Solid organ transplant is increasing globally. According to Kidney Research UK, around 5000 people in the UK are on the waiting list for a kidney and this is only increasing. Improved ...immunosuppression therapy and general management of transplanted patients mean their survival has improved. It will get more common for these patients to require input from a non-transplant centres. There are nuances of transplant patients which non-transplant anaesthetists and intensivists may not be aware of. A good understanding of some of these complexities are crucial to optimizing perioperative care and outcome.
To evaluate speech in noise results and subjective benefit in bilateral active bone conduction implant (ABCI) for bilateral mixed hearing loss.
Prospective, comparative.
Ear, Nose and Throat Unit, ...Department of Surgical Sciences, University of Turin.
Seven patients with conductive/mixed hearing loss.
Patients underwent simultaneous or sequential bilateral surgery for ABCI.
The speech intelligibility in noise was assessed with the Ita Matrix test in summation, squelch and head shadow settings. First, the tests were performed with one device activated in the ear with lower speech recognition score, then with both devices. Patients filled in an Abbreviated Profile of Hearing Aid Benefit (APHAB) questionnaire to investigate the hearing aid benefit.
When bilateral devices were activated, an improvement of signal-to-noise ratio was observed in all settings. The difference between bilateral and unilateral stimulation is 4.66 dB ( p = 0.016) in the summation, 2.24 dB ( p = 0.047) in the squelch, 7.50 dB ( p = 0.016) in the head shadow setting.Looking at the APHAB global score (GS), patients report lower mean scores, hence less difficulties, when using two devices (GS, 21.9%; standard deviation (SD), 8.28) rather than one (GS, 33.0%; SD, 10.24) ( p = 0.018).
In symmetric mixed bilateral hearing loss, rehabilitation with an ABCI fitted bilaterally shows audiologic advantages in speech perception in noise, not only thanks to the summation effect and by reducing head shadow but also by improving the binaural unmasking based on the squelch effect. Audiometric outcomes are confirmed by the GSs obtained in the APHAB questionnaire.
Summary
Objective
Information about the incidence of neonatal seizures (NS) is scarce. Previous studies relied primarily on a clinical diagnosis of seizures. This population‐based, retrospective ...study evaluated the incidence of electroencephalography (EEG)–confirmed seizures in neonates born in the province of Parma and the perinatal risk factors for mortality and epilepsy.
Methods
All neonates with suspected seizures or with medical conditions at high risk for seizures from the study area were recorded in the neonatal intensive care unit (NICU) of the Parma University Hospital. NS were EEG confirmed. Perinatal risk factors for mortality and epilepsy after NS were evaluated with Cox’s proportional hazards models.
Results
In a 13‐year period, 112 patients presented with NS: 102 newborns had electroclinical seizures (46 full‐term and 56 preterm), whereas 10 presented only electrical seizures. The incidence was 2.29/1000 live births (95% confidence interval CI 1.87‐2.72), with higher rates in preterm neonates (14.28/1000 in preterm vs 1.10/1000 in full‐term infants). The incidence increased with decreasing gestational age (31‐36 weeks of gestation: 5.01/1000, 28‐30: 54.9/1000, and <28: 85.6/1000) and with decreasing birth weight (≥2500 g: 1.19/1000, <1000 g: 127.57/1000). Twenty‐eight patients (25%) died, 16 (14.3%) had a diagnosis of epilepsy, 33 (29.5%) had cerebral palsy, and 39 (34.8%) had a developmental delay. Among the perinatal risk factors considered, the multivariate analysis showed an association between a 5‐minute Apgar score of 0‐7 and etiology with increased mortality and between female gender and status epilepticus with epilepsy.
Significance
The incidence of NS is inversely associated with gestational age and birth weight. The etiology and a low Apgar score are strongly related to mortality; female gender and status epilepticus are risk factors for the development of epilepsy.
The development of molecularly targeted anticancer agents relies on large panels of tumour-specific preclinical models closely recapitulating the molecular heterogeneity observed in patients. Here we ...describe the mutational and gene expression analyses of 151 colorectal cancer (CRC) cell lines. We find that the whole spectrum of CRC molecular and transcriptional subtypes, previously defined in patients, is represented in this cell line compendium. Transcriptional outlier analysis identifies RAS/BRAF wild-type cells, resistant to EGFR blockade, functionally and pharmacologically addicted to kinase genes including ALK, FGFR2, NTRK1/2 and RET. The same genes are present as expression outliers in CRC patient samples. Genomic rearrangements (translocations) involving the ALK and NTRK1 genes are associated with the overexpression of the corresponding proteins in CRC specimens. The approach described here can be used to pinpoint CRCs with exquisite dependencies to individual kinases for which clinically approved drugs are already available.
