with diabetes.

AIMS: The purpose of this study was to identify the number of pregnancies affected by pre-gestational diabetes in the Republic of Ireland; to report on pregnancy outcomes and to identify areas for improvement in care delivery and clinical outcomes. METHODS: Healthcare professionals caring for women with pre-gestational diabetes during pregnancy were invited to participate in this retrospective study. Data pertaining to 185 pregnancies in women attending 15 antenatal centres nationally were collected and analysed. Included pregnancies had an estimated date of delivery between 1 January and 31 December 2015. RESULTS: The cohort consisted of 122 (65.9%) women with Type 1 diabetes and 56 (30.3%) women with Type 2 diabetes. The remaining 7 (3.8%) pregnancies were to women with maturity-onset diabetes of the young (MODY) (n = 6) and post-transplant diabetes (n = 1). Overall women were poorly prepared for pregnancy and lapses in specific areas of service delivery including pre-pregnancy care and retinal screening were identified. The majority of pregnancies 156 (84.3%) resulted in a live birth. A total of 103 (65.5%) women had a caesarean delivery and 58 (36.9%) infants were large for gestational age. CONCLUSIONS: This audit identifies clear areas for improvement in delivery of care for women with diabetes in the Republic of Ireland before and during pregnancy.

Lessons learned from lifestyle prevention trials in gestational diabetes mellitus.

Gestational diabetes mellitus (GDM) is associated with an increased risk of adverse outcomes for mother and infant both at birth and later in life. A large body of evidence is now available relating to antenatal prevention of GDM. Overall, despite some individual trials of a variety of lifestyle interventions revealing benefit, many more have shown no effect from the second trimester onwards, even with significant gestational weight gain limitation. At-risk women often seem reluctant to engage in lifestyle changes and frequently cannot adhere to recommended interventions even within a clinical trial setting. Many trials have not considered the heterogeneity of diabetes first discovered in pregnancy, something of importance into the future. Future work should focus on designing interventions acceptable to the population at risk, whether those taking place before or during the first trimester of pregnancy are effective, and whether greater individualization can identify those women most likely to benefit.

Diabetes in pregnancy: worse medical outcomes in type 1 diabetes but worse psychological outcomes in gestational diabetes.

BACKGROUND: Women with diabetes experience an increased risk of adverse pregnancy outcomes. AIM: We aim to describe and quantify the psychological impact of the diagnosis of diabetes in pregnant women with type 1 diabetes and gestational diabetes mellitus (GDM) compared to each other and to their counterparts without diabetes. DESIGN: This is a survey-based study with prospective collection of pregnancy outcome data. METHODS: A total of 218 pregnant women (50% with diabetes) were administered questionnaires relating to psychological health. Maternal and neonatal characteristics and pregnancy outcomes were collected. Associations between key psychometric and health outcome variables were examined. RESULTS: At least 25% of women in all three pregnancy groups had scores indicating affective distress in at least one domain. Compared to those with type 1 diabetes, women with GDM evidenced a greater number of uplifts in pregnancy (U = 94, P = 0.041), but also higher levels of overall anxiety (U = 92, P = 0.03) and stress (U = 82, P < 0.01). Women with GDM also had significantly elevated overall depression scores, compared with the control group (U = 34, P = 0.02). Both groups of women with diabetes had clinically elevated levels of diabetes-related distress. There were no associations between maternal psychological variables and pregnancy outcomes. CONCLUSIONS: This work highlights a potential role for targeted psychological interventions to address and relieve symptoms of anxiety and depression among pregnant women with diabetes.

Care of women with diabetes before, during and after pregnancy: time for a new approach?

AIMS: This study assesses the impact of pregnancy and pre-pregnancy care on longer-term treatment goals in women with diabetes. METHODS: This retrospective study included women with Type 1 (n = 247) and Type 2 diabetes (n = 137) who were evaluated before, during and after pregnancy. RESULTS: Among women with Type 1 diabetes, average HbA1c at 12 months post-partum was similar to the preconception level [63 vs. 64 mmol/mol (7.9% vs. 8.0%), P = 0.60]. This was also the case for women with Type 2 diabetes [52 vs. 52 mmol/mol (6.9% vs. 6.9%), P = 0.79]. At 12 months post-partum, there was no improvement in other measures of diabetes control and one in five women are lost to follow-up from clinical care. In total, 44.9% of women with Type 1 diabetes and 27.7% of those with Type 2 diabetes attended pre-pregnancy care. Attendees maintained superior glycaemic control throughout the study and were more likely to be receiving specialist care post-partum. CONCLUSIONS: These findings identify a need to change our approach to the reproductive care of women with diabetes. In particular, efforts should be made to ensure all women have access to and attend pre-pregnancy care, and barriers to engagement with post-partum care should be addressed.

Maternal supplementation of seaweed-derived polysaccharides improves intestinal health and immune status of suckling piglets.

