"Anything that would help is a positive development": feasibility, tolerability, and user experience of smartphone-based digital phenotyping for people with and without type 2 diabetes.

Background: Digital phenotyping, the in-situ collection of passive (phone sensor) and active (daily surveys) data using a digital device, may provide new insights into the complex relationship between daily behaviour and mood for people with type 2 diabetes. However, there are critical knowledge gaps regarding its use in people with type 2 diabetes. This study assessed feasibility, tolerability, and user experience of digital phenotyping in people with and without type 2 diabetes after participation in a 2-month digital phenotyping study in Ireland. At study completion, participants rated methodology elements from "not a problem" to a "serious problem" on a 5-point scale and reported their comfort with the potential future use of digital phenotyping in healthcare, with space for qualitative expansion. Results: Eighty-two participants completed baseline. Attrition was 18.8%. Missing data ranged from 9-44% depending on data stream. Sixty-eight participants (82.9%) completed the user experience questionnaire (51.5% with type 2 diabetes; 61.8% female; median age-group 50-59). Tolerability of digital phenotyping was high, with "not a problem" being selected 76.5%-89.7% of the time across questions. People with type 2 diabetes (93.9%) were significantly more likely to be comfortable with their future healthcare provider having access to their digital phenotyping data than those without (53.1%), χ2 (1) = 14.01, p = < .001. Free text responses reflected a range of positive and negative experiences with the study methodology. Conclusions: An uncompensated, 2-month digital phenotyping study was feasible among people with and without diabetes, with low attrition and reasonable missing data rates. Participants found digital phenotyping to be acceptable, and even enjoyable. The potential benefits of digital phenotyping for healthcare may be more apparent to people with type 2 diabetes than the general population. Supplementary Information: The online version contains supplementary material available at 10.1186/s44247-024-00116-6.

Depressive symptoms and sleep problems as risk factors for heart disease: a prospective community study.

AIMS: The goals of the present study were to examine the associations between depressive symptoms, sleep problems and the risk of developing heart disease in a Canadian community sample. METHODS: Baseline data were from the CARTaGENE study, a community health survey of adults aged 40-69 years in Quebec, Canada. Incidence of heart disease was examined in N = 33 455 participants by linking survey data with administrative health insurance data. Incident heart disease was identified using the World Health Organization's International Classification of Diseases, 9th or 10th edition (ICD-9 and ICD-10) diagnostic codes for heart disease. Sleep problems were assessed with diagnostic codes for sleep disorders within the 2 years preceding the baseline assessment. Average sleep duration was assessed by self-report. Depressive symptoms were assessed with the nine-item Patient Health Questionnaire. RESULTS: In total, 2448 (7.3%) participants developed heart disease over an average follow-up period of 4.6 years. Compared to those without depressive symptoms and with no sleep disorders, those with elevated depressive symptoms and a sleep disorder (HR = 2.60, 95% CI 1.83-3.69), those with depressive symptoms alone (HR = 1.40, 95% CI 1.25-1.57) and those with sleep disorders alone (HR = 1.33, 95% CI 1.03-1.73) were more likely to develop heart disease. Test of additive interaction suggested a synergistic interaction between depressive symptoms and sleep disorders (synergy index = 2.17 [95% CI 1.01-4.64]). When sleep duration was considered, those with long sleep duration and elevated depressive symptoms were more likely to develop heart disease than those with long sleep alone (HR = 1.77, 95% CI 1.37-2.28; and HR = 1.16, 95% CI 0.99-1.36, respectively). CONCLUSIONS: Depression and diagnosed sleep disorders or long sleep duration are independent risk factors for heart disease and are associated with a stronger risk of heart disease when occurring together.

Investigating the longitudinal association between diabetes and anxiety: a systematic review and meta-analysis.

