Communications medicine最新文献

Background: Multiple sulfatase deficiency (MSD) is an exceptionally rare neurodegenerative disorder due to the absence or deficiency of 17 known cellular sulfatases. The activation of all these cellular sulfatases is dependent on the presence of the formylglycine-generating enzyme, which is encoded by the SUMF1 gene. Disease-causing homozygous or compound heterozygous variants in SUMF1 result in MSD. Other than symptomatic treatment, no curative therapy exists as of yet for MSD. Eight out of these 17 sulfatases are primarily localized in the lysosome.

Methods: Two siblings with attenuated MSD underwent hematopoietic cell transplantation (HCT), evaluating the possibility of lysosomal enzymatic cross-correction from the donor cells.

Results: There is evidence of correction of currently available biomarkers within 3 months post-HCT. Untargeted metabolomics also shows continued correction of multiple biochemical abnormalities in the post-HCT period. Furthermore, this article also presents the neuropsychological outcomes of these children as well as the results of untargeted metabolomics analysis in this condition.

Conclusions: These data suggest biochemical benefits post-transplant along with slowing of disease progression. Long-term follow-up is necessary to fully evaluate the therapeutic benefit of HCT in MSD.

Background: Cochlear implants (CIs) are neuroprosthetic devices which restore hearing in severe-to-profound hearing loss through electrical stimulation of the auditory nerve. Current CIs use an externally worn audio processor. A long-term goal in the field has been to develop a device in which all components are contained within a single implant. Here, we present initial clinical results with the totally implantable cochlear implant (TICI). The primary objective of this study was to assess the safety of the device in adults who suffer from bilateral severe-to-profound sensorineural hearing loss.

Methods: This study used a design with non-randomized single group assignment (trial registration: NCT04571333). Six implantations took place beginning in September 2020. Data collection took place at the two participating CI centers. Adverse events (the primary outcome), speech perception, patient reported outcomes, and device usage statistics were collected over the subsequent 52 weeks. A within-subjects comparison was used in which each participant was evaluated both with the TICI and with an external SONNET audio processor.

Results: One anticipated serious adverse device effect (ASADE) occurred. After treatment the event resolved without sequelae. No unanticipated serious adverse device effects (USADE) occurred. Speech perception in quiet and in noise scores were comparable between the TICI and the SONNET audio processor. Scores on the validated patient reported outcome instruments HUI3, SSQ-12, and HISQUI-19 all increased over the duration of the study. User satisfaction scores as reported in their daily diary also increased over the duration of the study. Based on device usage metrics, all but one user used the TICI without an external processor the majority of the time.

Conclusions: The primary outcome of assessing the safety of the device was achieved. The TICI provides high levels of hearing performance, comparable to those of a conventional CI. The development of the TICI expands the range of options for treatment of hearing loss.

Background: Gene signatures derived from transcriptomic-causal networks offer potential for tailoring clinical care in cancer treatment by identifying predictive and prognostic biomarkers. This study aimed to uncover such signatures in metastatic colorectal cancer (CRC) patients to aid treatment decisions.

Methods: We constructed transcriptomic-causal networks and integrated gene interconnectivity into overall survival (OS) analysis to control for confounding genes. This integrative approach involved germline genotype and tumor RNA-seq data from 1165 metastatic CRC patients. The patients were enrolled in a randomized clinical trial receiving either cetuximab or bevacizumab in combination with chemotherapy. An external cohort of paired CRC normal and tumor samples, along with protein-protein interaction databases, was used for replication.

Results: We identify promising predictive and prognostic gene signatures from pre-treatment gene expression profiles. Our study discerns sets of genes, each forming a signature that collectively contribute to define patient subgroups with different prognosis and response to the therapies. Using an external cohort, we show that the genes influencing OS within the signatures, such as FANCI and PRC1, are upregulated in CRC tumor vs. normal tissue. These signatures are highly associated with immune features, including macrophages, cytotoxicity, and wound healing. Furthermore, the corresponding proteins encoded by the genes within the signatures interact with each other and are functionally related.

Conclusions: This study underscores the utility of gene signatures derived from transcriptomic-causal networks in patient stratification for effective therapies. The interpretability of the findings, supported by replication, highlights the potential of these signatures to identify patients likely to benefit from cetuximab or bevacizumab.

