COVID-19 Death Determination Methods, Minnesota, USA, 2020-20221.

Accurate and timely mortality surveillance is crucial for elucidating risk factors, particularly for emerging diseases. We compared use of COVID-19 keywords on death certificates alone to identify COVID-19 deaths in Minnesota, USA, during 2020-2022, with use of a standardized mortality definition incorporating additional clinical data. For analyses, we used likelihood ratio χ2 and median 1-way tests. Death certificates alone identified 96% of COVID-19 deaths confirmed by the standardized definition and an additional 3% of deaths that had been classified as non-COVID-19 deaths by the standardized definition. Agreement between methods was >90% for most groups except children, although agreement among adults varied by demographics and location at death. Overall median time from death to filing of death certificate was 3 days; decedent characteristics and whether autopsy was performed varied. Death certificates are an efficient and timely source of COVID-19 mortality data when paired with SARS-CoV-2 testing data.

Clade 2.3.4.4b H5N1 high pathogenicity avian influenza virus (HPAIV) from the 2021/22 epizootic is highly duck adapted and poorly adapted to chickens.

The 2021/2022 epizootic of high pathogenicity avian influenza (HPAIV) remains one of the largest ever in the UK, being caused by a clade 2.3.4.4b H5N1 HPAIV. This epizootic affected more than 145 poultry premises, most likely through independent incursion from infected wild birds, supported by more than 1700 individual detections of H5N1 from wild bird mortalities. Here an H5N1 HPAIV, representative of this epizootic (H5N1-21), was used to investigate its virulence, pathogenesis and transmission in layer chickens and Pekin ducks, two species of epidemiological importance. We inoculated both avian species with decreasing H5N1-21 doses. The virus was highly infectious in ducks, with high infection levels and accompanying shedding of viral RNA, even in ducks inoculated with the lowest dose, reflecting the strong waterfowl adaptation of the clade 2.3.4.4 HPAIVs. Duck-to-duck transmission was very efficient, coupled with high environmental contamination. H5N1-21 was frequently detected in water sources, serving as likely sources of infection for ducks, but inhalable dust and aerosols represented low transmission risks. In contrast, chickens inoculated with the highest dose exhibited lower rates of infection compared to ducks. There was no evidence for experimental H5N1-21 transmission to any naive chickens, in two stocking density scenarios, coupled with minimal and infrequent contamination being detected in the chicken environment. Systemic viral dissemination to multiple organs reflected the pathogenesis and high mortalities in both species. In summary, the H5N1-21 virus is highly infectious and transmissible in anseriformes, yet comparatively poorly adapted to galliformes, supporting strong host preferences for wild waterfowl. Key environmental matrices were also identified as being important in the epidemiological spread of this virus during the continuing epizootic.

Trends in Laboratory-Confirmed SARS-CoV-2 Reinfections and Associated Hospitalizations and Deaths Among Adults Aged ≥18 Years - 18 U.S. Jurisdictions, September 2021-December 2022.

Although reinfections with SARS-CoV-2 have occurred in the United States with increasing frequency, U.S. epidemiologic trends in reinfections and associated severe outcomes have not been characterized. Weekly counts of SARS-CoV-2 reinfections, total infections, and associated hospitalizations and deaths reported by 18 U.S. jurisdictions during September 5, 2021-December 31, 2022, were analyzed overall, by age group, and by five periods of SARS-CoV-2 variant predominance (Delta and Omicron [BA.1, BA.2, BA.4/BA.5, and BQ.1/BQ.1.1]). Among reported reinfections, weekly trends in the median intervals between infections and frequencies of predominant variants during previous infections were calculated. As a percentage of all infections, reinfections increased substantially from the Delta (2.7%) to the Omicron BQ.1/BQ.1.1 (28.8%) periods; during the same periods, increases in the percentages of reinfections among COVID-19-associated hospitalizations (from 1.9% [Delta] to 17.0% [Omicron BQ.1/BQ.1.1]) and deaths (from 1.2% [Delta] to 12.3% [Omicron BQ.1/BQ.1.1]) were also substantial. Percentages of all COVID-19 cases, hospitalizations, and deaths that were reinfections were consistently higher across variant periods among adults aged 18-49 years compared with those among adults aged ≥50 years. The median interval between infections ranged from 269 to 411 days by week, with a steep decline at the start of the BA.4/BA.5 period, when >50% of reinfections occurred among persons previously infected during the Alpha variant period or later. To prevent severe COVID-19 outcomes, including those following reinfection, CDC recommends staying up to date with COVID-19 vaccination and receiving timely antiviral treatments, when eligible.