ALK, ROS1, and NTRK fusions occur in 0.2% to 2.4% of colorectal cancers. Pioneer cases of metastatic colorectal cancer (mCRC) patients bearing rearrangements who benefited from anti-ALK, ROS, and ...TrkA-B-C therapies have been reported previously. Here we aimed at characterizing the clinical and molecular landscape of ALK, ROS1, and NTRK rearranged mCRC.
Clinical features and molecular characteristics of 27 mCRC patients bearing ALK, ROS1, and NTRK rearranged tumors were compared with those of a cohort of 319 patients not bearing rearrangements by means of Fisher's exact, χ2 test, or Mann-Whitney test as appropriate. Overall survival curves were estimated with the Kaplan-Meier method and compared using the log-rank test. A Cox proportional hazard model was adopted in the multivariable analysis. Deep molecular and immunophenotypic characterizations of rearranged cases, including those described in The Cancer Genome Atlas database, were performed. All statistical tests were two-sided.
Closely recalling the "BRAF history," ALK, ROS1, and NTRK rearrangements more frequently occurred in elderly patients (P = .02) with right-sided tumors (P < .001) and node-spreading (P = .03), RAS wild-type (P < .001), and MSI-high (P < .001) cancers. All patients bearing ALK, ROS1, and NTRK fusions had shorter overall survival (15.6 months, 95% confidence interval CI = 0.0 to 20.4 months) than negative patients (33.7 months, 95% CI = 28.3 to 42.1 months), both in the univariate (hazard ratio HR = 2.17, 95% CI = 1.03 to 4.57, P < .001) and multivariable models (HR = 2.33, 95% CI = 1.10 to 4.95, P = .02). All four evaluable patients with rearrangements showed primary resistance to anti-epidermal growth factor receptor agents. Frequent association with potentially targetable RNF43 mutations was observed in MSI-high rearranged tumors.
ALK, ROS1, and NTRK rearrangements define a new rare subtype of mCRC with extremely poor prognosis. Primary tumor site, MSI-high, and RAS and BRAF wild-type status may help to identify patients bearing these alterations. While sensitivity to available treatments is limited, targeted strategies inhibiting ALK, ROS, and TrkA-B-C provided encouraging results.
Homonymous visual field defects (HVFDs) following acquired brain lesions affect independent living by hampering several activities of everyday life. Available treatments are intensive and week- or ...month-long. Transcranial Direct current stimulation (tDCS), a plasticity-modulating non-invasive brain stimulation technique, could be combined with behavioral trainings to boost their efficacy or reduce treatment duration. Some promising attempts have been made pairing occipital tDCS with visual restitution training, however less is knows about which area/network should be best stimulated in association with compensatory approaches, aimed at improving exploratory abilities, such as multisensory trainings.
In a proof-of-principle, sham-controlled, single-blind study, 15 participants with chronic HVFDs underwent four one-shot sessions of active or sham anodal tDCS applied over the ipsilesional occipital cortex, the ipsilesional or contralesional posterior parietal cortex. tDCS was delivered during a compensatory multisensory (audiovisual) training. Before and immediately after each tDCS session, participants carried out a visual detection task, and two visual search tasks (EF and Triangles search tests). Accuracy (ACC) and response times (RTs) were analyzed with generalized mixed models. We investigated differences in baseline performance, clinical-demographic and lesion factors between tDCS responders and non-responders, based on post-tDCS behavioral improvements. Lastly, we conducted exploratory analyses to compare left and right brain-damaged participants.
RTs improved after active ipsilesional occipital and parietal tDCS in the visual search tasks, while no changes in ACC were detected. Responders to ipsilesional occipital tDCS (Triangle task) had shorter disease duration and smaller lesions of the parietal cortex and the superior longitudinal fasciculus. On the other end, on the EF test, those participants with larger damage of the temporo-parietal cortex or the fronto-occipital white matter tracts showed a larger benefit from contralesional parietal tDCS. Overall, the visual search RTs improvements were larger in participants with right-sided hemispheric lesions.
The present result shows the facilitatory effects of occipital and parietal tDCS combined with compensatory multisensory training on visual field exploration in HVFDs, suggesting a potential for the development of new neuromodulation treatments to improve visual scanning behavior in brain-injured patients.
