Electronic Partner Notification for Sexually Transmitted Infections: A Qualitative Assessment of Patient, Clinical Staff, and State Field Epidemiologist Perspectives.

In Massachusetts (MA), partner notification is routinely offered for new HIV and infectious syphilis cases, but there are no formal partner notification services for gonorrhea and chlamydia. Electronic partner notification (ePN), which allows patients to anonymously notify their partners of sexually transmitted infection exposure, could fill this gap. We evaluated the acceptability of and ideal characteristics for a statewide ePN service in MA. We performed semistructured interviews with patients at a Boston area sexual health clinic and conducted focus groups with clinicians and Massachusetts Department of Public Health Field Epidemiologists (FEs). We developed a codebook and thematically analyzed interview and focus group data; 25% of interviews were double coded. We identified six main themes from our data: (1) partner notification is a relational process and (2) partner notification is situation dependent. There are three pairs of challenges and core values for an effective ePN system: (3) stigmatization versus inclusivity, (4) trust versus mistrust, and (5) privacy versus helpful information sharing. Therefore, (6) a statewide ePN platform must be customizable at each possible step. Although ePN was acceptable across all three groups, the likelihood of individual use was grounded in a patient's sociocultural context, interpersonal relationships, trust in the platform and health authorities, desire to avoid stigmatization, and privacy needs. These factors are best accommodated by a platform that adapts to users' preferences and needs. ePN presents an opportunity to link partners at risk for gonorrhea or chlamydia to clinical care that is complementary to the more labor-intensive FE role.

Drosophila melanogaster models of MPS IIIC (Hgsnat-deficiency) highlight the role of glia in disease presentation.

Sanfilippo syndrome (Mucopolysaccharidosis type III or MPS III) is a recessively inherited neurodegenerative lysosomal storage disorder. Mutations in genes encoding enzymes in the heparan sulphate degradation pathway lead to the accumulation of partially degraded heparan sulphate, resulting ultimately in the development of neurological deficits. Mutations in the gene encoding the membrane protein heparan-α-glucosaminide N-acetyltransferase (HGSNAT; EC2.3.1.78) cause MPS IIIC (OMIM#252930), typified by impaired cognition, sleep-wake cycle changes, hyperactivity and early death, often before adulthood. The precise disease mechanism that causes symptom emergence remains unknown, posing a significant challenge in the development of effective therapeutics. As HGSNAT is conserved in Drosophila melanogaster, we now describe the creation and characterisation of the first Drosophila models of MPS IIIC. Flies with either an endogenous insertion mutation or RNAi-mediated knockdown of hgsnat were confirmed to have a reduced level of HGSNAT transcripts and age-dependent accumulation of heparan sulphate leading to engorgement of the endo/lysosomal compartment. This resulted in abnormalities at the pre-synapse, defective climbing and reduced overall activity. Altered circadian rhythms (shift in peak morning activity) were seen in hgsnat neuronal knockdown lines. Further, when hgsnat was knocked down in specific glial subsets (wrapping, cortical, astrocytes or subperineural glia), impaired climbing or reduced activity was noted, implying that hgsnat function in these specific glial subtypes contributes significantly to this behaviour and targeting treatments to these cell groups may be necessary to ameliorate or prevent symptom onset. These novel models of MPS IIIC provide critical research tools for delineating the key cellular pathways causal in the onset of neurodegeneration in this presently untreatable disorder.

COVID-19 infected ST-Elevation myocardial infarction in India (COSTA INDIA).

