ATFS-1 counteracts mitochondrial DNA damage by promoting repair over transcription.

The ability to balance conflicting functional demands is critical for ensuring organismal survival. The transcription and repair of the mitochondrial genome (mtDNA) requires separate enzymatic activities that can sterically compete1, suggesting a life-long trade-off between these two processes. Here in Caenorhabditis elegans, we find that the bZIP transcription factor ATFS-1/Atf5 (refs. 2,3) regulates this balance in favour of mtDNA repair by localizing to mitochondria and interfering with the assembly of the mitochondrial pre-initiation transcription complex between HMG-5/TFAM and RPOM-1/mtRNAP. ATFS-1-mediated transcriptional inhibition decreases age-dependent mtDNA molecular damage through the DNA glycosylase NTH-1/NTH1, as well as the helicase TWNK-1/TWNK, resulting in an enhancement in the functional longevity of cells and protection against decline in animal behaviour caused by targeted and severe mtDNA damage. Together, our findings reveal that ATFS-1 acts as a molecular focal point for the control of balance between genome expression and maintenance in the mitochondria.

Lessons learned in the Apple Heart Study and implications for the data management of future digital clinical trials.

The digital clinical trial is fast emerging as a pragmatic trial that can improve a trial's design including recruitment and retention, data collection and analytics. To that end, digital platforms such as electronic health records or wearable technologies that enable passive data collection can be leveraged, alleviating burden from the participant and study coordinator. However, there are challenges. For example, many of these data sources not originally intended for research may be noisier than traditionally obtained measures. Further, the secure flow of passively collected data and their integration for analysis is non-trivial. The Apple Heart Study was a prospective, single-arm, site-less digital trial designed to evaluate the ability of an app to detect atrial fibrillation. The study was designed with pragmatic features, such as an app for enrollment, a wearable device (the Apple Watch) for data collection, and electronic surveys for participant-reported outcomes that enabled a high volume of patient enrollment and accompanying data. These elements led to challenges including identifying the number of unique participants, maintaining participant-level linkage of multiple complex data streams, and participant adherence and engagement. Novel solutions were derived that inform future designs with an emphasis on data management. We build upon the excellent framework of the Clinical Trials Transformation Initiative to provide a comprehensive set of guidelines for data management of the digital clinical trial that include an increased role of collaborative data scientists in the design and conduct of the modern digital trial.

The development of a mobile app-focused deduplication strategy for the Apple Heart Study that informs recommendations for future digital trials.

An app-based clinical trial enrolment process can contribute to duplicated records, carrying data management implications. Our objective was to identify duplicated records in real time in the Apple Heart Study (AHS). We leveraged personal identifiable information (PII) to develop a dissimilarity score (DS) using the Damerau-Levenshtein distance. For computational efficiency, we focused on four types of records at the highest risk of duplication. We used the receiver operating curve (ROC) and resampling methods to derive and validate a decision rule to classify duplicated records. We identified 16,398 (4%) duplicated participants, resulting in 419,297 unique participants out of a total of 438,435 possible. Our decision rule yielded a high positive predictive value (96%) with negligible impact on the trial's original findings. Our findings provide principled solutions for future digital trials. When establishing deduplication procedures for digital trials, we recommend collecting device identifiers in addition to participant identifiers; collecting and ensuring secure access to PII; conducting a pilot study to identify reasons for duplicated records; establishing an initial deduplication algorithm that can be refined; creating a data quality plan that informs refinement; and embedding the initial deduplication algorithm in the enrolment platform to ensure unique enrolment and linkage to previous records.

Arrhythmias Other Than Atrial Fibrillation in Those With an Irregular Pulse Detected With a Smartwatch: Findings From the Apple Heart Study.

[Figure: see text].

PINK1 and parkin shape the organism-wide distribution of a deleterious mitochondrial genome.