Background: Improvement in gene modifications of donor pigs has led to the prevention of early cardiac xenograft rejection and significantly prolonged cardiac xenograft survival in both heterotopic and orthotopic preclinical non-human primate (NHP) models. This progress formed the basis for FDA approval for compassionate use transplants in two patients.

Methods: Based on our earlier report of 9-month survival of seven gene-edited (7-GE) hearts transplanted (life-supporting orthotopic) in baboons, we transplanted 10 gene-edited pig hearts into baboons (n = 4) using non-ischemic continuous perfusion preservation (NICP) and immunosuppression regimen based on co-stimulation blockade by anti-CD40 monoclonal antibody. This pivotal study expands on the 7-GE backbone, with 3 additional gene edits, using 10-GE pigs as donors to baboon recipients.

Results: 10 GE cardiac xenografts provide life-supporting function up to 225 days (mean 128 ± 36 days) in a non-human primate model. Undetectable or latent porcine cytomegalovirus (PCMV) does not influence cardiac xenograft survival in this study but still needs more exploration with a larger cohort. Xenograft histology demonstrates adipose (Fat) deposition (n = 1), chronic vasculopathy (n = 1), micro and macro thrombosis, and acute cellular rejection (n = 1).

Conclusions: These data demonstrate that 10 GE cardiac xenografts have variable cardiac xenograft survival in NHP due to perhaps presence of 4th antigen and require further study. However, these 10GE organs may be suitable for clinical cardiac xenotransplantation and have already been utilized in two human cases.

Background: Digital data sources such as mobile phone call detail records (CDRs) are increasingly being used to estimate population mobility fluxes and to predict the spatiotemporal dynamics of infectious disease outbreaks. Differences in mobile phone operators' geographic coverage, however, may result in biased mobility estimates.

Methods: We leverage a unique dataset consisting of CDRs from three mobile phone operators in Bangladesh and digital trace data from Meta's Data for Good program to compare mobility patterns across these sources. We use a metapopulation model to compare the sources' effects on simulated outbreak trajectories, and compare results with a benchmark model with data from all three operators, representing around 100 million subscribers across the country.

Results: We show that mobility sources can vary significantly in their coverage of travel routes and geographic mobility patterns. Differences in projected outbreak dynamics are more pronounced at finer spatial scales, especially if the outbreak is seeded in smaller and/or geographically isolated regions. In some instances, a simple diffusion (gravity) model was better able to capture the timing and spatial spread of the outbreak compared to the sparser mobility sources.

Conclusions: Our results highlight the potential biases in predicted outbreak dynamics from a metapopulation model parameterized with non-population representative data, and the limits to the generalizability of models built on these types of novel human behavioral data.

Background: The ability to non-invasively measure left atrial pressure would facilitate the identification of patients at risk of pulmonary congestion and guide proactive heart failure care. Wearable cardiac monitors, which record single-lead electrocardiogram data, provide information that can be leveraged to infer left atrial pressures.

Methods: We developed a deep neural network using single-lead electrocardiogram data to determine when the left atrial pressure is elevated. The model was developed and internally evaluated using a cohort of 6739 samples from the Massachusetts General Hospital (MGH) and externally validated on a cohort of 4620 samples from a second institution. We then evaluated model on patch-monitor electrocardiographic data on a small prospective cohort.

Results: The model achieves an area under the receiver operating characteristic curve of 0.80 for detecting elevated left atrial pressures on an internal holdout dataset from MGH and 0.76 on an external validation set from a second institution. A further prospective dataset was obtained using single-lead electrocardiogram data with a patch-monitor from patients who underwent right heart catheterization at MGH. Evaluation of the model on this dataset yielded an area under the receiver operating characteristic curve of 0.875 for identifying elevated left atrial pressures for electrocardiogram signals acquired close to the time of the right heart catheterization procedure.

Conclusions: These results demonstrate the utility and the potential of ambulatory cardiac hemodynamic monitoring with electrocardiogram patch-monitors.

Background: Understanding factors associated with antimicrobial resistance (AMR) distribution across populations is a necessary step in planning mitigation measures. While associations between AMR and socioeconomic-status (SES), including employment and education have been increasingly recognized in low- and middle-income settings, connections are less clear in high-income countries where SES remains an important influence on other health outcomes.