OBJECTIVE: To find out differences in the presentation, management and outcomes of COVID-19 infected STEMI patients compared to age and sex-matched non-infected STEMI patients treated during the same period. METHODS: This was a retrospective multicentre observational registry in which we collected data of COVID-19 positive STEMI patients from selected tertiary care hospitals across India. For every COVID-19 positive STEMI patient, two age and sex-matched COVID-19 negative STEMI patients were enrolled as control. The primary endpoint was a composite of in-hospital mortality, re-infarction, heart failure, and stroke. RESULTS: 410 COVID-19 positive STEMI cases were compared with 799 COVID-19 negative STEMI cases. The composite of death/reinfarction/stroke/heart failure was significantly higher among the COVID-19 positive STEMI patients compared with COVID-19 negative STEMI cases (27.1% vs 20.7% p value = 0.01); though mortality rate did not differ significantly (8.0% vs 5.8% p value = 0.13). Significantly lower proportion of COVID-19 positive STEMI patients received reperfusion treatment and primary PCI (60.7% vs 71.1% p value=< 0.001 and 15.4% vs 23.4% p value = 0.001 respectively). Rate of systematic early PCI (pharmaco-invasive treatment) was significantly lower in the COVID-19 positive group compared with COVID-19 negative group. There was no difference in the prevalence of high thrombus burden (14.5% and 12.0% p value = 0.55 among COVID-19 positive and negative patients respectively) CONCLUSIONS: In this large registry of STEMI patients, we did not find significant excess in in-hospital mortality among COVID-19 co-infected patients compared with non-infected patients despite lower rate of primary PCI and reperfusion treatment, though composite of in-hospital mortality, re-infarction, stroke and heart failure was higher.

Microtubule nucleation from the fibrous corona by LIC1-pericentrin promotes chromosome congression.

Error-free chromosome segregation in mitosis and meiosis relies on the assembly of a microtubule-based spindle that interacts with kinetochores to guide chromosomes to the cell equator before segregation in anaphase. Microtubules sprout from nucleation sites such as centrosomes, but kinetochores can also promote microtubule formation. It is unclear, however, how kinetochore-derived microtubules are generated and what their role is in chromosome segregation. Here, we show that the transient outer-kinetochore meshwork known as the fibrous corona serves as an autonomous microtubule nucleation platform. The fibrous corona is essential for the nucleation of kinetochore-derived microtubules, and when dissociated from the core kinetochore, it retains microtubule nucleation capacity. Nucleation relies on a fibrous-corona-bound pool of the LIC1 subunit of the dynein motor complex, which interacts with the γ-tubulin-tethering protein pericentrin (PCNT). PCNT is essential for microtubule nucleation from fibrous coronas, and in centrosome-depleted cells, where nearly all mitotic nucleation occurs at fibrous coronas, chromosome congression is fully dependent on PCNT. We further show that chromosomes in bovine oocytes, which naturally lack centrosomes, have highly expanded fibrous coronas that drive chromosome-derived microtubule nucleation. Preventing fibrous corona expansion in these cells impairs chromosome congression and causes spindle assembly defects. Our results show that fibrous coronas are autonomous microtubule-organizing centers that are important for spindle assembly, which may be especially relevant in acentrosomal cells such as oocytes.

Care teams misunderstand what most upsets patients about their care.

BACKGROUND: Negative healthcare delivery experiences can cause lasting patient distress and medical service misuse and disuse. Yet no multi-site study has examined whether care-team members understand what most upsets patients about their care. METHODS: We interviewed 373 patients and 360 care-team members in the medical oncology and ambulatory surgery clinics of 11 major healthcare organizations across six U.S. census regions. Patients deeply upset by a service-related experience (n = 99, 27%) answered questions about that experience, while care-team members (n = 360) answered questions about their beliefs regarding what most upsets patients. We performed content analysis to identify memorably upsetting care (MUC) themes; a generalized estimating equation to explore whether MUC theme mention frequencies varied by participant role (care-team member vs. patient), specialty (oncology vs. surgery), facility (academic vs. community), and gender; and logistic regressions to investigate the effects of participant characteristics on individual themes. RESULTS: MUC themes included three systems issues (inefficiencies, access barriers, and facilities problems) and four care-team issues (miscommunication, neglect, coldness, and incompetence). MUC theme frequencies differed by role (all Ps < 0.001), with more patients mentioning care-team coldness (OR = 0.37; 95% CI, 0.23-0.60) and incompetence (OR = 0.17; 95% CI, 0.09-0.31); but more care-team members mentioning system inefficiencies (OR = 7.01; 95% CI, 4.31-11.40) and access barriers (OR, 5.48; 95% CI, 2.81-10.69). CONCLUSIONS: When considering which service experiences most upset patients, care-team members underestimate the impact of their own behaviors and overestimate the impact of systems issues. IMPLICATIONS: Healthcare systems should reconsider how they collect, interpret, disseminate, and respond to patient service reports. LEVEL OF EVIDENCE: Level III.

