Delineating genotype and parent-of-origin effect on the phenotype in MSH6-associated Lynch syndrome.

BACKGROUND: This study investigates the potential influence of genotype and parent-of-origin effects (POE) on the clinical manifestations of Lynch syndrome (LS) within families carrying (likely) disease-causing MSH6 germline variants. PATIENTS AND METHODS: A cohort of 1615 MSH6 variant carriers (310 LS families) was analyzed. Participants were categorized based on RNA expression and parental inheritance of the variant. Hazard ratios (HRs) were calculated using weighted Cox regression, considering external information to address ascertainment bias. The findings were cross-validated using the Prospective Lynch Syndrome Database (PLSD) for endometrial cancer (EC). RESULTS: No significant association was observed between genotype and colorectal cancer (CRC) risk (HR = 1.06, 95% confidence interval [CI]: 0.77-1.46). Patients lacking expected RNA expression exhibited a reduced risk of EC (Reference Cohort 1: HR = 0.68, 95% CI: 0.43-1.03; Reference Cohort 2: HR = 0.63, 95% CI: 0.46-0.87). However, these results could not be confirmed in the PLSD. Moreover, no association was found between POE and CRC risk (HR = 0.78, 95% CI: 0.52-1.17) or EC risk (Reference Cohort 1: HR = 0.93, 95% CI: 0.65-1.33; Reference Cohort 2: HR = 0.8, 95% CI: 0.64-1.19). DISCUSSION AND CONCLUSION: No evidence of POE was detected in MSH6 families. While RNA expression may be linked to varying risks of EC, further investigation is required to explore this observation.

Discordant Staining Patterns and Microsatellite Results in Tumors of MSH6 Pathogenic Variant Carriers.

Diagnosis of Lynch syndrome (LS) caused by a pathogenic germline MSH6 variant may be complicated by discordant immunohistochemistry (IHC) and/or by a microsatellite stable (MSS) phenotype. This study aimed to identify the various causes of the discordant phenotypes of colorectal cancer (CRC) and endometrial cancer (EC) in MSH6-associated LS. Data were collected from Dutch family cancer clinics. Carriers of a (likely) pathogenic MSH6 variant diagnosed with CRC or EC were categorized based on an microsatellite instability (MSI)/IHC test outcome that might fail to result in a diagnosis of LS (eg, retained staining of all 4 mismatch repair proteins, with or without an MSS phenotype, and other staining patterns). When tumor tissue was available, MSI and/or IHC were repeated. Next-generation sequencing (NGS) was performed in cases with discordant staining patterns. Data were obtained from 360 families with 1763 (obligate) carriers. MSH6 variant carriers with CRC or EC (n = 590) were included, consisting of 418 CRCs and 232 ECs. Discordant staining was reported in 77 cases (36% of MSI/IHC results). Twelve patients gave informed consent for further analysis of tumor material. Upon revision, 2 out of 3 MSI/IHC cases were found to be concordant with the MSH6 variant, and NGS showed that 4 discordant IHC results were sporadic rather than LS-associated tumors. In 1 case, somatic events explained the discordant phenotype. The use of reflex IHC mismatch repair testing, the current standard in most Western countries, may lead to the misdiagnosis of germline MSH6 variant carriers. The pathologist should point out that further diagnostics for inheritable colon cancer, including LS, should be considered in case of a strong positive family history. Germline DNA analysis of the mismatch repair genes, preferably as part of a larger gene panel, should therefore be considered in potential LS patients.

Overwhelmed to ownership: The lived experience of parents learning to become caregivers of children with tracheostomies.