Administration of Human Derived Upper gut Commensal Prevotella histicola delays the onset of type 1 diabetes in NOD mice.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease that is increasing in prevalence worldwide. One of the contributing factors to the pathogenesis of T1D is the composition of the intestinal microbiota, as has been demonstrated. in T1D patients, with some studies demonstrating a deficiency in their levels of Prevotella. We have isolated a strain of Prevotella histicola from a duodenal biopsy that has anti-inflammatory properties, and in addition, alters the development of autoimmune diseases in mouse models. Therefore, our hypothesis is that the oral administration of P. histicola might delay the development of T1D in the non-obese diabetic (NOD) mice. To assess this, we used the following materials and methods. Female NOD mice (ages 5-8 weeks) were administered every other day P. histicola that was cultured in-house. Blood glucose levels were measured every other week. Mice were sacrificed at various time points for histopathological analysis of the pancreas. Modulation of immune response by the commensal was tested by analyzing regulatory T-cells and NKp46+ cells using flow cytometry and intestinal cytokine mRNA transcript levels using quantitative RT-PCR. For microbial composition, 16 s rRNA gene analysis was conducted on stool samples collected at various time points. RESULTS: Administration of P. histicola in NOD mice delayed the onset of T1D. Beta diversity in the fecal microbiomes demonstrated that the microbial composition of the mice administered P. histicola was different from those that were not treated. Treatment with P. histicola led to a significant increase in regulatory T cells with a concomitant decrease in NKp46+ cells in the pancreatic lymph nodes as compared to the untreated group after 5 weeks of treatment. CONCLUSIONS: These observations suggest that P. histicola treatment delayed onset of diabetes by increasing the levels of regulatory T cells in the pancreatic lymph nodes. This preliminary work supports the rationale that enteral exposure to a non pathogenic commensal P. histicola be tested as a future therapy for T1D.

Multistate Outbreak of SARS-CoV-2 B.1.1.529 (Omicron) Variant Infections Among Persons in a Social Network Attending a Convention - New York City, November 18-December 20, 2021.

On December 2, 2021, the Minnesota Department of Health (MDH) notified CDC of a COVID-19 case caused by sequence-confirmed SARS-CoV-2 B.1.1.529 (Omicron) variant in a Minnesota resident (patient A), the first such case identified in the state and one of the earliest identified in the United States. Patient A had attended a large indoor convention in New York, New York with approximately 53,000 attendees from 52 U.S jurisdictions and 30 foreign countries during November 19-21, 2021, and had close contact† during 5 days with 29 fellow attendees. The convention required attendees to have received ≥1 COVID-19 vaccine dose and enforced mask-use while indoors. On November 22, these close contact attendees were directly and immediately notified by patient A of their exposure to SARS-CoV-2, and they sought testing over the next few days while quarantined or isolated. As part of the larger investigation into SARS-CoV-2 transmission at the convention, a subinvestigation was conducted during December by CDC, MDH, and respective state and local health departments to characterize the epidemiology of Omicron variant infection among this group of close contacts and determine the extent of secondary household transmission. Among 30 convention attendees that included patient A (the index patient) and the 29 other close contacts, 23 were interviewed, among whom all were fully vaccinated, including 11 (48%) who had received a booster dose; all 23 sought testing, and 16 (70%) received a positive SARS-CoV-2 test result. Fewer attendees who had received a booster dose before the convention received a positive test result (six of 11) compared with those who had not received a booster dose (10 of 12). The 16 attendees with positive test results had a total of 20 household contacts, 18 of whom sought testing after exposure; six received a positive test result for SARS-CoV-2. None of the persons with positive test results was hospitalized or died. There was limited convention-associated transmission identified outside of this cluster; the larger investigation included cases of both SARS-CoV-2 B.1.617.2 (Delta) and Omicron, and all Omicron cases were associated with this group (1). Data from this investigation reinforces the importance of COVID-19 booster doses in combination with early notification and other multicomponent prevention measures to limit transmission and prevent severe illness from Omicron and other SARS-CoV-2 variants.

First Identified Cases of SARS-CoV-2 Variant P.1 in the United States - Minnesota, January 2021.