Genomic and phenotypic characterization of 404 individuals with neurodevelopmental disorders caused by CTNNB1 variants.

PURPOSE: Germline loss-of-function variants in CTNNB1 cause neurodevelopmental disorder with spastic diplegia and visual defects (NEDSDV; OMIM 615075) and are the most frequent, recurrent monogenic cause of cerebral palsy (CP). We investigated the range of clinical phenotypes owing to disruptions of CTNNB1 to determine the association between NEDSDV and CP. METHODS: Genetic information from 404 individuals with collectively 392 pathogenic CTNNB1 variants were ascertained for the study. From these, detailed phenotypes for 52 previously unpublished individuals were collected and combined with 68 previously published individuals with comparable clinical information. The functional effects of selected CTNNB1 missense variants were assessed using TOPFlash assay. RESULTS: The phenotypes associated with pathogenic CTNNB1 variants were similar. A diagnosis of CP was not significantly associated with any set of traits that defined a specific phenotypic subgroup, indicating that CP is not additional to NEDSDV. Two CTNNB1 missense variants were dominant negative regulators of WNT signaling, highlighting the utility of the TOPFlash assay to functionally assess variants. CONCLUSION: NEDSDV is a clinically homogeneous disorder irrespective of initial clinical diagnoses, including CP, or entry points for genetic testing.

Professional Behavior and Value Erosion: A Qualitative Study of Physicians and the Electronic Health Record.

GOAL: Occurrences of physician burnout have reached epidemic numbers, and the electronic health record (EHR) is a commonly cited cause of the distress. To enhance current understanding of the relationship between burnout and the EHR, we explored the connections between physicians' distress and the EHR. METHODS: In this qualitative study, physicians and graduate medical trainees from two healthcare organizations in California were interviewed about EHR-related distressing events and the impact on their emotions and actions. We analyzed physician responses to identify themes regarding the negative impact of the EHR on physician experience and actions. EHR "distressing events" were categorized using the Accreditation Council for Graduate Medical Education (ACGME) Physician Professional Competencies. PRINCIPAL FINDINGS: Every participating physician reported EHR-related distress affecting professional activities. Five main themes emerged from our analysis: system blocks to patient care; poor implementation, design, and functionality of the EHR; billing priorities conflicting with ideal workflow and best-practice care; lack of efficiency; and poor teamwork function. When mapped to the ACGME competencies, physician distress frequently stemmed from situations where physicians prioritized systems-based practice above other desired professional actions and behaviors. Physicians also reported a climate of silence in which physicians would not share problems due to fear of retribution or lack of confidence that the problems would be addressed. PRACTICAL APPLICATIONS: Physicians and administrators need to address the hierarchy of values that prioritizes system requirements such as those required by the EHR above physicians' other desired professional actions and behaviors. Balancing the importance of competing competencies may help to address rising burnout. We also recommend that administrators consider qualitative anonymous interviews as an effective method to uncover and understand physician distress in light of physicians' reported climate of silence.

Induced hypernatremia in patients with moderate-to-severe ARDS: a randomized controlled study.