BACKGROUND: Caring for a child with a tracheostomy is challenging and requires parents to master advanced medical skills, often without prior medical training. Tracheostomy education programs are well-established, yet the experience of parents becoming competent caregivers is unexplored. Providing effective education may impact long-term child and caregiver outcomes and mitigates preventable hospital readmissions. OBJECTIVE: This study aimed to explore parents' experience completing tracheostomy education within a children's hospital and understand the factors that promote or hinder learning. METHODS: We conducted a qualitative descriptive study on twenty-three purposively sampled parents of children with new tracheostomies from 2020 to 2021 who were admitted to the Transitional Intensive Care Unit (TICU) at a quaternary pediatric hospital. Semi-structured interviews were conducted after parents completed tracheostomy education and before discharge. Inductive thematic analysis was employed to identify themes and subthemes. RESULTS: Five major themes emerged: decision making, balancing benefits, becoming a caregiver, healthcare providers (HCPs) as barriers and facilitators for learning, and recommendations for tracheostomy education programs. Parents described becoming a caregiver in four stages: initial realization, overwhelmed, owning care, and role transition. Learning tracheostomy management in a positive, collaborative, supportive environment helped parents be more confident in their skills and eased their transition to home. Previous life experience, learning style, and healthcare professional behaviors influenced parents' transition into the caregiver role. CONCLUSIONS: Findings will inform interventions for improving pediatric tracheostomy education programs, including the HCP's role in supporting families. Equipping caregivers with the skills to provide tracheostomy interventions in the home could decrease preventable readmissions and improve outcomes in this medically fragile, high-risk pediatric population.

Transfusion-Associated Adverse Events: A Case Report of Nurse Hemovigilance and Recognition of Respiratory Distress.

Although blood transfusions are considered a potentially life-saving therapy, noninfectious and infectious adverse events can lead to significant morbidities and even mortality. Vital signs and visual observation of patients during blood transfusions are thoroughly taught in nursing school. Updated terms of hemovigilance and transfusion-associated adverse events ( TAAEs ) are presented through this case study. A patient with factor V deficiency, which requires chronic plasma transfusions, experienced 2 types of TAAEs, anaphylaxis and transfusion-associated circulatory overload. The patient's history and TAAEs are presented and discussed to provide evidence for the importance of vigilant bedside surveillance. Early identification of TAAEs may prevent unnecessary morbidity and/or mortality. The primary nursing functions and responsibilities are presented with algorithmic supplementation to facilitate better understanding of best practice. Ongoing assessment of hemovigilance practices is indicated to ascertain which monitoring tools can lead to optimal patient care.

Universal Immunohistochemistry for Lynch Syndrome: A Systematic Review and Meta-analysis of 58,580 Colorectal Carcinomas.

BACKGROUND & AIMS: Lynch syndrome is a form of hereditary colorectal cancer (CRC) caused by pathogenic germline variants (PV) in DNA mismatch repair (MMR) genes. Currently, many Western countries perform universal immunohistochemistry testing on CRC to increase the identification of Lynch syndrome patients and their relatives. For a clear understanding of health benefits and costs, data on its outcomes are required: proportions of Lynch syndrome, sporadic MMR-deficient (MMRd) cases, and unexplained MMRd cases. METHODS: Ovid Medline, Embase, and Cochrane CENTRAL were searched for studies reporting on universal MMR immunohistochemistry, followed by MMR germline analysis, until March 20, 2020. Proportions were calculated, subgroup analyses were performed based on age and diagnostics used, and random effects meta-analyses were conducted. Quality was assessed using the Joanna Briggs Critical Appraisal Tool for Prevalence Studies. RESULTS: Of 2723 identified articles, 56 studies covering 58,580 CRCs were included. In 6.22% (95% CI, 5.08%-7.61%; I2 = 96%) MMRd was identified. MMR germline PV was present in 2.00% (95% CI, 1.59%-2.50%; I2 = 92%), ranging from 1.80% to 7.27% based on completeness of diagnostics and age restriction. Immunohistochemistry outcomes were missing in 11.81%, and germline testing was performed in 76.30% of eligible patients. In 7 studies, including 6848 CRCs completing all diagnostic stages, germline PV and biallelic somatic MMR inactivation were found in 3.01% and 1.75%, respectively; 0.61% remained unexplained MMRd. CONCLUSIONS: Age, completeness, and type of diagnostics affect the percentage of MMR PV and unexplained MMRd percentages. Complete diagnostics explain almost all MMRd CRCs, reducing the amount of subsequent multigene panel testing. This contributes to optimizing testing and surveillance in MMRd CRC patients and relatives.

The diverse molecular profiles of lynch syndrome-associated colorectal cancers are (highly) dependent on underlying germline mismatch repair mutations.