AIM: Previous research has indicated an association between diabetes and anxiety. However, no synthesis has determined the direction of this association. The aim of this study was to determine the longitudinal relationship between anxiety and diabetes. METHODS: We searched seven databases for studies examining the longitudinal relationship between anxiety and diabetes. Two independent reviewers screened studies from a population aged 16 or older that examined either anxiety as a risk factor for incident diabetes or diabetes as a risk factor for incident anxiety. Studies that met eligibility criteria were put forward for data extraction and meta-analysis. RESULTS: In total 14 studies (n = 1 760 800) that examined anxiety as a risk factor for incident diabetes and two (n = 88 109) that examined diabetes as a risk factor for incident anxiety were eligible for inclusion in the review. Only studies examining anxiety as a risk factor for incident diabetes were put forward for the meta-analysis. The least adjusted (unadjusted or adjusted for age only) estimate indicated a significant association between baseline anxiety with incident diabetes (odds ratio 1.47, 1.23-1.75). Furthermore, most-adjusted analyses indicated a significant association between baseline anxiety and incident diabetes. Included studies that examined diabetes to incident anxiety found no association. CONCLUSIONS: There was an association between baseline anxiety and incident diabetes. The results also indicate the need for more research to examine the direction of association from diabetes to incident anxiety. This work adds to the growing body of evidence that poor mental health increases the risk of developing diabetes.

Monitoring the efficacy of omega-3 supplementation on liver steatosis and carotid intima-media thickness: a pilot study.

PURPOSE: To determine the effects of omega-3 supplementation on liver fat and carotid intima-media thickness (IMT) and to assess accuracy of ultrasound (US) for grading liver steatosis. MATERIALS AND METHODS: In this one-way crossover pilot study, we assigned children with obesity and liver steatosis to receive 1.2 g daily of omega-3 supplementation vs. inactive sunflower oil for 24 or 12 weeks. Liver fat content was assessed by magnetic resonance spectroscopy (MRS), magnetic resonance imaging (MRI) and US, and common carotid IMT by US. Statistical analysis included Chi-square, Student's t-tests, ANOVA tests and receiver operating characteristic (ROC) curves. RESULTS: Omega-3 supplementation was associated with a trend towards decrease in MRS-determined liver fat fraction (0.7% and 2.1% decrease in the 24-week and 12-week omega-3 group, respectively) compared with the sunflower oil group (1.0% increase). These changes were not significant, whether assessed by MRS (P = 0.508), MRI (P = 0.508) or US (P = 0.678). Using US, the area under the ROC curves were 0.964, 0.817 and 0.783 for distinguishing inferred steatosis grades 0 vs. 1-2-3, 0-1 vs. 2-3 and 0-1-2 vs. 3, respectively, indicating good accuracy of US-based fat grading. Omega-3 supplementation was associated with a decrease in US-determined IMT (0.05-mm decrease in the 24-week omega-3 group. A 0.015-mm increase was found in the 12-week omega-3 group, and a 0.007-mm decrease in the sunflower oil group (P = 0.003). CONCLUSION: Omega-3 supplementation had no significant effect on liver fat fraction, but led to carotid IMT decrease in children with obesity and liver steatosis.

Depression and risk of type 2 diabetes: the potential role of metabolic factors.

The aim of the present study was to evaluate the interaction between depressive symptoms and metabolic dysregulations as risk factors for type 2 diabetes. The sample comprised of 2525 adults who participated in a baseline and a follow-up assessment over a 4.5-year period in the Emotional Health and Wellbeing Study (EMHS) in Quebec, Canada. A two-way stratified sampling design was used, on the basis of the presence of depressive symptoms and metabolic dysregulation (obesity, elevated blood sugar, high blood pressure, high levels of triglycerides and decreased high-density lipoprotein). A total of 87 (3.5%) individuals developed diabetes. Participants with both depressive symptoms and metabolic dysregulation had the highest risk of diabetes (adjusted odds ratio=6.61, 95% confidence interval (CI): 4.86-9.01), compared with those without depressive symptoms and metabolic dysregulation (reference group). The risk of diabetes in individuals with depressive symptoms and without metabolic dysregulation did not differ from the reference group (adjusted odds ratio=1.28, 95% CI: 0.81-2.03), whereas the adjusted odds ratio for those with metabolic dysregulation and without depressive symptoms was 4.40 (95% CI: 3.42-5.67). The Synergy Index (SI=1.52; 95% CI: 1.07-2.17) suggested that the combined effect of depressive symptoms and metabolic dysregulation was greater than the sum of individual effects. An interaction between depression and metabolic dysregulation was also suggested by a structural equation model. Our study highlights the interaction between depressive symptoms and metabolic dysregulation as a risk factor for type 2 diabetes. Early identification, monitoring and a comprehensive management approach of both conditions might be an important diabetes prevention strategy.