Since December 2020, the Minnesota Department of Health (MDH) Public Health Laboratory has been receiving 100 specimens per week (50 from each of two clinical partners) with low cycle threshold (Ct) values for routine surveillance for SARS-CoV-2, the virus that causes COVID-19. On January 25, 2021, MDH identified the SARS-CoV-2 variant P.1 in one specimen through this surveillance system using whole genome sequencing, representing the first identified case of this variant in the United States. The P.1 variant was first identified in travelers from Brazil during routine airport screening in Tokyo, Japan, in early January 2021 (1). This variant has been associated with increased transmissibility (2), and there are concerns that mutations in the spike protein receptor-binding domain might disrupt both vaccine-induced and natural immunity (3,4). As of February 28, 2021, a total of 10 P.1 cases had been identified in the United States, including the two cases described in this report, followed by one case each in Alaska, Florida, Maryland, and Oklahoma (5).

First Identified Cases of SARS-CoV-2 Variant B.1.1.7 in Minnesota - December 2020-January 2021.

On January 9, 2021, the Minnesota Department of Health (MDH) announced the identification of the SARS-CoV-2 variant of concern (VOC) B.1.1.7, also referred to as 20I/501Y.V1 and VOC 202012/01, in specimens from five persons; on January 25, MDH announced the identification of this variant in specimens from three additional persons. The B.1.1.7 variant, which is reported to be more transmissible than certain other SARS-CoV-2 lineages*,† (1), was first reported in the United Kingdom in December 2020 (1). As of February 14, 2021, a total of 1,173 COVID-19 cases of the B.1.1.7 variant had been identified in 39 U.S. states and the District of Columbia (2). Modeling data suggest that B.1.1.7 could become the predominant variant in the United States in March 2021 (3).

Monitoring Incidence of COVID-19 Cases, Hospitalizations, and Deaths, by Vaccination Status - 13 U.S. Jurisdictions, April 4-July 17, 2021.

COVID-19 vaccine breakthrough infection surveillance helps monitor trends in disease incidence and severe outcomes in fully vaccinated persons, including the impact of the highly transmissible B.1.617.2 (Delta) variant of SARS-CoV-2, the virus that causes COVID-19. Reported COVID-19 cases, hospitalizations, and deaths occurring among persons aged ≥18 years during April 4-July 17, 2021, were analyzed by vaccination status across 13 U.S. jurisdictions that routinely linked case surveillance and immunization registry data. Averaged weekly, age-standardized incidence rate ratios (IRRs) for cases among persons who were not fully vaccinated compared with those among fully vaccinated persons decreased from 11.1 (95% confidence interval [CI] = 7.8-15.8) to 4.6 (95% CI = 2.5-8.5) between two periods when prevalence of the Delta variant was lower (<50% of sequenced isolates; April 4-June 19) and higher (≥50%; June 20-July 17), and IRRs for hospitalizations and deaths decreased between the same two periods, from 13.3 (95% CI = 11.3-15.6) to 10.4 (95% CI = 8.1-13.3) and from 16.6 (95% CI = 13.5-20.4) to 11.3 (95% CI = 9.1-13.9). Findings were consistent with a potential decline in vaccine protection against confirmed SARS-CoV-2 infection and continued strong protection against COVID-19-associated hospitalization and death. Getting vaccinated protects against severe illness from COVID-19, including the Delta variant, and monitoring COVID-19 incidence by vaccination status might provide early signals of changes in vaccine-related protection that can be confirmed through well-controlled vaccine effectiveness (VE) studies.

Sub-Lethal Peak Exposure to Insecticides Triggers Olfaction-Mediated Avoidance in Zebrafish Larvae.

In agricultural areas, insecticides inevitably reach water bodies via leaching or run-off. While designed to be neurotoxic to insects, insecticides have adverse effects on a multitude of organisms due to the high conservation of the nervous system among phyla. To estimate the ecological effects of insecticides, it is important to investigate their impact on non-target organisms such as fish. Using zebrafish as the model, we investigated how different classes of insecticides influence fish behavior and uncovered neuronal underpinnings of the associated behavioral changes, providing an unprecedented insight into the perception of these chemicals by fish. We observed that zebrafish larvae avoid diazinon and imidacloprid while showing no response to other insecticides with the same mode of action. Moreover, ablation of olfaction abolished the aversive responses, indicating that fish smelled the insecticides. Assessment of neuronal activity in 289 brain regions showed that hypothalamic areas involved in stress response were among the regions with the largest changes, indicating that the observed behavioral response resembles reactions to stimuli that threaten homeostasis, such as changes in water chemistry. Our results contribute to the understanding of the environmental impact of insecticide exposure and can help refine acute toxicity assessment.