Lynch syndrome (LS) is a hereditary cancer syndrome that accounts for 3% of all new colorectal cancer (CRC) cases. Patients carry a germline pathogenic variant in one of the mismatch repair (MMR) genes (MLH1, MSH2, MSH6 or PMS2), which encode proteins involved in a post-replicative proofreading and editing mechanism. The clinical presentation of LS is highly heterogeneous, showing high variability in age at onset and penetrance of cancer, which may be partly attributable to the molecular profiles of carcinomas. This review discusses the frequency of alterations in the WNT/B-CATENIN, RAF/MEK/ERK and PI3K/PTEN/AKT pathways identified in all four LS subgroups and how these changes may relate to the 'three pathway model' of carcinogenesis, in which LS CRCs develop from MMR-proficient adenomas, MMR-deficient adenomas or directly from MMR-deficient crypts. Understanding the specific differences in carcinogenesis for each LS subgroup will aid in the further optimization of guidelines for diagnosis, surveillance and treatment.

Virtual Communication Embedded Bedside ICU Rounds: A Hybrid Rounds Practice Adapted to the Coronavirus Pandemic.

OBJECTIVES: Coronavirus disease 2019 containment strategies created challenges with patient-centered ICU rounds. We examined how hybrid rounds with virtual communication added to in-person rounds could facilitate social distancing while maintaining patient-centered care. DESIGN: Continuous quality improvement. SETTING: Quaternary care referral pediatric hospital. PATIENTS: Daytime rounds conducted on PICU patients. INTERVENTIONS: Following a needs assessment survey and pilot trials, multiple technological solutions were implemented in a series of plan-do-study-act cycles. Hybrid rounds model was deployed where a videoconference platform was used to establish communication between the bedside personnel (nurse, patient/family, and partial ICU team) with remotely located remaining ICU team, ancillary, and consultant providers. Floor labels marking 6-feet distance were placed for rounders. MEASUREMENTS AND MAIN RESULTS: Outcome metrics included compliance with social distancing, mixed methods analysis of surveys, direct interviews of providers and families, and reports of safety concerns. The clinicians adopted hybrid rounds readily. Compliance with social distancing and use of floor labels needed reminders. One-hundred fourteen providers completed the feedback survey. Twenty-five providers and 11 families were interviewed. Feedback about hybrid rounds included inability to teach effectively, suboptimal audio-video quality, loss of situational awareness of patient/unit acuity, alarm interference, and inability to socially distance during other ICU interactions. Benefits noted were improved ancillary input, fewer interruptions, improved efficiency, opportunity to integrate with data platforms, and engage remote consultants and families. Nurses and families appreciated the efforts to ensure safety but wanted the ICU attending/fellow supervising the team to participate at bedside, during rounds. Clinicians appreciated the multidisciplinary input but felt that teaching was difficult. CONCLUSIONS: Hybrid rounds employed during pandemic facilitated social distancing while retaining patient-centered multidisciplinary ICU rounds but compromised teaching during rounds. A change to ingrained rounding habits needs team commitment and ongoing optimization. The hybrid rounds model has potential for generalizability to other settings.

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in the Million Veteran Program.

We conducted genome-wide association analyses of over 250,000 participants of European (EUR) and African (AFR) ancestry from the Million Veteran Program using electronic health record-validated post-traumatic stress disorder (PTSD) diagnosis and quantitative symptom phenotypes. Applying genome-wide multiple testing correction, we identified three significant loci in European case-control analyses and 15 loci in quantitative symptom analyses. Genomic structural equation modeling indicated tight coherence of a PTSD symptom factor that shares genetic variance with a distinct internalizing (mood-anxiety-neuroticism) factor. Partitioned heritability indicated enrichment in several cortical and subcortical regions, and imputed genetically regulated gene expression in these regions was used to identify potential drug repositioning candidates. These results validate the biological coherence of the PTSD syndrome, inform its relationship to comorbid anxiety and depressive disorders and provide new considerations for treatment.

Putting genome-wide sequencing in neonates into perspective.