Depressive symptoms and glycated hemoglobin A1c: a reciprocal relationship in a prospective cohort study.

BACKGROUND: The aim of this study was to evaluate the dynamic association between depressive symptoms and glycated hemoglobin A1c (HbA1c) levels using data from the English Longitudinal Study of Ageing (ELSA). METHOD: The sample was comprised of 2886 participants aged ⩾50 years who participated in three clinical assessments over an 8-year period (21% with prediabetes and 7% with diabetes at baseline). Structural equation models were used to address reciprocal associations between depressive symptoms and HbA1c levels and to evaluate the mediating effects of lifestyle-related behaviors and cardiometabolic factors. RESULTS: We found a reciprocal association between depressive symptoms and HbA1c levels: depressive symptoms at one assessment point predicted HbA1c levels at the next assessment point (standardized ß = 0.052) which in turn predicted depressive symptoms at the following assessment point (standardized ß = 0.051). Mediation analysis suggested that both lifestyle-related behaviors and cardiometabolic factors might mediate the association between depressive symptoms and HbA1c levels: depressive symptoms at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted HbA1c levels 4 years later. A similar association was observed for the other direction: HbA1c levels at baseline predicted lifestyle-related behaviors and cardiometabolic factors at the next assessment, which in turn predicted depressive symptoms 4 years later. CONCLUSIONS: Our results suggest a dynamic relationship between depressive symptoms and HbA1c which might be mediated by both lifestyle and cardiometabolic factors. This has important implications for investigating the pathways which could link depressive symptoms and increased risk of diabetes.

Cyclical relationship between depressive symptoms and diabetes distress in people with Type 2 diabetes mellitus: results from the Montreal Evaluation of Diabetes Treatment Cohort Study.

AIMS: To determine if longitudinal cyclical relationships exist between depressive symptoms and diabetes distress in people with Type 2 diabetes mellitus. METHODS: Data were obtained from the Montreal Evaluation of Diabetes Treatment study, a cohort study of 1691 people with Type 2 diabetes mellitus. Depressive symptoms and diabetes distress, measured with the Patient Health Questionnaire and Diabetes Distress Scale, respectively, were assessed at baseline, 1 year and 2 years. A cross-lagged path model analysis with all autoregressive associations was used. Paths and indirect associations were examined. RESULTS: All paths in the model were significant. Depressive symptoms were positively associated with diabetes distress across consecutive time points and diabetes distress was positively associated with depressive symptoms across consecutive time points. The association between depressive symptoms at baseline and depressive symptoms at 2 years was mediated by both depressive symptoms and diabetes distress at 1 year. The association between diabetes distress at baseline and diabetes distress at 2 years was also mediated by both depressive symptoms and diabetes distress. CONCLUSIONS: Depressive symptoms and diabetes distress are cyclically related; results suggest that depressive symptoms influence diabetes distress, which, in turn, influences depressive symptoms. Although many studies focus on the differences between depressive symptoms and diabetes distress, the present study is the first to provide longitudinal evidence that these constructs are cyclically related.

3D reconstruction of the pelvis from bi-planar radiography.

3D personalized models are more and more requested for clinical and biomechanical studies. Techniques based on bi-planar X-rays present the advantage of a low radiation dose for the patient. However, up to now, such techniques have shown limited accuracy in the case of pelvis reconstruction. This study proposes and validates a method providing accurate 3D personalized model of the pelvis from bi-planar X-rays. The algorithm is based on the fast computation of an initial solution followed by local deformations based on 2D anatomical points and contours that are digitized in both radiographs. Results were close to CT-scan reconstructions (mean difference 1.6 mm and differences under 4.3 mm for 95% of the points). Moreover, 3D morphometry of the pelvis could be obtained with an accuracy of 5%. This technique provides 3D patient specific model with a low radiation dose.