BACKGROUND: Induced hypernatremia and hyperosmolarity is protective in animal models of lung injury. We hypothesized that increasing and maintaining plasma sodium between 145 and 150 mmol/l in patients with moderate-to-severe ARDS would be safe and will reduce lung injury. This was a prospective randomized feasibility study in moderate-to-severe ARDS, comparing standard care with intravenous hypertonic saline to achieve and maintain plasma sodium between 145 and 150 mmol/l for 7 days (HTS group). Both groups of patients were managed with lung protective ventilation and conservative fluid management. The primary outcome was 1-point reduction in lung injury score (LIS) or successful extubation by day 7. RESULTS: Forty patients were randomized with 20 in each group. Baseline characteristics of severity of illness were well balanced. Patients in the HTS group had higher plasma sodium levels during the first 7 days after randomization when compared with the control group (p = 0.04). Seventy five percent (15/20) of patients in the HTS group were extubated or had ≥ 1-point reduction in LIS compared with 35% (7/20) in the control group (p = 0.02). There was also a decrease in length of mechanical ventilation and hospital length of stay in the HTS group. CONCLUSION: We have shown clinical improvement in patients with moderate-to-severe ARDS following induced hypernatremia, suggesting that administration of hypertonic saline is a safe and feasible intervention in patients with moderate-to-severe ARDS. This suggests progress to a phase II study. Clinical Trial Registration Australian and New Zealand Clinical Trials Registry (ACTRN12615001282572).

Visualizing protein-protein interactions in plants by rapamycin-dependent delocalization.

Identifying protein-protein interactions (PPIs) is crucial for understanding biological processes. Many PPI tools are available, yet only some function within the context of a plant cell. Narrowing down even further, only a few tools allow complex multi-protein interactions to be visualized. Here, we present a conditional in vivo PPI tool for plant research that meets these criteria. Knocksideways in plants (KSP) is based on the ability of rapamycin to alter the localization of a bait protein and its interactors via the heterodimerization of FKBP and FRB domains. KSP is inherently free from many limitations of other PPI systems. This in vivo tool does not require spatial proximity of the bait and prey fluorophores and it is compatible with a broad range of fluorophores. KSP is also a conditional tool and therefore the visualization of the proteins in the absence of rapamycin acts as an internal control. We used KSP to confirm previously identified interactions in Nicotiana benthamiana leaf epidermal cells. Furthermore, the scripts that we generated allow the interactions to be quantified at high throughput. Finally, we demonstrate that KSP can easily be used to visualize complex multi-protein interactions. KSP is therefore a versatile tool with unique characteristics and applications that complements other plant PPI methods.

Safety and immunogenicity of an inactivated eastern equine encephalitis virus vaccine.

BACKGROUND: Eastern equine encephalitis virus (EEEV) is a mosquito borne alphavirus spread primarily in Atlantic and Gulf Coast regions of the United States. EEEV is the causative agent of a devastating meningoencephalitis syndrome, with approximately 30% mortality and significant morbidity. There is no licensed human vaccine against EEEV. An inactivated EEEV vaccine has been offered under investigational new drug (IND) protocols at the United States Army Medical Research Institute of Infectious Diseases (USAMRIID) since 1976. METHODS: Healthy at-risk laboratory personnel received inactivated PE-6 strain EEEV (TSI-GSD 104) vaccine under two separate IND protocols. Protocol FY 99-11 (2002-2008) had a primary series consisting of doses on day 0, 7, and 28. Protocol FY 06-31 (2008-2016) utilized a primary series with doses on day 0 and 28, and month 6. Participants with an inadequate immune response, plaque reduction neutralization test with 80% cut-off (PRNT80) titer < 40, received booster vaccination. Volunteers with prior EEEV vaccination were eligible to enroll for booster doses based on annual titer evaluation. RESULTS: The FY06-31 dosing schema resulted in significantly greater post-primary series immune response (PRNT80 ≥ 40) rates (84% vs 54%) and geometric mean titers (184.1 vs 39.4). The FY 06-31 dosing schema also resulted in significantly greater cumulative annual immune response rates from 1 to up to 7 years post vaccination (75% vs 59%) and geometric mean of titers (60.1 vs 43.0). The majority of probably or definitely related adverse events were mild and local; there were no probably or definitely related serious adverse events. CONCLUSIONS: Inactivated PE-6 EEEV vaccine is safe and immunogenic in at-risk laboratory personnel. A prolonged primary series, with month 6 dose, significantly improved vaccine immunogenicity both post-primary series and longitudinally on annual titers. Despite decades of safe use under IND, full licensure is not planned due to manufacturing constraints, and ongoing development of alternatives.