Combining the best interest standard with shared decision-making in paediatrics-introducing the shared optimum approach based on a qualitative study.

Paediatric decision-making is the art of respecting the interests of child and family with due regard for evidence, values and beliefs, reconciled using two important but potentially conflicting concepts: best interest standard (BIS) and shared decision-making (SD-M). We combine qualitative research, our own data and the normative framework of the United Nations Convention on the Rights of Children (UNCRC) to revisit current theoretical debate on the interrelationship of BIS and SD-M. Three cohorts of child, parent and health care professional interviewees (Ntotal = 47) from Switzerland and the United States considered SD-M an essential part of the BIS. Their responses combined with the UNCRC text to generate a coherent framework which we term the shared optimum approach (SOA) combining BIS and SD-M. The SOA separates different tasks (limiting harm, showing respect, defining choices and implementing plans) into distinct dimensions and steps, based on the principles of participation, provision and protection. The results of our empirical study call into question reductive approaches to the BIS, as well as other stand-alone decision-making concepts such as the harm principle or zone of parental discretion.Conclusion: Our empirical study shows that the BIS includes a well-founded harm threshold combined with contextual information based on SD-M. We propose reconciling BIS and SD-M within the SOA as we believe this will improve paediatric decision-making. What is Known: • Parents have wide discretion in deciding for their child in everyday life, while far-reaching treatment decisions should align with the child's best interest. • Shared decision-making harbours potential conflict between parental authority and a child's best interest. What is New: • The best interest standard should not be used narrowly as a way of saying "Yes" or "No" to a specific action, but rather in a coherent framework and process which we term the shared optimum approach. • By supporting this child-centred and family-oriented process, shared decision-making becomes crucial in implementing the best interest standard.

A Chiral Pentafluorinated Isopropyl Group via Iodine(I)/(III) Catalysis.

An I(I)/(III) catalysis strategy to construct an enantioenriched fluorinated isostere of the i Pr group is reported. The difluorination of readily accessible α-CF3 -styrenes is enabled by the in situ generation of a chiral ArIF2 species to forge a stereocentre with the substituents F, CH2 F and CF3 (up to 95 %, >20:1 vicinal:geminal difluorination). The replacement of the metabolically labile benzylic proton results in a highly preorganised scaffold as was determined by X-ray crystallography (π→σ* and stereoelectronic gauche σ→σ* interactions). A process of catalyst editing is disclosed in which preliminary validation of enantioselectivity is placed on a structural foundation.

Decreased Susceptibility to Azithromycin in Clinical Shigella Isolates Associated with HIV and Sexually Transmitted Bacterial Diseases, Minnesota, USA, 2012-2015.

Shigellosis outbreaks caused by Shigella with decreased susceptibility to azithromycin (DSA-Shigella) among men who have sex with men (MSM) have been reported worldwide. We describe sexual health indicators and antimicrobial drug resistance for shigellosis cases in Minnesota, USA. We analyzed a sample of isolates received during 2012-2015 and cross-referenced cases with the Minnesota Department of Health Sexually Transmitted Disease Database to ascertain patients' HIV status and recent chlamydia, gonorrhea, and syphilis infections. Of 691 Shigella isolates, 46 (7%) were DSA-Shigella; 91% of DSA-Shigella patients were men, of whom 60% were living with HIV. Among men, those with DSA-Shigella infection had greater odds of living with HIV, identifying as MSM, or having a recent diagnosis of a sexually transmitted disease. DSA-Shigella was associated with MSM, HIV infection, and recent sexually transmitted disease. To decrease spread of DSA-Shigella, interventions targeted at communities at high risk are needed.

Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1.