Intracellular transport, assembly, and degradation of wild-type and disease-linked mutant gap junction proteins.

More than 130 different mutations in the gap junction integral plasma membrane protein connexin32 (Cx32) have been linked to the human peripheral neuropathy X-linked Charcot-Marie-Tooth disease (CMTX). How these various mutants are processed by the cell and the mechanism(s) by which they cause CMTX are unknown. To address these issues, we have studied the intracellular transport, assembly, and degradation of three CMTX-linked Cx32 mutants stably expressed in PC12 cells. Each mutant had a distinct fate: E208K Cx32 appeared to be retained in the endoplasmic reticulum (ER), whereas both the E186K and R142W mutants were transported to perinuclear compartments from which they trafficked either to lysosomes (R142W Cx32) or back to the ER (E186K Cx32). Despite these differences, each mutant was soluble in nonionic detergent but unable to assemble into homomeric connexons. Degradation of both mutant and wild-type connexins was rapid (t(1/2) < 3 h) and took place at least in part in the ER by a process sensitive to proteasome inhibitors. The mutants studied are therefore unlikely to cause disease by accumulating in degradation-resistant aggregates but instead are efficiently cleared from the cell by quality control processes that prevent abnormal connexin molecules from traversing the secretory pathway.

Nonsense mutations in the COL1A1 gene preferentially reduce nuclear levels of mRNA but not hnRNA in osteogenesis imperfecta type I cell strains.

Osteogenesis imperfecta (OI) is a heterogeneous disorder of type I collagen resulting in varying degrees of severity. The mildest form of OI (Type I) is associated with bone fragility, normal or near normal stature and blue sclerae. All forms of OI are the result of mutations in COL1A1 or COL1A2, the genes that encode the proalpha1(I) and proalpha2(I) chains of type I collagen, respectively. Mutations identified in patients with OI type I lead to premature termination codons and allele-specific reductions of nuclear mRNA (termed nonsense-mediated mRNA decay or NMD), resulting in a COL1A1 null allele. In mammals, this process primarily effects RNA that co-purifies with the nuclear fraction of the cell. Using a semi-quantitative RT-PCR assay, we compare the relative amounts of normal and mutant transcripts in unprocessed hnRNA and mature mRNA isolated from the nuclear fraction of cells from 11 OI type I individuals with previously identified mutations distributed throughout the COL1A1 gene. While we detect about equal amounts of normal and mutant hnRNA from each cell strain, there is preferential reduction in the relative amount of mutant mRNA when compared to normal; only the cell strain with a mutation in the last exon escapes the major effects of NMD. Our data indicate that NMD targets mRNA rather than hnRNA for degradation, and that this occurs either during or after splicing but prior to cytoplasmic translation.

Genetic markers, bone mineral density, and serum osteocalcin levels.

We evaluated five genetic markers for products that contribute to skeletal mineralization including the Sp1 polymorphism for type I collagen Ai (COLIA1), the vitamin D receptor (VDR) translation initiation site polymorphism, the promoter of the osteocalcin gene containing a C/T polymorphism, the estrogen receptor (ER) gene containing a TA repeat, and the polymorphic (AGC)n site in the androgen receptor. These markers were evaluated for their potential relationship with bone mineral density (BMD), measured by dual-energy X-ray densitometry, or its 3-year change. Additionally, potential associations of these genotypes and with baseline osteocalcin concentration or its 3-year change (assessed using radioimmunoassay) were evaluated. The study was conducted in 261 pre- and perimenopausal women of the Michigan Bone Health Study, a population-based longitudinal study of musculoskeletal characteristics and diseases. The polymorphic (AGC)n site in the androgen receptor showed a strong association with BMD of the femoral neck (FN) and lumbar spine and remained highly significant after adjusting for body mass index (BMI), oophorectomy/hysterectomy, oral contraceptive (OC) use and hormone replacement use (p < 0.001). The TA repeat at the 5' end of the ER gene was associated with total body calcium (p < 0.05) after adjusting for BMI, oophorectomy and hysterectomy, and OC use. The frequency of oophorectomy and hysterectomy within selected genotypes explained much of the statistically significant association of the ER genotypes with BMD of the FN and spine. There was no association of measures of BMD or bone turnover with the Sp1 polymorphism for COLIA1, the VDR translation initiation site polymorphism, or the C/T promoter polymorphism of the osteocalcin gene. These findings suggest that sex hormone genes may be important contributors to the variation in BMD among pre- and perimenopausal women.