Mutations disrupting neuritogenesis genes confer risk for cerebral palsy.

In addition to commonly associated environmental factors, genomic factors may cause cerebral palsy. We performed whole-exome sequencing of 250 parent-offspring trios, and observed enrichment of damaging de novo mutations in cerebral palsy cases. Eight genes had multiple damaging de novo mutations; of these, two (TUBA1A and CTNNB1) met genome-wide significance. We identified two novel monogenic etiologies, FBXO31 and RHOB, and showed that the RHOB mutation enhances active-state Rho effector binding while the FBXO31 mutation diminishes cyclin D levels. Candidate cerebral palsy risk genes overlapped with neurodevelopmental disorder genes. Network analyses identified enrichment of Rho GTPase, extracellular matrix, focal adhesion and cytoskeleton pathways. Cerebral palsy risk genes in enriched pathways were shown to regulate neuromotor function in a Drosophila reverse genetics screen. We estimate that 14% of cases could be attributed to an excess of damaging de novo or recessive variants. These findings provide evidence for genetically mediated dysregulation of early neuronal connectivity in cerebral palsy.

Definition and diagnosis of cerebral palsy in genetic studies: a systematic review.

AIM: To conduct a systematic review of phenotypic definition and case ascertainment in published genetic studies of cerebral palsy (CP) to inform guidelines for the reporting of such studies. METHOD: Inclusion criteria comprised genetic studies of candidate genes, with CP as the outcome, published between 1990 and 2019 in the PubMed, Embase, and BIOSIS Citation Index databases. RESULTS: Fifty-seven studies met the inclusion criteria. We appraised how CP was defined, the quality of information on case ascertainment, and compliance with international consensus guidelines. Seven studies (12%) were poorly described, 33 studies (58%) gave incomplete information, and 17 studies (30%) were well described. Missing key information precluded determining how many studies complied with the definition by Rosenbaum et al. Only 18 out of 57 studies (32%) were compliant with the Surveillance of Cerebral Palsy in Europe (SCPE) international guidelines on defining CP. INTERPRETATION: Limited compliance with international consensus guidelines on phenotypic definition and mediocre reporting of CP case ascertainment hinders the comparison of results among genetic studies of CP (including meta-analyses), thereby limiting the quality, interpretability, and generalizability of study findings. Compliance with the SCPE guidelines is important for ongoing gene discovery efforts in CP, given the potential for misclassification of unrelated neurological conditions as CP.

Of Cell Shapes and Motion: The Physical Basis of Animal Cell Migration.

Motile cells have developed a variety of migration modes relying on diverse traction-force-generation mechanisms. Before the behavior of intracellular components could be easily imaged, cell movements were mostly classified by different types of cellular shape dynamics. Indeed, even though some types of cells move without any significant change in shape, most cell propulsion mechanisms rely on global or local deformations of the cell surface. In this review, focusing mostly on metazoan cells, we discuss how different types of local and global shape changes underlie distinct migration modes. We then discuss mechanical differences between force-generation mechanisms and finish by speculating on how they may have evolved.

Genetic screening identifies a SUMO protease dynamically maintaining centromeric chromatin.