Microcephalin-1 (MCPH1) exists as 2 isoforms that regulate cyclin-dependent kinase-1 activation and chromosome condensation during mitosis, with MCPH1 mutations causing primary microcephaly. MCPH1 is also a tumor suppressor protein, with roles in DNA damage repair/checkpoints. Despite these important roles, there is little information on the cellular regulation of MCPH1. We show that both MCPH1 isoforms are phosphorylated in a cyclin-dependent kinase-1-dependent manner in mitosis and identify several novel phosphorylation sites. Upon mitotic exit, MCPH1 isoforms were degraded by the anaphase-promoting complex/cyclosome-CDH1 E3 ligase complex. Anaphase-promoting complex/cyclosome-CDH1 target proteins generally have D-Box or KEN-Box degron sequences. We found that MCPH1 isoforms are degraded independently, with the long isoform degradation being D-Box dependent, whereas the short isoform was KEN-Box dependent. Our research identifies several novel mechanisms regulating MCPH1 and also highlights important issues with several commercial MCPH1 antibodies, with potential relevance to previously published data.-Meyer, S. K., Dunn, M., Vidler, D. S., Porter, A., Blain, P. G., Jowsey, P. A. Phosphorylation of MCPH1 isoforms during mitosis followed by isoform-specific degradation by APC/C-CDH1.

Making the most of small samples: Optimization of tissue allocation of pediatric solid tumors for clinical and research use.

INTRODUCTION: Tissue from pediatric solid tumors is in high demand for use in high-impact research studies, making the allocation of tissue from an anatomic pathology laboratory challenging. We designed, implemented, and assessed an interdepartmental process to optimize tissue allocation of pediatric solid tumors for both clinical care and research. METHODS: Oncologists, pathologists, surgeons, interventional radiologists, pathology technical staff, and clinical research coordinators participated in the workflow design. Procedures were created to address patient identification and consent, prioritization of protocols, electronic communication of requests, tissue preparation, and distribution. Pathologists were surveyed about the value of the new workflow. RESULTS: Over a 5-year period, 644 pediatric solid tumor patients consented to one or more studies requesting archival or fresh tissue. Patients had a variety of tumor types, with many rare and singular diagnoses. Sixty-seven percent of 1768 research requests were fulfilled. Requests for archival tissue were fulfilled at a significantly higher rate than those for fresh tissue (P > .001), and requests from resection specimens were fulfilled at a significantly higher rate than those from biopsies (P > .0001). In an anonymous survey, seven of seven pathologists reported that the process had improved since the introduction of the electronic communication model. CONCLUSIONS: A collaborative and informed model for tissue allocation is successful in distributing archival and fresh tissue for clinical research studies. Our workflows and policies have gained pathologists' approval and streamlined our processes. As clinical and research programs evolve, a thoughtful tissue allocation process will facilitate ongoing research.

Enhancing POLST Completion in a Hospital Setting: An Interdisciplinary Approach.

EXECUTIVE SUMMARY: With increased therapeutic capabilities in healthcare today, many patients with multiple progressive comorbidities are living longer. They experience recurrent hospitalizations and often undergo procedures that are not aligned with their personal goals. That is why it is essential to discuss and document healthcare preferences prior to an acute event when significant interventions could occur, especially for patients with serious and progressive illness. Completion of an advance directive and a physician order for life-sustaining treatment (POLST) supports provision of goal-concordant care. Further, for patients who have do not attempt resuscitation (DNAR) orders or are diagnosed with advanced dementia, having a POLST is essential. This may be best accomplished with hospitalization discharge plans. Our 896-bed academic medical center, Cedars-Sinai Medical Center, launched a quality initiative in 2015 to complete POLSTs for patients being discharged with DNAR status or with dementia returning to a skilled nursing facility. As part of interdisciplinary progression of care rounds, emphasis was placed on those patients for whom POLST completion was indicated. Proactive, facilitated discussions with patients, family members, and attending physicians were initiated to support POLST completion. The completed forms were then uploaded to the electronic health record. Individual units and physicians received regular feedback on POLST completion rates, and the data were later shared at medical staff quality improvement meetings.During the initiative, POLST completion rates for DNAR patients discharged alive rose from 41% in fiscal year (FY) 2014 to 75% in FY 2019. Similar improvement was seen for patients with dementia discharged to skilled nursing facilities, regardless of code status (rising from 14% in FY 2014 to 54% in FY 2019). Subsequently, we have expanded our efforts to include early discussion and completion of these advanced care planning documents for patients recently diagnosed with high mortality cancers (ovarian, pancreatic, lung, glioblastoma), focusing on the completion of advanced care planning documentation and palliative care referrals.

Development of a patient-reported outcome measure for psychotherapeutic interventions in people with seizures: A mixed methods study.