In multiple species, certain tissue types are prone to acquiring greater loads of mitochondrial genome (mtDNA) mutations relative to others, but the mechanisms that drive these heteroplasmy differences are unknown. We find that the conserved PTEN-induced putative kinase (PINK1/PINK-1) and the E3 ubiquitin-protein ligase parkin (PDR-1), which are required for mitochondrial autophagy (mitophagy), underlie stereotyped differences in heteroplasmy of a deleterious mitochondrial genome mutation (ΔmtDNA) between major somatic tissues types in Caenorhabditis elegans. We demonstrate that tissues prone to accumulating ΔmtDNA have lower mitophagy responses than those with low mutation levels. Moreover, we show that ΔmtDNA heteroplasmy increases when proteotoxic species that are associated with neurodegenerative disease and mitophagy inhibition are overexpressed in the nervous system. These results suggest that PINK1 and parkin drive organism-wide patterns of heteroplasmy and provide evidence of a causal link between proteotoxicity, mitophagy, and mtDNA mutation levels in neurons.

Large-Scale Assessment of a Smartwatch to Identify Atrial Fibrillation.

BACKGROUND: Optical sensors on wearable devices can detect irregular pulses. The ability of a smartwatch application (app) to identify atrial fibrillation during typical use is unknown. METHODS: Participants without atrial fibrillation (as reported by the participants themselves) used a smartphone (Apple iPhone) app to consent to monitoring. If a smartwatch-based irregular pulse notification algorithm identified possible atrial fibrillation, a telemedicine visit was initiated and an electrocardiography (ECG) patch was mailed to the participant, to be worn for up to 7 days. Surveys were administered 90 days after notification of the irregular pulse and at the end of the study. The main objectives were to estimate the proportion of notified participants with atrial fibrillation shown on an ECG patch and the positive predictive value of irregular pulse intervals with a targeted confidence interval width of 0.10. RESULTS: We recruited 419,297 participants over 8 months. Over a median of 117 days of monitoring, 2161 participants (0.52%) received notifications of irregular pulse. Among the 450 participants who returned ECG patches containing data that could be analyzed - which had been applied, on average, 13 days after notification - atrial fibrillation was present in 34% (97.5% confidence interval [CI], 29 to 39) overall and in 35% (97.5% CI, 27 to 43) of participants 65 years of age or older. Among participants who were notified of an irregular pulse, the positive predictive value was 0.84 (95% CI, 0.76 to 0.92) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular pulse notification and 0.71 (97.5% CI, 0.69 to 0.74) for observing atrial fibrillation on the ECG simultaneously with a subsequent irregular tachogram. Of 1376 notified participants who returned a 90-day survey, 57% contacted health care providers outside the study. There were no reports of serious app-related adverse events. CONCLUSIONS: The probability of receiving an irregular pulse notification was low. Among participants who received notification of an irregular pulse, 34% had atrial fibrillation on subsequent ECG patch readings and 84% of notifications were concordant with atrial fibrillation. This siteless (no on-site visits were required for the participants), pragmatic study design provides a foundation for large-scale pragmatic studies in which outcomes or adherence can be reliably assessed with user-owned devices. (Funded by Apple; Apple Heart Study ClinicalTrials.gov number, NCT03335800.).

Circulating iron levels influence the regulation of hepcidin following stimulated erythropoiesis.