The role of the gap junction protein connexin32 in the pathogenesis of X-linked Charcot-Marie-Tooth disease.

Mutations in the gene encoding the gap junction protein connexin32 (Cx32; beta 1) cause the X-linked form of Charcot-Marie-Tooth disease (CMTX), a common form of inherited demyelinating neuropathy. Cx32 is localized to the paranodes and incisures of myelinating Schwann cells, and probably participates in the formation of gap junctions at these locations, thereby allowing the diffusion of ions and small molecules directly across the myelin sheath. In transfected cells different CMTX mutations have different effects on the ability of the mutant protein to form functional gap junctions; some mutant proteins cannot be detected within the cell, other mutant proteins accumulate within the cell but do not reach the cell membrane, while other mutants reach the cell membrane and some of these form functional gap junctions. In transgenic mice two mutants, R142W and 175 frameshift, have similar effects on protein trafficking as in transfected cells: the R142W mutant protein remains in the perinuclear region and does not reach the paranodes or incisures, and the 175 frameshift protein cannot be detected. Thus, different CMTX mutations have different effects on Cx32 protein, and these differences may help to explain the phenotypic differences seen in CMTX kindreds.

Mammalian DNA mismatch repair.

DNA mismatch repair (MMR) is one of multiple replication, repair, and recombination processes that are required to maintain genomic stability in prokaryotes and eukaryotes. In the wake of the discoveries that hereditary nonpolyposis colorectal cancer (HNPCC) and other human cancers are associated with mutations in MMR genes, intensive efforts are under way to elucidate the biochemical functions of mammalian MutS and MutL homologs, and the consequences of defects in these genes. Genetic studies in cultured mammalian cells and mice are proving to be instrumental in defining the relationship between the functions of MMR in mutation and tumor avoidance. Furthermore, these approaches have raised awareness that MMR homologs contribute to DNA damage surveillance, transcription-coupled repair, and recombinogenic and meiotic processes.

Monochromatic electromagnetic wavelets and the huygens principle.

For the first time, to our knowledge, optical diffraction is shown to be a wavelet transform with the electromagnetic wavelets. We show that the optical wavelets proposed by Onural [Opt. Lett. 18, 846 (1993)] are the Huygens wavelets under a Fresnel approximation, and the electromagnetic wavelets proposed by Kaiser [A Friendly Guide to Wavelets (Birkhauser, Boston, Mass., 1994)] reduce to Hyugens wavelets in the case of a monochromatic field.

Altered trafficking of mutant connexin32.

We examined the cellular localization of nine different connexin32 (Cx32) mutants associated with X-linked Charcot-Marie-Tooth disease (CMTX) in communication-incompetent mammalian cells. Cx32 mRNA was made, but little or no protein was detected in one class of mutants. In another class of mutants, Cx32 protein was detectable in the cytoplasm and at the cell surface, where it appeared as plaques and punctate staining. Cx32 immunoreactivity in a third class of mutants was restricted to the cytoplasm, where it often colocalized with the Golgi apparatus. Our studies suggest that CMTX mutations have a predominant effect on the trafficking of Cx32 protein, resulting in a potentially toxic cytoplasmic accumulation of Cx32 in these cells. These results and evidence of cytoplasmic accumulation of other mutated myelin proteins suggest that diseases affecting myelinating cells may share a common pathophysiology.

Connexin32 and X-linked Charcot-Marie-Tooth disease.