BACKGROUND: Generic or even disease-specific quality of life measures are unlikely to be equally responsive to different epilepsy treatment modalities, such as pharmacotherapy, surgery, or psychotherapy. The purpose of the present study was to summarize the development of a patient-reported outcome measure (PROM) designed to be particularly sensitive to change mediated by psychotherapeutic interventions in people with seizures. METHODS: The development of this instrument involved seven steps: (1) Development of a candidate item set based on the outcome of previous qualitative research, (2) initial quantitative-descriptive study yielding an assessment of content validity by clinical experts, (3) qualitative-descriptive posttherapy cognitive debriefing interviews with patients with epileptic and/or nonepileptic seizures (NES), (4) English translation, (5) elicitation of qualitative feedback from international experts, (6) assessment of internal consistency and correlation with similar previously validated generic and epilepsy-specific measures in a pilot study, and (7) final expert content validity rating. RESULTS: (1) The candidate item set comprised 29 stem items; five of which were followed by a follow-up (FU) item that refers to the statement of the stem item. (2) Eight clinical experts assessed content validity. Informed by rating and experts' qualitative comments, 15 items remained unchanged, eleven underwent substantial revisions, three were excluded, and six added. (3) Cognitive debriefing interviews were conducted with 14 patients with epilepsy and/or NES. Based on the interviewees' feedback, 29 of 32 items remained unchanged, two were excluded, one reworded, and four added. (4) The forwards-backwards English translation prompted substantial revision of two items because the verbatim back translation of the corresponding English items was conceptually more convincing than the original German wording. (5) The international experts identified problems with item comprehensibility/clarity of four stem and three FU items that were subsequently reworded. Ten items were added to incorporate their qualitative feedback resulting in a total of 44 items. (6) Thirty-one patients with epilepsy participated in the pilot study. The overall internal consistency of the self-Efficacy, Assertiveness, Social support, self-awareness, and hElpful thinking in people with seizures (EASE) was very good (α = 0.92). Analysis at item-level revealed problems with inverted and self-evident items. Based on this analysis, three items were eliminated and two items were revised (one FU item was turned into a stem item) resulting in a total of 42 items. (7) The second content validity rating showed final item-content validity indices (I-CVIs) between 0.38 and 1 and an excellent mean CVI of 0.92 at scale level (S-CVI/ave). Fourteen stem items were substantially revised by incorporating the experts' qualitative feedback, three items with low I-CVIs were excluded, and one item was added. The final questionnaire consisted of 40 stem items; eight of which include at least one FU item. CONCLUSION: Based on these results, the EASE is valid in terms of content, internally consistent, clear, and acceptable to patients with seizures. The measure has now been developed to the stage at which the validity and reliability as well as the psychometric properties and factorial structure of the new instrument can be assessed in larger patient groups in a prospective clinical study.

Binding of MBD proteins to DNA blocks Tet1 function thereby modulating transcriptional noise.

Aberrant DNA methylation is a hallmark of various human disorders, indicating that the spatial and temporal regulation of methylation readers and modifiers is imperative for development and differentiation. In particular, the cross-regulation between 5-methylcytosine binders (MBD) and modifiers (Tet) has not been investigated. Here, we show that binding of Mecp2 and Mbd2 to DNA protects 5-methylcytosine from Tet1-mediated oxidation. The mechanism is not based on competition for 5-methylcytosine binding but on Mecp2 and Mbd2 directly restricting Tet1 access to DNA. We demonstrate that the efficiency of this process depends on the number of bound MBDs per DNA molecule. Accordingly, we find 5-hydroxymethylcytosine enriched at heterochromatin of Mecp2-deficient neurons of a mouse model for Rett syndrome and Tet1-induced reexpression of silenced major satellite repeats. These data unveil fundamental regulatory mechanisms of Tet enzymes and their potential pathophysiological role in Rett syndrome. Importantly, it suggests that Mecp2 and Mbd2 have an essential physiological role as guardians of the epigenome.

Identification of a xenobiotic as a potential environmental trigger in primary biliary cholangitis.