The stimulation of erythrocyte formation increases the demand for iron by the bone marrow and this in turn may affect the levels of circulating diferric transferrin. As this molecule influences the production of the iron regulatory hormone hepcidin, we hypothesized that erythropoiesis-driven changes in diferric transferrin levels could contribute to the decrease in hepcidin observed following the administration of erythropoietin. To examine this, we treated mice with erythropoietin and examined diferric transferrin at various time points up to 18 hours. We also investigated the effect of altering diferric transferrin levels on erythropoietin-induced inhibition of Hamp1, the gene encoding hepcidin. We detected a decrease in diferric transferrin levels 5 hours after erythropoietin injection and prior to any inhibition of the hepatic Hamp1 message. Diferric transferrin returned to control levels 12 hours after erythropoietin injection and had increased beyond control levels by 18 hours. Increasing diferric transferrin levels via intravenous iron injection prevented the inhibition of Hamp1 expression by erythropoietin without altering hepatic iron concentration or the expression of Erfe, the gene encoding erythroferrone. These results suggest that diferric transferrin likely contributes to the inhibition of hepcidin production in the period shortly after injection of erythropoietin and that, under the conditions examined, increasing diferric transferrin levels can overcome the inhibitory effect of erythroferrone on hepcidin production. They also imply that the decrease in Hamp1 expression in response to an erythropoietic stimulus is likely to be mediated by multiple signals.

Does preoperative 25-hydroxyvitamin D status significantly affect the calcium kinetics after total thyroidectomy?

BACKGROUND: Although previous studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) is a risk factor for hypocalcemia after total thyroidectomy, the impact of preoperative 25-OHD on calcium (Ca)/parathyroid hormone (PTH) kinetics in the immediate postoperative period remains unclear. The study compared the postoperative Ca/PTH kinetics between different preoperative 25-OHD levels. PATIENTS: A total of 281 patients who underwent a total thyroidectomy were analyzed. Serum Ca was measured preoperatively within 1 h after surgery (Ca-D0) and on the following morning (Ca-D1). Preoperative 25-OHD was also measured after overnight fasting while postoperative PTH was checked at skin closure on day 0 (PTH-D0) and on the following morning on day 1 (PTH-D1). The Ca/PTH kinetics were compared between three groups (group I: preoperative 25-OHD < 10 ng/mL; group II: 25-OHD = 10-20 ng/mL; group III: 25-OHD > 20 ng/mL). RESULTS: Group I had significantly lower preoperative Ca (p = 0.016) and Ca-D0 (p = 0.036) but higher PTH-D1 (p = 0.015) than groups II and III. PTH-D0, Ca-D1, and the rate of clinically significant hypocalcemia were similar in the three groups. Group I had a significantly smaller Ca drop (-0.02 vs. 0.01 and 0.02 mmol/L, p = 0.011) and a tendency for a significantly smaller PTH drop (0.4 vs. 0.5 and 1.0 pmol/L, p = 0.073) than groups II and III. PTH-D1 (OR = 1.550) and 25-OHD (OR = 0.958) were independent factors for Ca drop from day 0 to day 1. CONCLUSIONS: Although group I began with lower serum Ca, those patients tended to have a greater PTH response to Ca drop and so preoperative 25-OHD did not significantly affect the overall Ca kinetics from preoperative to day 1.

Do low preoperative vitamin D levels reduce the accuracy of quick parathyroid hormone in predicting postthyroidectomy hypocalcemia?

BACKGROUND: Although some studies have suggested that low preoperative 25-hydroxyvitamin D (25-OHD) levels may increase the risk of hypocalcemia and decrease the accuracy of single quick parathyroid hormone in predicting hypocalcemia after total thyroidectomy, the literature remains scarce and inconsistent. Our study aimed to address these issues. METHODS: Of the 281 consecutive patients who underwent a total/completion total thyroidectomy, 244 (86.8%) did not require any oral calcium and/or calcitriol supplements (group 1), while 37 (13.2%) did (group 2) at hospital discharge. 25-OHD level was checked 1 day before surgery, and postoperative quick parathyroid hormone (PTH) was checked at skin closure (PTH-SC). Postoperative serum calcium was checked regularly. Hypocalcemia was defined by the presence of symptoms or adjusted calcium of <1.90 mmol/L. Significant factors for hypocalcemia were determined by univariate and multivariate analyses. The accuracy of PTH-SC in predicting hypocalcemia was measured by area under a receiver operating characteristic curve (AUC), and the AUC of PTH-SC was compared between patients with preoperative 25-OHD <15 and ≥15 ng/mL via bootstrapping. RESULTS: Preoperative 25-OHD level was not significantly different between groups 1 and 2 (13.1 vs. 12.5 ng/mL, p = 0.175). After adjusting for other significant factors, PTH-SC (odds ratio 2.49, 95% confidence interval 1.52-4.07, p < 0.001) and parathyroid autotransplantation (odds ratio 3.23, 95% confidence interval 1.22-8.60, p = 0.019) were the two independent factors for hypocalcemia. The AUC of PTH-SC was similar between those with 25-OHD <15 and ≥15 ng/mL (0.880 vs. 0.850, p = 0.61) CONCLUSIONS: Low 25-OHD was not a significant factor for hypocalcemia and did not lower the accuracy of quick PTH in predicting postthyroidectomy hypocalcemia.

