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Abstract Context Hypoglycemia attenuates cardiovascular homeostatic autonomic control. This attenuation, known as the cardiovascular component of hypoglycemia-associated autonomic failure (HAAF), is characterized most notably by decreased baroreflex sensitivity (BRS) that begins during hypoglycemia and persists until at least the next day, despite return to euglycemia. Understanding the mechanisms underlying this reduction in BRS is important because BRS attenuation is associated with increased morbidity and mortality. Objective The objective of this work is to investigate the role of the adrenocorticotropin (ACTH)-adrenal axis in decreasing BRS. We tested the hypothesis that infusion of ACTH 1–24 (cosyntropin), as compared to placebo, would acutely suppress BRS, and that this decrease in BRS would be present the next day. Design A double-blind, placebo-controlled, random-order, cross-over study was conducted. Setting This study took place in a clinical research center. Participants Participants included healthy men and women. Interventions Interventions included an intravenous infusion of cosyntropin (70 μg/hour for 2.5 hours in the morning and again in the early afternoon) vs normal saline placebo. Main Outcome Measures Outcome measures included BRS during and 16 hours after cosyntropin vs placebo infusions. Results Cosyntropin infusion attenuated BRS (mm Hg/ms) as compared to placebo (baseline 17.8 ± 1.38 vs 17.0 ± 2.07; during 14.4 ± 1.43 vs 17.3 ± 1.65; and next day 14.8 ± 1.42 vs 18.9 ± 2.04; P < .05, time by treatment, analysis of variance). BRS was decreased during the final 30 minutes of the morning cosyntropin infusion as compared to baseline (P < .01) and remained suppressed the next day (16 hours after afternoon infusion) (P < .025). Placebo infusion did not significantly change BRS. Corrected QT interval was not affected. Conclusions ACTH attenuates BRS, raising the possibility that hypoglycemia-induced increases in ACTH may contribute to the cardiovascular component of HAAF.

The management of prolactinoma in the setting of gender-affirming hormone therapy (GAHT) is lacking in the literature. We present the case of a transgender woman who was found to have prolactinoma prior to initiating GAHT. Initially, medication effectively managed prolactin levels; however, upon starting GAHT, maintaining control of these levels became challenging. Opting to sustain GAHT without disruption and gain control over symptomatic hyperprolactinemia, the patient underwent endoscopic endonasal surgery, resulting in gross total tumor resection including the medial wall of the cavernous sinus. Postoperative assessments revealed normal prolactin levels without dopamine agonist medication, allowing uninterrupted continuation of GAHT; in the following months, prolactin has minimally increased with plans for monitoring without treatment for now due to intolerance of oral antidopaminergics and lack of visible lesion on follow-up magnetic resonance imaging.

Background, aim and scope This study is the first to investigate PBDE body burden with regard to the concurrent analyses of multiple human matrices, namely milk, placenta, and hair, collected from a group of childbearing-aged women at an electronic waste (e-waste) recycling site to determine the partitioning of PBDEs in these different human matrices and the possible health risks imposed to infants at the e-waste recycling site. Methods and methods Five sets of milk, placenta, and hair samples were collected from an e-waste site (Taizhou, Zhejiang Province) and a reference site (Lin'an city, Zhejiang Province; 245 km away from Taizhou) in China. The concentrations of total PBDEs in different human tissues were analyzed according to US EPA standard methods. Results PBDE body burdens of women from the e-waste site (milk 117 ± 191, 8.89-457 ng/g fat, placenta 19.5 ± 29.9, 1.28-72.1 ng/g fat, hair 110 ± 210, 8.47-486 ng/g dry wt.) showed significantly higher levels than those from the reference site (milk 2.06 ± 0.94, 1.0-3.56 ng/g fat, placenta 1.02 ± 0.36, 0.59-1.42 ng/g fat, hair 3.57 ± 2.03, 1.56-5.61 ng/g dry wt.) and were higher than those reported in other studies, due to e-waste recycling operations, especially open burning. On a dry-weight basis, the following trend was found for PBDE among the samples from Taizhou: hair≫milk>placenta. Among the donors, the body burden of an e-waste worker ranked second. Higher brominated BDEs (hepta-BDEs) contributed a significantly greater proportion to total PBDEs in hair of the Taizhou women (20%) than that in milk (2.9%) and in placenta (2.6%). The estimated intake of PBDEs of 6-month-old breastfed infants living at the e-waste site was 572 ± 839 ng/kg body wt/day, which was 57 times higher than that of infants from the reference site (10.1 ± 4.60 ng/kg body wt/day). Moreover, the maximum calculated value (2,240 ng/kg body wt/day) exceeded the chronic oral reference dose for penta-BDE (2,000 ng/kg/day) of US EPA. Discussion BDE-47 was the dominant congener accounting for 20-30% in all the individual samples, while higher-brominated congeners, for example, BDE-183 and BDE-190, contributed between 2% and 20%. The presence of hepta-BDE congeners (BDE-181, BDE-190) in hair of the women in Taizhou suggest that thermal degradation of Deca-BDE from the open burning of e-waste may have been their source because these congeners are not found in either Penta-BDE or Octa-BDE technical products. Of the three types of samples analyzed, it was also suspected that hair may be more favorable to higher-brominated compounds which might explain why the hair samples contained the highest total PBDE concentrations and the highest proportion of higher-brominated BDEs (hepta-BDEs). Conclusion This study provides evidence that primitive e-waste recycling in China leads to high PBDE body burdens in local residents and can potentially threaten the health of infants. Recommendations and perspectives Control measures should be imposed to minimize the level of pollutants resulting from e-waste processing operations to the environment and to humans. In-depth investigations on epidemiological studies of health impacts caused by e-waste recycling operations should be conducted. It is recommended that further measurements of PBDE levels in local food (e.g., fish, shellfish, dairy products, meat, fruits, and vegetables), dust, air, water, and human specimens be collected from a larger sample size at the e-waste processing site for the determination of human exposure pathways to PBDEs.