Targeted therapies, chemotherapy, and immunotherapy are used to treat patients with mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) colorectal cancer. The clinical ...effectiveness of targeted therapy and chemotherapy is limited by resistance and drug toxicities, and about half of patients receiving immunotherapy have disease that is refractory to immune checkpoint inhibitors. Loss of Werner syndrome ATP-dependent helicase (WRN) is a synthetic lethality in dMMR/MSI-H cells. To inform the development of WRN as a therapeutic target, we performed WRN knockout or knockdown in 60 heterogeneous dMMR colorectal cancer preclinical models, demonstrating that WRN dependency is an almost universal feature and a robust marker for patient selection. Furthermore, models of resistance to clinically relevant targeted therapy, chemotherapy, and immunotherapy retain WRN dependency. These data show the potential of therapeutically targeting WRN in patients with dMMR/MSI-H colorectal cancer and support WRN as a therapeutic option for patients with dMMR/MSI-H cancers refractory to current treatment strategies. SIGNIFICANCE: We found that a large, diverse set of dMMR/MSI-H colorectal cancer preclinical models, including models of treatment-refractory disease, are WRN-dependent. Our results support WRN as a promising synthetic-lethal target in dMMR/MSI-H colorectal cancer tumors as a monotherapy or in combination with targeted agents, chemotherapy, or immunotherapy.
.
Mutations in cell-free circulating DNA (cfDNA) have been studied for tracking disease relapse in colorectal cancer (CRC). This approach requires personalised assay design due to the lack of ...universally mutated genes. In contrast, early methylation alterations are restricted to defined genomic loci allowing comprehensive assay design for population studies. Our objective was to identify cancer-specific methylated biomarkers which could be measured longitudinally in cfDNA (liquid biopsy) to monitor therapeutic outcome in patients with metastatic CRC (mCRC).
Genome-wide methylation microarrays of CRC cell lines (n=149) identified five cancer-specific methylated loci (
,
,
,
). Digital PCR assays were employed to measure methylation of these genes in tumour tissue DNA (n=82) and cfDNA from patients with mCRC (n=182). Plasma longitudinal assessment was performed in a patient subset treated with chemotherapy or targeted therapy.
Methylation in at least one marker was detected in all tumour tissue samples and in 156 mCRC patient cfDNA samples (85.7%). Plasma marker prevalence was 71.4% for
, 68.5% for
, 69.7% for
, 69.1% for
and 65.1% for
. Dynamics of methylation markers was not affected by treatment type and correlated with objective tumour response and progression-free survival.
This five-gene methylation panel can be used to circumvent the absence of patient-specific mutations for monitoring tumour burden dynamics in liquid biopsy under different therapeutic regimens. This method might be proposed for assessing pharmacodynamics in clinical trials or when conventional imaging has limitations.
Hydrogeological field studies rely often on a single conceptual representation of the subsurface. This is problematic since the impact of a poorly chosen conceptual model on predictions might be ...significantly larger than the one caused by parameter uncertainty. Furthermore, conceptual models often need to incorporate geological concepts and patterns in order to provide meaningful uncertainty quantification and predictions. Consequently, several geologically realistic conceptual models should ideally be considered and evaluated in terms of their relative merits. Here, we propose a full Bayesian methodology based on Markov chain Monte Carlo to enable model selection among 2‐D conceptual models that are sampled using training images and concepts from multiple‐point statistics. More precisely, power posteriors for the different conceptual subsurface models are sampled using sequential geostatistical resampling and Graph Cuts. To demonstrate the methodology, we compare and rank five alternative conceptual geological models that have been proposed in the literature to describe aquifer heterogeneity at the MAcroDispersion Experiment site in Mississippi, USA. We consider a small‐scale tracer test for which the spatial distribution of hydraulic conductivity impacts multilevel solute concentration data observed along a 2‐D transect. The thermodynamic integration and the stepping‐stone sampling methods were used to compute the evidence and associated Bayes factors using the computed power posteriors. We find that both methods are compatible with multiple‐point statistics‐based inversions and provide a consistent ranking of the competing conceptual models considered.
Key Points
A full Bayesian method is proposed for model selection among geologically realistic conceptual models
Thermodynamic integration and stepping‐stone sampling provide consistent ranking of conceptual models
The method is applied to solute concentration data collected during a tracer test at the MADE site
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