Centromeres are defined by a self-propagating chromatin structure based on stable inheritance of CENP-A containing nucleosomes. Here, we present a genetic screen coupled to pulse-chase labeling that allow us to identify proteins selectively involved in deposition of nascent CENP-A or in long-term transmission of chromatin-bound CENP-A. These include factors with known roles in DNA replication, repair, chromatin modification, and transcription, revealing a broad set of chromatin regulators that impact on CENP-A dynamics. We further identify the SUMO-protease SENP6 as a key factor, not only controlling CENP-A stability but virtually the entire centromere and kinetochore. Loss of SENP6 results in hyper-SUMOylation of CENP-C and CENP-I but not CENP-A itself. SENP6 activity is required throughout the cell cycle, suggesting that a dynamic SUMO cycle underlies a continuous surveillance of the centromere complex that in turn ensures stable transmission of CENP-A chromatin.

Practices to Foster Physician Presence and Connection With Patients in the Clinical Encounter.

Importance: Time constraints, technology, and administrative demands of modern medicine often impede the human connection that is central to clinical care, contributing to physician and patient dissatisfaction. Objective: To identify evidence and narrative-based practices that promote clinician presence, a state of awareness, focus, and attention with the intent to understand patients. Evidence Review: Preliminary practices were derived through a systematic literature review (from January 1997 to August 2017, with a subsequent bridge search to September 2019) of effective interpersonal interventions; observations of primary care encounters in 3 diverse clinics (n = 27 encounters); and qualitative interviews with physicians (n = 10), patients (n = 27), and nonmedical professionals whose occupations involve intense interpersonal interactions (eg, firefighter, chaplain, social worker; n = 30). After evidence synthesis, promising practices were reviewed in a 3-round modified Delphi process by a panel of 14 researchers, clinicians, patients, caregivers, and health system leaders. Panelists rated each practice using 9-point Likert scales (-4 to +4) that reflected the potential effect on patient and clinician experience and feasibility of implementation; after the third round, panelists selected their "top 5" practices from among those with median ratings of at least +2 for all 3 criteria. Final recommendations incorporate elements from all highly rated practices and emphasize the practices with the greatest number of panelist votes. Findings: The systematic literature review (n = 73 studies) and qualitative research activities yielded 31 preliminary practices. Following evidence synthesis, 13 distinct practices were reviewed by the Delphi panel, 8 of which met criteria for inclusion and were combined into a final set of 5 recommendations: (1) prepare with intention (take a moment to prepare and focus before greeting a patient); (2) listen intently and completely (sit down, lean forward, avoid interruptions); (3) agree on what matters most (find out what the patient cares about and incorporate these priorities into the visit agenda); (4) connect with the patient's story (consider life circumstances that influence the patient's health; acknowledge positive efforts; celebrate successes); and (5) explore emotional cues (notice, name, and validate the patient's emotions). Conclusions and Relevance: This mixed-methods study identified 5 practices that have the potential to enhance physician presence and meaningful connection with patients in the clinical encounter. Evaluation and validation of the outcomes associated with implementing the 5 practices is needed, along with system-level interventions to create a supportive environment for implementation.

Can Patient-Provider Interpersonal Interventions Achieve the Quadruple Aim of Healthcare? A Systematic Review.

BACKGROUND: Human connection is at the heart of medical care, but questions remain as to the effectiveness of interpersonal interventions. The purpose of this review was to characterize the associations between patient-provider interpersonal interventions and the quadruple aim outcomes (population health, patient experience, cost, and provider experience). METHODS: We sourced data from PubMed, EMBASE, and PsycInfo (January 1997-August 2017). Selected studies included randomized controlled trials and controlled observational studies that examined the association between patient-provider interpersonal interventions and at least one outcome measure of the quadruple aim. Two abstractors independently extracted information about study design, methods, and quality. We characterized evidence related to the objective of the intervention, type and duration of intervention training, target recipient (provider-only vs. provider-patient dyad), and quadruple aim outcomes. RESULTS: Seventy-three out of 21,835 studies met the design and outcome inclusion criteria. The methodological quality of research was moderate to high for most included studies; 67% of interventions targeted the provider. Most studies measured impact on patient experience; improvements in experience (e.g., satisfaction, patient-centeredness, reduced unmet needs) often corresponded with a positive impact on other patient health outcomes (e.g., quality of life, depression, adherence). Enhanced interpersonal interactions improved provider well-being, burnout, stress, and confidence in communicating with difficult patients. Roughly a quarter of studies evaluated cost, but the majority reported no significant differences between intervention and control groups. Among studies that measured time in the clinical encounter, intervention effects varied. Interventions with lower demands on provider time and effort were often as effective as those with higher demands. DISCUSSION: Simple, low-demand patient-provider interpersonal interventions may have the potential to improve patient health and patient and provider experience, but there is limited evidence that these interventions influence cost-related outcomes.