The experiment investigated the effect of maternal dietary supplementation of seaweed-derived polysaccharides (SDP) (-SDP v. +SDP, n   20) from day 83 of gestation until weaning (day 28) on selected sow faeces and piglet digesta microbiota populations, piglet small-intestinal morphology, and intestinal nutrient transporter and inflammatory cytokine gene expression at birth, 48 h after birth and weaning. The effect of maternal dietary treatment on the piglet gene expression profile of inflammatory cytokines in the colon following a lipopolysaccharide (LPS) challenge was also investigated. Dietary SDP reduced sow faecal Enterobacteriaceae gene numbers at parturition. Small-intestinal morphology, nutrient transporter and cytokine gene expression in newborn piglets did not differ between maternal dietary treatments (P > 0·10). At 48 h after birth, sodium-glucose-linked transporter 1 gene expression was down-regulated in the ileum of piglets suckling the SDP-supplemented sows compared with those suckling the basal sows (P = 0·050). There was a SDP × LPS challenge interaction on IL-1 and IL-6 gene expression in the colon of piglets (P < 0·05). The gene expression of IL-1 and IL-6 was down-regulated in the LPS-challenged colon of piglets suckling the SDP sows compared with those suckling the basal sows (P < 0·05). However, there was no difference in IL-1 and IL-6 gene expression in the unchallenged colon between treatment groups. At weaning, piglets suckling the SDP-supplemented sows had increased villus height in the jejunum and ileum compared with those suckling the basal-fed sows (P < 0·05). In conclusion, maternal dietary SDP supplementation enhanced the immune response of suckling piglets and improved gut morphology, making them more immune competent to deal with post-weaning adversities.

Postpartum glucose testing for women with gestational diabetes mellitus: Improving regional recall rates.

Our aim was to evaluate attendance for postpartum glucose testing among women attending five antenatal centres with a diagnosis of GDM in the preceding pregnancy. A central, regional coordinator who made verbal and written contact with each individual facilitated a favourable recall rate of 75%.

The management of type 1 and type 2 diabetes in pregnancy.

Pregestational diabetes is a common medical complication of pregnancy and preconception planning is an essential component of care for affected women of childbearing age. Once pregnant, structured care in a multidisciplinary team setting is necessary to ensure optimal outcomes. Although significant progress has been made, these women and their offspring remain to have a significantly elevated risk of multiple adverse complications. Structured programmes using information technology and enabling access to novel technologies may facilitate our goal of ensuring an outcome closer to that of a pregnancy unaffected by diabetes.

Impact of patient and navigator race and language concordance on care after cancer screening abnormalities.

BACKGROUND: Patient navigation improves the timely diagnosis of cancer among minorities, but little is known about the effects of patient and navigator race and language concordance on health outcomes. METHODS: The authors investigated the effects of patient and navigator race and language concordance on the time to diagnosis of cancer screening abnormalities among participants in the Boston Patient Navigation Research Program, a clinical effectiveness trial for women who had breast or cervical cancer screening abnormalities identified from January 1, 2007 to December 31, 2008. Hazard ratios and 95% confidence intervals were estimated using proportional hazards regression adjusting for clinical and demographic factors. RESULTS: In total, 1257 women had breast cancer screening abnormalities (n = 655) or cervical cancer screening abnormalities (n = 602) identified, and 56% were nonwhite. Language concordance was associated with timelier resolution for all patients in the cervical cancer screening abnormalities group during the first 90 days (adjusted hazard ratio, 1.46; 95% confidence interval, 1.18-1.80), and specifically for Spanish speakers during the first 90 days (adjusted hazard ratio, 1.43; 95% confidence interval, 1.10-1.84), but no difference was observed after 90 days for women who had cervical cancer screening abnormalities or at any time for those who had breast cancer screening abnormalities. Race concordance was associated with significant decreases in the time to diagnosis for minority women with breast and cervical cancer screening abnormalities in analyses stratified by race, but no differences were observed in analyses that included all women. CONCLUSIONS: Patient navigator race and language concordance improved the timeliness of care in a minority population. Patient navigators who are racially/ethnically diverse and multilingual may help address barriers to care and improve cancer outcomes for low-income minorities.

A white paper--consensus and recommendations of a global harmonization team on assessing the impact of immunogenicity on pharmacokinetic measurements.

The Global Bioanalysis Consortium (GBC) set up an international team to explore the impact of immunogenicity on pharmacokinetic (PK) assessments. The intent of this paper is to define the field and propose best practices when developing PK assays for biotherapeutics. We focus on the impact of anti-drug antibodies (ADA) on the performance of PK assay leading to the impact on the reported drug concentration and exposure. The manuscript describes strategies to assess whether the observed change in the drug concentration is due to the ADA impact on drug clearance rates or is a consequence of ADA interference in the bioanalytical method applied to measure drug concentration. This paper provides the bioanalytical scientist guidance for developing ADA-tolerant PK methods. It is essential that the data generated in the PK, ADA, pharmacodynamic and efficacy/toxicity evaluations are viewed together. Therefore, the extent for the investigation of the PK sensitivity to the presence of ADA should be driven by the project needs and risk based.