PURPOSE: Several studies have reported diagnostic yields up to 57% for rapid exome or genome sequencing (rES/GS) as a single test in neonatal intensive care unit (NICU) patients, but the additional yield of rES/GS compared with other available diagnostic options still remains unquantified in this population. METHODS: We retrospectively evaluated all genetic NICU consultations in a 2-year period. RESULTS: In 132 retrospectively evaluated NICU consultations 27 of 32 diagnoses (84.4%) were made using standard genetic workup. Most diagnoses (65.6%) were made within 16 days. Diagnostic ES yield was 5/29 (17.2%). Genetic diagnoses had a direct effect on clinical management in 90.6% (29/32) of patients. CONCLUSIONS: Our study shows that exome sequencing has a place in NICU diagnostics, but given the associated costs and the high yield of alternative diagnostic strategies, we recommend to first perform clinical genetic consultation.

Correction: Putting genome-wide sequencing in neonates into perspective.

The original version of this Article contained an error in the spelling of the author Pleuntje J. van der Sluijs, which was incorrectly given as Eline (P. J.) van der Sluijs. This has now been corrected in both the PDF and HTML versions of the Article.

Pilot study on the use of data mining to identify cochlear implant candidates.

OBJECTIVES: The goal of this pilot study was to determine the clinical utility of data-mining software that screens for cochlear implant (CI) candidacy. METHODS: The Auditory Implant Initiative developed a software module that screens for CI candidates via integration with a software system (Noah 4) that serves as a depository for hearing test data. To identify candidates, patient audiograms from one practice were exported into the screening module. Candidates were tracked to determine if any eventually underwent implantation. RESULTS: After loading 4836 audiograms from the Noah 4 system, the screening module identified 558 potential CI candidates. After reviewing the data for the potential candidates, 117 were targeted and invited to an educational event. Following the event, a total of six candidates were evaluated, and two were implanted. DISCUSSION: This objective approach to identifying candidates has the potential to address the gross underutilization of CIs by removing any bias or lack of knowledge regarding the management of severe to profound sensorineural hearing loss with CIs. CONCLUSION: The screening module was an effective tool for identifying potential CI candidates at one ENT practice. On a larger scale, the screening module has the potential to impact thousands of CI candidates worldwide.

Assessing Cochlear Implant Outcomes in Older Adults Using HERMES: A National Web-based Database.

OBJECTIVE: Cochlear implant (CI) outcomes research has been largely limited to retrospective or single-institution studies in the United States. The objective is to demonstrate the feasibility of using a novel, national, web-based CI database through evaluating CI outcomes in older adults. STUDY DESIGN: Analysis of a prospective, national, web-based database designed for CI outcome tracking (HERMES; HIPAA-secure, Encrypted, Research Management and Evaluation Solution). SETTING: Multi-centered at 18 private practice and academic US medical centers. PATIENTS: Older (age ≥75, n = 47) or younger (age <75, n = 103) adult CI patients (n = 150 total, n = 160 ears). MAIN OUTCOME MEASURE(S): Arizona Biomedical (AzBio), CI usage, postoperative complications. RESULTS: Older adults had slightly lower performance on most recent AzBio (56.0%, n = 26, 12.2 ±â€Š6.5 mo postoperatively) compared with younger adults (74.0%, n = 52, 12.6 ±â€Š6.5 mo postoperatively; p < 0.01, Mann-Whitney). However, on multiple regression, age was not a significant predictor of AzBio scores after controlling for sex, hearing loss duration, use, and postoperative follow-up duration. Most recent CI use was similar but significantly different (11.4 h/d in older, n = 24 versus 13.0 in younger, n = 45; p = 0.01). Usage also did not decline over time (p = 0.81 in older versus p = 0.46, in younger). The most common complications were similar (vertigo 25 versus 20%, p = 0.45; tinnitus 4 versus 4%, p = 0.93) in older and younger adults, respectively. CONCLUSION: We demonstrate the feasibility of a novel user-friendly, web-based, national CI database to analyze CI outcomes. Older age was not a significant predictor of AzBio scores after adjusting for multiple factors. Additionally, CI use did not decline over time.

Creating a framework for data sharing in cochlear implant research.