What is clinician presence? A qualitative interview study comparing physician and non-physician insights about practices of human connection.

OBJECTIVE: We sought to investigate the concept and practices of 'clinician presence', exploring how physicians and professionals create connection, engage in interpersonal interaction, and build trust with individuals across different circumstances and contexts. DESIGN: In 2017-2018, we conducted qualitative semistructured interviews with 10 physicians and 30 non-medical professionals from the fields of protective services, business, management, education, art/design/entertainment, social services, and legal/personal services. SETTING: Physicians were recruited from primary care clinics in an academic medical centre, a Veterans Affairs clinic, and a federally qualified health centre. PARTICIPANTS: Participants were 55% men and 45% women; 40% were non-white. RESULTS: Qualitative analyses yielded a definition of presence as a purposeful practice of awareness, focus, and attention with the intent to understand and connect with individuals/patients. For both medical and non-medical professionals, creating presence requires managing and considering time and environmental factors; for physicians in particular, this includes managing and integrating technology. Listening was described as central to creating the state of being present. Within a clinic, presence might manifest as a physician listening without interrupting, focusing intentionally on the patient, taking brief re-centering breaks throughout a clinic day, and informing patients when attention must be redirected to administrative or technological demands. CONCLUSIONS: Clinician presence involves learning to step back, pause, and be prepared to receive a patient's story. Building on strategies from physicians and non-medical professionals, clinician presence is best enacted through purposeful intention to connect, conscious navigation of time, and proactive management of technology and the environment to focus attention on the patient. Everyday practice or ritual supporting these strategies could support physician self-care as well as physician-patient connection.

Erratum: Author Correction: Pathogenic copy number variants that affect gene expression contribute to genomic burden in cerebral palsy.

[This corrects the article DOI: 10.1038/s41525-018-0073-4.].

Non-self mutation: double-stranded RNA elicits antiviral pathogenic response in a Drosophila model of expanded CAG repeat neurodegenerative diseases.

Inflammation is activated prior to symptoms in neurodegenerative diseases, providing a plausible pathogenic mechanism. Indeed, genetic and pharmacological ablation studies in animal models of several neurodegenerative diseases demonstrate that inflammation is required for pathology. However, while there is growing evidence that inflammation-mediated pathology may be the common mechanism underlying neurodegenerative diseases, including those due to dominantly inherited expanded repeats, the proximal causal agent is unknown. Expanded CAG.CUG repeat double-stranded RNA causes inflammation-mediated pathology when expressed in Drosophila. Repeat dsRNA is recognized by Dicer-2 as a foreign or 'non-self' molecule triggering both antiviral RNA and RNAi pathways. Neither of the RNAi pathway cofactors R2D2 nor loquacious are necessary, indicating antiviral RNA activation. RNA modification enables avoidance of recognition as 'non-self' by the innate inflammatory surveillance system. Human ADAR1 edits RNA conferring 'self' status and when co-expressed with expanded CAG.CUG dsRNA in Drosophila the pathology is lost. Cricket Paralysis Virus protein CrPV-1A is a known antagonist of Argonaute-2 in Drosophila antiviral defense. CrPV-1A co-expression also rescues pathogenesis, confirming anti-viral-RNA response. Repeat expansion mutation therefore confers 'non-self' recognition of endogenous RNA, thereby providing a proximal, autoinflammatory trigger for expanded repeat neurodegenerative diseases.