Does using an energized device in open thyroidectomy reduce complications?

BACKGROUND: Although using energy devices during open thyroidectomy might shorten the procedure time compared with the conventional technique, its effect on procedure-related complications remains unclear and controversial. In an era of cost containment, we aimed to compare the rate of procedure-related complications (particularly vocal cord palsy and hypoparathyroidism) between patients who underwent thyroidectomy using reusable ultrasonic shears and those who did not. METHODS: Of 508 eligible patients, 237 (46.7%) underwent thyroidectomy using the SonoSurg (reusable ultrasonic shears; SonoSurg group) and 271 (53.3%) underwent thyroidectomy using the conventional technique (suture ligation and clips; conventional technique group). The reusable shears were autoclaved at the end of each procedure and replaced after every 20 cases. To evaluate the effect of the ultrasonic shears on procedure-related complications, the patient characteristics and outcomes were compared between the 2 groups. RESULTS: In the SonoSurg group, the total operating time (60 min versus 105 min, P < 0.001) and temporary (12.4% versus 25.5%, P = 0.009) and permanent hypoparathyroidism (1.9% versus 9.8%, P = 0.003) rates were significantly less than those in the conventional technique group. The permanent vocal cord palsy rate was similar (P = 0.262). On multivariate analysis, using the reusable shears (odds ratio 0.163; 95% confidence interval 0.047-0.570; P = 0.005) and parathyroid autotransplantation of at least 1 gland (odds ratio 0.370; 95% confidence interval 0.146-0.943; P = 0.037) were the 2 independent variables for permanent hypoparathyroidism after completion/total thyroidectomy. CONCLUSIONS: Using the reusable shears during open thyroidectomy was significantly associated with a shortened operating time and lower permanent hypoparathyroidism rate, although the vocal cord palsy rate remained similar.

Mercury accumulation in surface sediments of salt marshes of the Bay of Fundy.

Mercury contamination in Canada's Bay of Fundy is a priority concern because of elevated levels observed in fish, birds and wildlife. Salt marshes constitute an important part of the Bay's coastline and are potential stores of mercury for the region. We measured the amount of mercury accumulated over a 5-yr period from 1997 to 2002 in surface sediments of seven salt marshes along the New Brunswick coast of the Bay. The seven study sites extended from outer to inner Bay, spanning a gradient in tidal range (6-12 m) and sediment characteristics such as %LOI (4-29%) and sediment deposition rate (0.27-1.76 cm yr(-1)). In each study site, mercury was measured in low and high marsh areas. Sediment mercury concentrations ranged from 7 to 79 ng g(-1) and loading rates ranged from 0.1 to 1.1 mg m(-2). Total estimated 5-yr storage of mercury in salt marsh sediments of the Bay is 854+/-465 kg. We also compared sediment mercury loading to atmospheric inputs measured at a deposition monitoring station operating in New Brunswick from 1997 to 2002 and found that direct atmospheric deposition appears to be a minor input of mercury to these sediments. We are unaware of documentation of mercury loading in salt marshes on a bay-wide scale and over a constrained (5-yr) time period elsewhere.