OBJECTIVES: To summarize the development process of a national database that was designed to facilitate communication and collaboration, improve care, and create a framework for aggregate data sharing in cochlear implant (CI) research. METHODS: A group of nationally represented, multidisciplinary CI providers cooperated to define a standard set of data elements to incorporate into a database built by them in association with a group of computer scientists and software designers. CI centers across the USA, then, joined the non-profit Auditory Implant Initiative to use the database for their own clinical purposes and to help contribute to the national de-identified dataset for research and analytics. RESULTS: Approximately 12 months after the full release of the database, clinical information on 373 patients has been entered from 17 different CI centers representing 61 hearing professionals. A blend of six academic, seven private, and four non-profit CI centers participated in this phase of the data sharing network. DISCUSSION: The adoption of a single, standardized database by 17 centers throughout the USA has begun a framework for data sharing in CI research. Future steps include (1) expanding adoption, (2) scaling the database to include more patients, (3) streamlining the legal hurdles required for adoption, and (4) integrating the database with other software platforms (e.g. electronic health records, processors). CONCLUSION: A standardized clinical outcomes database that is utilized by a growing network of CI centers can help strengthen research through aggregate data sharing.

Neural communication patterns underlying conflict detection, resolution, and adaptation.

In an ever-changing environment, selecting appropriate responses in conflicting situations is essential for biological survival and social success and requires cognitive control, which is mediated by dorsomedial prefrontal cortex (DMPFC) and dorsolateral prefrontal cortex (DLPFC). How these brain regions communicate during conflict processing (detection, resolution, and adaptation), however, is still unknown. The Stroop task provides a well-established paradigm to investigate the cognitive mechanisms mediating such response conflict. Here, we explore the oscillatory patterns within and between the DMPFC and DLPFC in human epilepsy patients with intracranial EEG electrodes during an auditory Stroop experiment. Data from the DLPFC were obtained from 12 patients. Thereof four patients had additional DMPFC electrodes available for interaction analyses. Our results show that an early θ (4-8 Hz) modulated enhancement of DLPFC γ-band (30-100 Hz) activity constituted a prerequisite for later successful conflict processing. Subsequent conflict detection was reflected in a DMPFC θ power increase that causally entrained DLPFC θ activity (DMPFC to DLPFC). Conflict resolution was thereafter completed by coupling of DLPFC γ power to DMPFC θ oscillations. Finally, conflict adaptation was related to increased postresponse DLPFC γ-band activity and to θ coupling in the reverse direction (DLPFC to DMPFC). These results draw a detailed picture on how two regions in the prefrontal cortex communicate to resolve cognitive conflicts. In conclusion, our data show that conflict detection, control, and adaptation are supported by a sequence of processes that use the interplay of θ and γ oscillations within and between DMPFC and DLPFC.

Can the neural basis of repression be studied in the MRI scanner? New insights from two free association paradigms.

BACKGROUND: The psychodynamic theory of repression suggests that experiences which are related to internal conflicts become unconscious. Previous attempts to investigate repression experimentally were based on voluntary, intentional suppression of stimulus material. Unconscious repression of conflict-related material is arguably due to different processes, but has never been studied with neuroimaging methods. METHODS: We used functional magnetic resonance imaging (fMRI) in addition with skin conductance recordings during two free association paradigms to identify the neural mechanisms underlying forgetting of freely associated words according to repression theory. RESULTS: In the first experiment, free association to subsequently forgotten words was accompanied by increases in skin conductance responses (SCRs) and reaction times (RTs), indicating autonomic arousal, and by activation of the anterior cingulate cortex. These findings are consistent with the hypothesis that these associations were repressed because they elicited internal conflicts. To test this idea more directly, we conducted a second experiment in which participants freely associated to conflict-related sentences. Indeed, these associations were more likely to be forgotten than associations to not conflict-related sentences and were accompanied by increases in SCRs and RTs. Furthermore, we observed enhanced activation of the anterior cingulate cortex and deactivation of hippocampus and parahippocampal cortex during association to conflict-related sentences. CONCLUSIONS: These two experiments demonstrate that high autonomic arousal during free association predicts subsequent memory failure, accompanied by increased activation of conflict-related and deactivation of memory-related brain regions. These results are consistent with the hypothesis that during repression, explicit memory systems are down-regulated by the anterior cingulate cortex.

