Between loss and restoration: The role of liminality in advancing theories of grief and bereavement.

A recent national survey of bereaved partners found high levels of complicated grief and psychological distress, with evidence that loneliness and isolation may contribute to these outcomes. However, the mechanisms of action for this have not been explored. To advance grief theory this paper reports analysis of the survey free-text data to examine the relationship between social support and emotional responses to bereavement. Individuals bereaved of a civil partner or spouse 6-10 months previously were identified through death registration data. 569/1945 (29 %) completed surveys were received. Of those, 311 participants (55 %) provided responses to two free-text questions which asked about their 'feelings since the death of their partner or spouse', and 'about the support around' them. Data were analysed using corpus-assisted discourse analysis and the discourse dynamics approach for figurative language. Participants described diverse emotional responses to the bereavement (e.g. sadness, anger, denial, acceptance), and the value of formal and informal bereavement support. Although many of the experiences described are accounted for in existing grief theory, some participants described a liminal experience not recognised within these theories. They felt trapped, unable to engage with loss or restoration, and unable to move forward as their planned future no longer existed. They sought out 'communitas' (solidarity in experiences), but often found support from their social networks had diminished. Metaphors were used to describe this liminality, with partner grief expressed as a dark agentic force, a monster, an abyss, and as water. The findings of this study offer original insights into experiences and trajectories of bereavement, and our understandings of prolonged or complicated grief. A novel model 'Between Loss and Restoration' is presented to include these experiences. Recognition of the place for liminality within the spectrum of grief experiences could enhance grief literacy and improve formal and informal bereavement support provision.

Acrylate-Induced ß-H Elimination in Coordination Insertion Copolymerizaton Catalyzed by Nickel.

Polar monomer-induced ß-H elimination is a key elementary step in polar polyolefin synthesis by coordination polymerization but remains underexplored. Herein, we show that a bulky neutral Ni catalyst, 1Ph, is not only a high-performance catalyst in ethylene/acrylate copolymerization (activity up to ∼37,000 kg/(mol·h) at 130 °C in a batch reactor, mol % tBA ∼ 0.3) but also a suitable platform for investigation of acrylate-induced ß-H elimination. 4Ph-tBu, a novel Ni alkyl complex generated after acrylate-induced ß-H elimination and subsequent acrylate insertion, was identified and characterized by crystallography. A combination of catalysis and mechanistic studies reveals effects of the acrylate monomer, bidentate ligand, and the labile ligand (e.g., pyridine) on the kinetics of ß-H elimination, the role of ß-H elimination in copolymerization catalysis as a chain-termination pathway, and its potential in controlling the polymer microstructure in polar polyolefin synthesis.

Communication about sexual orientation and gender between clinicians, LGBT+ people facing serious illness and their significant others: a qualitative interview study of experiences, preferences and recommendations.

BACKGROUND: Healthcare organisations have legal and ethical duties to reduce inequalities in access to healthcare services and related outcomes. However, lesbian, gay, bisexual and/or transgender (LGBT+) people continue to experience and anticipate discrimination in health and social care. Skilled communication is vital for quality person-centred care, but there is inconsistent provision of evidence-based clinician education on health needs and experiences of LGBT+ people to support this. This study aimed to identify key stakeholders' experiences, preferences and best practices for communication regarding sexual orientation, gender identity and gender history in order to reduce inequalities in healthcare. METHODS: Semistructured qualitative interviews with LGBT+ patients with serious illness, significant others and clinicians, recruited via UK-wide LGBT+ groups, two hospitals and one hospice in England. We analysed the interview data using reflexive thematic analysis. RESULTS: 74 stakeholders participated: 34 LGBT+ patients with serious illness, 13 significant others and 27 multiprofessional clinicians. Participants described key communication strategies to promote inclusive practice across three domains: (1) 'Creating positive first impressions and building rapport' were central to relationship building and enacted through routine use of inclusive language, avoiding potentially negative non-verbal signals and echoing terminology used by patients and caregivers; (2) 'Enhancing care by actively exploring and explaining the relevance of sexual orientation and gender identity', participants described the benefits of clinicians initiating these discussions, pursuing topics guided by the patient's response or expressed preferences for disclosure. Active involvement of significant others was encouraged to demonstrate recognition of the relationship; these individual level actions are underpinned by a foundation of (3) 'visible and consistent LGBT+ inclusiveness in care systems'. Although participants expressed hesitance talking about LGBT+ identities with individuals from some sociocultural and religious backgrounds, there was widespread support for institutions to adopt a standardised, LGBT+ inclusive, visibly supportive approach. CONCLUSIONS: Person-centred care can be enhanced by incorporating discussions about sexual orientation and gender identity into routine clinical practice. Inclusive language and sensitive exploration of relationships and identities are core activities. Institutions need to support clinicians through provision of adequate training, resources, inclusive monitoring systems, policies and structures. Ten inclusive communication recommendations are made based on the data.