BACKGROUND & AIMS: Primary biliary cholangitis (PBC) is an autoimmune-associated chronic liver disease triggered by environmental factors, such as exposure to xenobiotics, which leads to a loss of tolerance to the lipoic acid-conjugated regions of the mitochondrial pyruvate dehydrogenase complex, typically to the E2 component. We aimed to identify xenobiotics that might be involved in the environmental triggering of PBC. METHODS: Urban landfill and control soil samples from a region with high PBC incidence were screened for xenobiotic activities using analytical, cell-based xenobiotic receptor activation assays and toxicity screens. RESULTS: A variety of potential xenobiotic classes were ubiquitously present, as identified by their interaction with xenobiotic receptors - aryl hydrocarbon receptor, androgen receptor and peroxisome proliferator activated receptor alpha - in cell-based screens. In contrast, xenoestrogens were present at higher levels in soil extracts from around an urban landfill. Furthermore, two landfill sampling sites contained a chemical(s) that inhibited mitochondrial oxidative phosphorylation and induced the apoptosis of a hepatic progenitor cell. The mitochondrial effect was also demonstrated in human liver cholangiocytes from three separate donors. The chemical was identified as the ionic liquid [3-methyl-1-octyl-1H-imidazol-3-ium]+ (M8OI) and the toxic effects were recapitulated using authentic pure chemical. A carboxylate-containing human hepatocyte metabolite of M8OI, bearing structural similarity to lipoic acid, was also enzymatically incorporated into the E2 component of the pyruvate dehydrogenase complex via the exogenous lipoylation pathway in vitro. CONCLUSIONS: These results identify, for the first time, a xenobiotic in the environment that may be related to and/or be a component of an environmental trigger for PBC. Therefore, further study in experimental animal models is warranted, to determine the risk of exposure to these ionic liquids. LAY SUMMARY: Primary biliary cholangitis is a liver disease in which most patients have antibodies to mitochondrial proteins containing lipoic acid binding site(s). This paper identified a man-made chemical present in soils around a waste site. It was then shown that this chemical was metabolized into a product with structural similarity to lipoic acid, which was capable of replacing lipoic acid in mitochondrial proteins.

1,2,4-Triazolsulfone: A novel isosteric replacement of acylsulfonamides in the context of NaV1.7 inhibition.

Recently, the identification of several classes of aryl sulfonamides and acyl sulfonamides that potently inhibit NaV1.7 and demonstrate high levels of selectivity over other NaV isoforms have been reported. The fully ionizable nature of these inhibitors has been shown to be an important part of the pharmacophore for the observed potency and isoform selectivity. The requirement of this functionality, however, has presented challenges associated with optimization toward inhibitors with drug-like properties and minimal off-target activity. In an effort to obviate these challenges, we set out to develop an orally bioavailable, selective NaV1.7 inhibitor, lacking these acidic functional groups. Herein, we report the discovery of a novel series of inhibitors wherein a triazolesulfone has been designed to serve as a bioisostere for the acyl sulfonamide. This work culminated in the delivery of a potent series of inhibitors which demonstrated good levels of selectivity over NaV1.5 and favorable pharmacokinetics in rodents.

Response Evaluation Criteria in Solid Tumors (RECIST) following neoadjuvant chemotherapy in osteosarcoma.

BACKGROUND: In osteosarcoma, patient survival has not changed in over 30 years. Multiple phase II trials have been conducted in osteosarcoma using the Response Evaluation Criteria in Solid Tumors (RECIST) as a primary endpoint; however, none of these have revealed new treatment strategies. We investigated RECIST in newly diagnosed patients who received neoadjuvant chemotherapy proven to be beneficial. METHODS: Patients treated from 1986 to 2011 for newly diagnosed osteosarcoma with paired tumor imaging before and after adequate neoadjuvant chemotherapy were included in this retrospective study. Two radiologists performed independent, blinded (to image timing) RECIST measurements of primary tumor and lung metastases at diagnosis and post-neoadjuvant chemotherapy. Association between RECIST and histological necrosis and outcome were assessed. RESULTS: Seventy-four patients met inclusion criteria. Five-year overall survival and progression-free survival (PFS) were 77 ± 7% and 61 ± 8%, respectively. No patients had RECIST partial or complete response in the primary tumor. Sixty-four patients (86%) had stable disease, and 10 (14%) had progressive disease (PD). PD in the primary tumor was associated with significantly worse PFS in localized disease patients (P = 0.02). There was no association between RECIST in the primary tumor and necrosis. There were an insufficient number of patients with lung nodules ≥1 cm at diagnosis to evaluate RECIST in pulmonary metastases. CONCLUSIONS: PD by RECIST predicts poor outcome in localized disease patients. In bone lesions, chemotherapy proven to improve overall survival does not result in radiographic responses as measured by RECIST. Further investigation of RECIST in pulmonary metastatic disease in osteosarcoma is needed.