Memory modulation by weak synchronous deep brain stimulation: a pilot study.

Zero-lag phase synchronization of EEG activity has been reported to be a central mechanism accompanying long-term memory formation. In this pilot study, we examined the effects of synchronous low-amplitude stimulation of the rhinal cortex and the hippocampus in eleven temporal lobe epilepsy patients. The impact of in-phase stimulation (zero lag) on long-term memory encoding of words was contrasted with anti-phase (180° phase lag) and sham stimulation. We hypothesized more correctly remembered words for the in-phase compared to the sham condition and fewer correctly remembered words for the anti-phase vs. the sham condition. Indeed, we observed a trend for a linear condition effect for correctly remembered words, which is in accordance to our prediction (in-phase > sham > anti-phase). This finding suggests that even weak synchronous deep brain stimulation of rhinal cortex and hippocampus may modulate memory performance, while clear evidence for an enhancement of memory by this kind of deep brain simulation is still lacking.

Local category-specific gamma band responses in the visual cortex do not reflect conscious perception.

Which neural processes underlie our conscious experience? One theoretical view argues that the neural correlates of consciousness (NCC) reside in local activity in sensory cortices. Accordingly, local category-specific gamma band responses in visual cortex correlate with conscious perception. However, as most studies manipulated conscious perception by altering the amount of sensory evidence, it is possible that they reflect prerequisites or consequences of consciousness rather than the actual NCC. Here we directly address this issue by developing a new experimental paradigm in which conscious perception is modulated either by sensory evidence or by previous exposure of the images while recording intracranial EEG from the higher-order visual cortex of human epilepsy patients. A clear prediction is that neural processes directly reflecting conscious perception should be present regardless of how it comes about. In contrast, we observed that although subjective reports were modulated both by sensory evidence and by previous exposure, gamma band responses solely reflected sensory evidence. This result contradicts the proposal that local gamma band responses in the higher-order visual cortex reflect conscious perception.

Memory signals are temporally dissociated in and across human hippocampus and perirhinal cortex.

In the endeavor to understand how our brains enable our multifaceted memories, much controversy surrounds the contributions of the hippocampus and perirhinal cortex (PrC). We recorded functional magnetic resonance imaging (fMRI) in healthy controls and intracranial electroencephalography (EEG) in patients during a recognition memory task. Although conventional fMRI analysis showed indistinguishable roles of the hippocampus and PrC in familiarity-based item recognition and recollection-based source retrieval, event-related fMRI and EEG time courses revealed a clear temporal dissociation of memory signals in and across these regions. An early source retrieval effect was followed by a late, post-decision item novelty effect in hippocampus, whereas an early item novelty effect was followed by a sustained source retrieval effect in PrC. Although factors such as memory strength were not experimentally controlled, the temporal pattern across regions suggests that a rapid item recognition signal in PrC triggers a source retrieval process in the hippocampus, which in turn recruits PrC representations and/or mechanisms, evidenced here by increased hippocampal-PrC coupling during source recognition.

Monitoring the mind: the neurocognitive correlates of metamemory.

Memory performance in everyday life is often far from perfect and therefore needs to be monitored and controlled by metamemory evaluations, such as judgments of learning (JOLs). JOLs support monitoring for goal-directed modification of learning. Behavioral studies suggested retrieval processes as providing a basis for JOLs. Previous functional imaging research on JOLs found a dissociation between processes underlying memory prediction, located in the medial prefrontal cortex (mPFC), and actual encoding success, located in the medial temporal lobe. However, JOL-specific neural correlates could not be identified unequivocally, since JOLs were given simultaneously with encoding. Here, we aimed to identify the neurocognitive basis of JOLs, i.e., the cognitive processes and neural correlates of JOL, separate from initial encoding. Using functional magnetic resonance imaging (fMRI), we implemented a face-name paired associative design. In general, we found that actual memory success was associated with increased brain activation of the hippocampi bilaterally, whereas predicted memory success was accompanied by increased activation in mPFC, orbital frontal and anterior cingulate cortices. Masking brain activation during predicted memory success with activation during retrieval success revealed BOLD increases of the mPFC. Our findings indicate that JOLs actually incorporate retrieval processes.