Methods: We explored the relationship between SES and AMR in Calgary, Canada using spatially-resolved wastewater-based surveillance of resistomes detected by metagenomics across eight socio-economically diverse urban neighborhoods. Resistomes were established by shotgun-sequencing of wastewater pellets, and qPCR of targeted-AMR genes. SES status was established using 2021 Canadian census data. Conducting this comparison during the height of COVID-related international travel restrictions (Dec. 2020-Oct. 2021) allowed the hypotheses linking SES and AMR to be assessed with limited confounding. These were compared with sewage metagenomes from 244 cities around the world, linked with Human Development Index (HDI).

Results: Wastewater metagenomes from Calgary's socioeconomically diverse neighborhoods exhibit highly similar resistomes, with no quantitative differences (p > 0.05), low Bray-Curtis dissimilarity, and no significant correlations with SES. By comparison, dissimilarity is observed between globally-sourced resistomes (p < 0.05), underscoring the homogeneity of resistomes in Calgary's sub-populations. The analysis of globally-sourced resistomes alongside Calgary's resistome further reveals lower AMR burden in Calgary relative to other cities around the world. This is particularly pronounced for the most clinically-relevant AMR genes (e.g., beta-lactamases, macrolide-lincosamide-streptogramin).

Conclusions: This work showcases the effectiveness of inclusive and comprehensive wastewater-based surveillance for exploring the interplay between SES and AMR.

Background: Prior case series suggest that a 5-day course of oral Paxlovid (nirmatrelvir/ritonavir) benefits some people with Long COVID, within and/or outside of the context of an acute reinfection. To the best of our knowledge, there have been no prior case series of people with Long COVID who have attempted longer courses of nirmatrelvir/ritonavir.

Methods: We documented a case series of 13 individuals with Long COVID who initiated extended courses (>5 days; range: 7.5-30 days) of oral nirmatrelvir/ritonavir outside (n = 11) of and within (n = 2) the context of an acute SARS-CoV-2 infection. Participants reported on symptoms and health experiences before, during, and after their use of nirmatrelvir/ritonavir.

Results: Among those who take an extended course of nirmatrelvir/ritonavir outside of the context of an acute infection, some experience a meaningful reduction in symptoms, although not all benefits persist. Others experience no effect on symptoms. One participant stopped early due to intense stomach pain. For the two participants who took an extended course of nirmatrelvir/ritonavir within the context of an acute reinfection, both report eventually returning to their pre-re-infection baseline.

Conclusions: Extended courses of nirmatrelvir/ritonavir may have meaningful benefits for some people with Long COVID but not others. We encourage researchers to study how and why nirmatrelvir/ritonavir benefits some and what course length is most effective, with the goal of informing clinical recommendations for using nirmatrelvir/ritonavir and/or other antivirals as a potential treatment for Long COVID.

Background: Chronic kidney disease (CKD) causes progressive and irreversible damage to the kidneys. Renal biopsies are essential for diagnosing the etiology and prognosis of CKD, while accurate quantification of tubulo-interstitial injuries from whole slide images (WSIs) of renal biopsy specimens is challenging with visual inspection alone.

Methods: We develop a deep learning-based method named DLRS to quantify interstitial fibrosis and inflammatory cell infiltration as tubulo-interstitial injury scores, from WSIs of renal biopsy specimens. DLRS segments WSIs into non-tissue areas, glomeruli, tubules, interstitium, and arteries, and detects interstitial nuclei. It then quantifies these tubulo-interstitial injury scores using the segmented tissues and detected nuclei.

Results: Applied to WSIs from 71 Japanese CKD patients with diabetic nephropathy or benign nephrosclerosis, DLRS-derived scores show concordance with nephrologists' evaluations. Notably, the DLRS-derived fibrosis score has a higher correlation with the estimated glomerular filtration rate (eGFR) at biopsy than scores from nephrologists' evaluations. Validated on WSIs from 28 Japanese tubulointerstitial nephritis patients and 49 European-ancestry patients with nephrosclerosis, DLRS-derived scores show a significant correlation with eGFR. In an expanded analysis of 238 Japanese CKD patients, including 167 from another hospital, deviations in eGFR from expected values based on DLRS-derived scores correlate with annual eGFR decline after biopsy. Inclusion of these deviations and DLRS-derived fibrosis scores improve predictions of the annual eGFR decline.

Conclusions: DLRS-derived tubulo-interstitial injury scores are concordant with nephrologists' evaluations and correlated with eGFR across different populations and institutions. The effectiveness of DLRS-derived scores for predicting annual eGFR decline highlights the potential of DLRS as a predictor of renal prognosis.