ObjectiveSerrated polyps (hyperplastic polyps, sessile or traditional serrated adenomas), which can arise in a sporadic or polyposis setting, predispose to colorectal cancer (CRC), especially those with microsatellite instability (MSI) due to MLH1 promoter methylation (MLH1me+). We investigate genetic alterations in the serrated polyposis pathway.DesignWe used a combination of exome sequencing and target gene Sanger sequencing to study serrated polyposis families, sporadic serrated polyps and CRCs, with validation by analysis of The Cancer Genome Atlas (TCGA) cohort, followed by organoid-based functional studies.ResultsIn one out of four serrated polyposis families, we identified a germline RNF43 mutation that displayed autosomal dominant cosegregation with the serrated polyposis phenotype, along with second-hit inactivation through loss of heterozygosity or somatic mutations in all serrated polyps (16), adenomas (5) and cancer (1) examined, as well as coincidental BRAF mutation in 62.5% of the serrated polyps. Concurrently, somatic RNF43 mutations were identified in 34% of sporadic sessile/traditional serrated adenomas, but 0% of hyperplastic polyps (p=0.013). Lastly, in MSI CRCs, we found significantly more frequent RNF43 mutations in the MLH1me+ (85%) versus MLH1me− (33.3%) group (p<0.001). These findings were validated in the TCGA MSI CRCs (p=0.005), which further delineated a significant differential involvement of three Wnt pathway genes between these two groups (RNF43 in MLH1me+; APC and CTNNB1 in MLH1me−); and identified significant co-occurrence of BRAF and RNF43 mutations in the MSI (p<0.001), microsatellite stable (MSS) (p=0.002) and MLH1me+ MSI CRCs (p=0.042). Functionally, organoid culture of serrated adenoma or mouse colon with CRISPR-induced RNF43 mutations had reduced dependency on R-spondin1.ConclusionsThese results illustrate the importance of RNF43, along with BRAF mutation in the serrated neoplasia pathway (both the sporadic and familial forms), inform genetic diagnosis protocol and raise therapeutic opportunities through Wnt inhibition in different stages of evolution of serrated polyps.

Leukaemia of various subtypes are driven by distinct chromosomal rearrangement or genetic abnormalities. The leukaemogenic fusion transcripts or genetic mutations serve as molecular markers for minimal residual disease (MRD) monitoring. The current study evaluated the applicability of several droplet digital PCR assays for the detection of these targets at RNA and DNA levels (atypical BCR::ABL1 e19a2, e23a2ins52, e13a2ins74, rare types of CBFB::MYH11 (G and I), PCM1::JAK2 , KMT2A::ELL2, PICALM::MLLT10 fusion transcripts and CEBPA frame-shift and insertion/duplication mutations) with high sensitivity. The analytical performances were assessed by the limit of blanks, limit of detection, limit of quantification and linear regression. Our data demonstrated serial MRD monitoring for patients at molecular level could become “digitalized”, which was deemed important to guide clinicians in treatment decision for better patient care.