Mutations in the gap junction gene connexin32 (Cx32) cause the X-linked form of Charcot-Marie-Tooth disease, an inherited demyelinating neuropathy. More than 130 different mutations have been described, affecting all portions of the Cx32 protein. In transfected cells, the mutant Cx32 proteins encoded by some Cx32 mutations fall to reach the cell surface; other mutant proteins reach the cell surface, but only one of these forms functional gap junctions. In peripheral nerve, Cx32 is localized to incisures and paranodes, regions of noncompact myelin within the myelin sheath. This localization suggests that Cx32 forms "reflexive" gap junctions that allow ions and small molecules to diffuse directly across the myelin sheath, which is a thousandfold shorter distance than the circumferential pathway through the Schwann cell cytoplasm. Cx32 mutations may interrupt this shorter pathway or have other toxic effects, thereby injuring myelinating Schwann cells and their axons.

Premature chain termination is a unifying mechanism for COL1A1 null alleles in osteogenesis imperfecta type I cell strains.

Nonsense and frameshift mutations, which predict premature termination of translation, often cause a dramatic reduction in the amount of transcript from the mutant allele (nonsense-mediated mRNA decay). In some genes, these mutations also influence RNA splicing and induce skipping of the exon that contains the nonsense codon. To begin to dissect how premature termination alters the metabolism of RNA from the COL1A1 gene, we studied nonsense and frameshift mutations distributed over exons 11-49 of the gene. These mutations were originally identified in 10 unrelated families with osteogenesis imperfecta (OI) type 1. We observed marked reduction in steady-state amounts of mRNA from the mutant allele in both total cellular and nuclear RNA extracts of cells from affected individuals, suggesting that nonsense-mediated decay of COL1A1 RNA is a nuclear phenomenon. Position of the mutation within the gene did not influence this observation. None of the mutations induced skipping of either the exon containing the mutation or, for the frameshifts, the downstream exons with the new termination sites. Our data suggest that nonsense and frameshift mutations throughout most of the COL1A1 gene result in a null allele, which is associated with the predictable mild clinical phenotype, OI type 1.

Mutagenicity of acridines in a reversion assay based on tetracycline resistance in plasmid pBR322 in Escherichia coli.

The mutagenicity of a series of acridine compounds was studied in an assay based on the reversion of mutations in the tetracycline-resistance gene (tet) of plasmid pBR322 in Escherichia coli. Mutations that restore the tetracycline-resistant phenotype were detected in tetracycline-sensitive strains carrying mutant plasmids. Mutations that revert by +2, +1, -1 and -2 frameshift mutations and by base-pair substitutions were used to analyze the mutagenicity of two simple acridines, two acridine mustards, and a nitroacridine. The simple acridines (9-aminoacridine and quinacrine) effectively induced -1 frameshifts and weakly induced +1 frameshifts. The acridine mustards (quinacrine mustard and ICR-191) were more potent inducers of -1 and +1 frameshifts than the simple acridines. Reactive acridines, including both the mustards and the nitroacridine Entozon, were effective inducers of -2 frameshifts but the simple acridines were not. The two classes of reactive acridines differed from one another, in that the mustards were better inducers of +1 frameshifts than Entozon, whereas Entozon was a particularly potent inducer of -2 frameshifts. None of the compounds induced +2 frameshifts, and the induction of base-pair substitutions was negligible. These results confirm and extend studies showing that adduct-forming acridines are stronger frameshift mutagens than simple intercalating acridines and that the acridines differ from one another not only in overall mutagenic potency but also in the prevalence of different classes of frameshift mutations.

Connexin32 is a myelin-related protein in the PNS and CNS.

We have examined the expression of a gap junction protein, connexin32 (Cx32), in Schwann cells and oligodendrocytes. In peripheral nerve, Cx32 is found in the paranodal myelin loops and Schmidt-Lanterman incisures of myelinating Schwann cells, and the levels of Cx32 protein and mRNA change in parallel with those of other myelin-related genes during development, Wallerian degeneration, and axonal regeneration. In the central nervous system, Cx32 is found in oligodendrocytes and their processes, but not in compact myelin, and the levels of Cx32 protein and mRNA increase during development in parallel with those of the other myelin genes. Thus, Cx32 is expressed as part of the myelinating phenotype of both Schwann cells and oligodendrocytes, indicating that this gap junction protein plays in important role in the biology of myelin-forming cells.