Akt plays indispensable roles in cell proliferation, survival and metabolism. Mechanisms underlying posttranslational modification-mediated Akt activation have been extensively studied yet the Akt interactome is less understood. Here, we report that SAV1, a Hippo signaling component, inhibits Akt, a function independent of its role in Hippo signaling. Binding to a proline-tyrosine motif in the Akt-PH domain, SAV1 suppresses Akt activation by blocking Akt’s movement to plasma membrane. We further identify cancer-associated SAV1 mutations with impaired ability to bind Akt, leading to Akt hyperactivation. We also determine that MERTK phosphorylates Akt1-Y26, releasing SAV1 binding and allowing Akt responsiveness to canonical PI-3K pathway activation. This work provides a mechanism underlying MERTK-mediated Akt activation and survival signaling in kidney cancer. Akt activation drives oncogenesis and therapeutic resistance; this mechanism of Akt regulation by MERTK/SAV1 provides yet another complexity in an extensively studied pathway, and may yield prognostic information and therapeutic targets. Hyperactivation of Akt promotes tumorigenesis. Here, the authors show that SAV1, a member of Hippo signalling, interacts with Akt to suppress Akt activity and MERTK-mediated Akt phosphorylation relieves this suppression to facilitate Akt oncogenic activity in clear cell renal carcinomas.

This study aimed to examine the role of positive relationships and academic achievement in predicting student well-being, i.e. subjective happiness. This study employed a longitudinal design with two waves of data collection on a sample of 786 primary school students in Hong Kong. Students completed questionnaires on parent-child relationship, teacher-student relationship, peer relationship, academic achievement, and happiness at the beginning and end of the school year. Path analysis was used for data analysis. The results indicated that Time 1 parent-child relationship and peer relationship were associated with Time 2 academic achievement, after controlling for Time 1 academic achievement. However, only Time 1 parent-child relationship was predictive of Time 2 happiness. Time 2 academic achievement was a mediator between Time 1 parent-child relationship and peer relationship and Time 2 happiness. Furthermore, girls reported higher levels of academic achievement when they perceived better peer relationship than did boys, and girls were happier when they had higher levels of academic achievement than were boys. The results suggested the need to put in place strategies to enhance parent-child relationship, peer relationship, and a harmonious classroom.

In this trial of a recombinant VZV glycoprotein E subunit vaccine with the adjuvant AS01 B , the risk of herpes zoster and postherpetic neuralgia is shown to be significantly lower in association with the vaccine than with placebo among persons 70 years of age or older. Herpes zoster, or shingles, results from the reactivation of latent varicella–zoster virus (VZV) and typically manifests as a vesicular, painful dermatomal rash. 1 , 2 The most common complication of herpes zoster, postherpetic neuralgia, manifests as chronic neuropathic pain that can greatly limit daily activities. 1 , 3 – 6 The overall incidence of herpes zoster is 2.0 to 4.6 cases per 1000 person-years but increases with age to 10.0 to 12.8 per 1000 person-years among persons 80 years of age or older. 7 – 10 Similarly, the incidence of postherpetic neuralgia also increases with age. 10 – 13 Antiviral therapy can reduce the duration of herpes zoster rash . . .

This study introduced a novel but simple method to continuously measure footstrike patterns in runners using inexpensive force sensors. Two force sensing resistors were firmly affixed at the heel and second toe of both insoles to collect the time signal of foot contact. A total of 109 healthy young adults (42 males and 67 females) were recruited in this study. They ran on an instrumented treadmill at 0°, +10°, and -10° inclinations and attempted rearfoot, midfoot, and forefoot landings using real time visual biofeedback. Intra-step strike index and onset time difference between two force sensors were measured and analyzed with univariate linear regression. We analyzed 25,655 footfalls and found that onset time difference between two sensors explained 80-84% of variation in the prediction model of strike index (R-squared = 0.799-0.836, p<0.001). However, the time windows to detect footstrike patterns on different surface inclinations were not consistent. These findings may allow laboratory-based gait retraining to be implemented in natural running environments to aid in both injury prevention and performance enhancement.

ObjectivesThis is a qualitative study which aims to understand the lived experience of dietary changes among Chinese survivors of colorectal cancer who participated in a dietary intervention.SettingThe surgical and oncological departments of four public hospitals in Hong Kong.ParticipantsFifty-five Chinese colorectal cancer survivors who were aged 18 years or above and had received potentially curative treatment in the surgical and oncological departments in Hong Kong were examined. Participants’ mean age was 64 years, with 29 (53%) males.InterventionA 12-month dietary intervention delivered via face-to-face motivational interviews, fortnightly motivational phone calls, monthly electronic pamphlets, quarterly newsletters and quarterly group meeting.Outcome measureWe adopted the qualitative approach to capture participants’ perspectives and to apply the understanding pragmatically in everyday life. Content analysis was conducted.ResultsWe identified themes of motives to changes of dietary practices including (1) individual commitment to dietary change; (2) adaptive strategies in interpersonal contexts and (3) working with healthcare professionals during the journey.ConclusionsThe findings demonstrated how Chinese custom and culture posing unique challenges to colorectal cancer survivors and the need of having dietary advice from healthcare professionals. Participants were motivated to change their eating habits by support from family, friends and healthcare professionals. Our findings could help healthcare professionals provide specific dietary advice and guidance to Chinese colorectal cancer survivors.Trial registration numberNCT01708824.