LGBT+ partner bereavement and appraisal of the Acceptance-Disclosure Model of LGBT+ bereavement: A qualitative interview study.

BACKGROUND: Support from social networks is vital after the death of a partner. Lesbian, gay, bisexual and/or transgender (LGBT+) people can face disenfranchisement and isolation in bereavement. The Acceptance-Disclosure Model (of LGBT+ bereavement) posits that experiences are shaped by the extent to which individuals feel able to disclose their bereavement to others, and whether that loss is acknowledged appropriately. AIM: To explore LGBT+ specific experiences of partner bereavement; determine decision-making processes regarding disclosure of relationships/identities; and appraise the Acceptance-Disclosure Model using primary qualitative data. DESIGN: Exploratory in-depth qualitative interview study positioned within a social constructivist paradigm. Data were analysed using inductive and deductive reflexive thematic analysis. SETTING/PARTICIPANTS: 21 LGBT+ people from across England bereaved of their civil partner/spouse. RESULTS: Participants described LGBT+ specific stressors in bereavement: lack of recognition of their loss; inappropriate questioning; unwanted disclosure of gender history; and fears of discrimination when accessing support. Disclosure of LGBT+ identities varied across social networks. Some participants described hiding their identities and bereavement to preserve relationships, and challenging intersections between LGBT+ identities and other aspects of culture or self. These findings provide primary evidence to support the Acceptance-Disclosure Model. CONCLUSIONS: LGBT+ people face additional stressors in bereavement. Not all LGBT+ people want to talk directly about their relationships/identities. Sensitive exploration of support needs, aligned with preferences around disclosure of identities, can help foster trust. Five recommendations for inclusive practice are presented. Further research should consider whether the Acceptance-Disclosure Model has utility to explain bereavement experiences for other isolated or disenfranchised groups.

Does the impact of bereavement vary between same and different gender partnerships? A representative national, cross-sectional study.

BACKGROUND: Data suggest poorer bereavement outcomes for lesbian, gay and bisexual people, but this has not been estimated in population-based research. This study compared bereavement outcomes for partners of same-gender and different-gender decedents. METHODS: In this population-based, cross-sectional survey of people bereaved of a civil partner or spouse 6-10 months previously, we used adjusted logistic and linear regression to investigate outcomes of interest: (1) positive screen on Inventory of Complicated Grief (ICG), (2) positive screen on General Health Questionnaire (GHQ), (3) grief intensity (ICG) and (4) psychiatric symptoms (GHQ-12). RESULTS: Among 233 same-gender partners and 329 of different-gender partners, 66.1% [95% confidence interval (CI) 60.0-72.2] and 59.2% [95% CI (53.9-64.6)] respectively screened positive for complicated grief on the ICG, whilst 76.0% [95% CI (70.5-81.5)] and 69.3% [95% CI (64.3-74.3)] respectively screened positive on the GHQ-12. Same-gender bereaved partners were not significantly more likely to screen positive for complicated grief than different-gender partners [adjusted odds ratio (aOR) 1.56, 95% CI (0.98-2.47)], p = 0.059, but same-gender bereaved partners were significantly more likely to screen for psychiatric caseness [aOR 1.67 (1.02, 2.71) p = 0.043]. We similarly found no significant association of partner gender with grief intensity [B = 1.86, 95% CI (-0.91to 4.63), p = 0.188], but significantly greater psychological distress for same-gender partners [B = 1.54, 95% CI (-0.69-2.40), p < 0.001]. CONCLUSIONS: Same-gender bereaved partners report significantly more psychological distress. In view of their poorer sub-clinical mental health, clinical and bereavement services should refine screening processes to identify those at risk of poor mental health outcomes.

Consensus Head Acceleration Measurement Practices (CHAMP): Study Design and Statistical Analysis.

Head impact measurement devices enable opportunities to collect impact data directly from humans to study topics like concussion biomechanics, head impact exposure and its effects, and concussion risk reduction techniques in sports when paired with other relevant data. With recent advances in head impact measurement devices and cost-effective price points, more and more investigators are using them to study brain health questions. However, as the field's literature grows, the variance in study quality is apparent. This brief paper aims to provide a high-level set of key considerations for the design and analysis of head impact measurement studies that can help avoid flaws introduced by sampling biases, false data, missing data, and confounding factors. We discuss key points through four overarching themes: study design, operational management, data quality, and data analysis.

Strategies for recruiting the dependent children of patients with a life-limiting illness as research participants.

BACKGROUND: The voices of children and adolescents have historically been substituted by the perspective of adults. There is growing recognition that children (<18 years old) are able to participate in research and appreciate the opportunity to participate in studies. AIM: To share the strategies employed by two research teams from USA and UK, who have successfully recruited children living with parental life-limiting illness as research participants. FINDINGS: The researchers overcame common challenges when negotiating ethics committees by anticipating the IRB/REC concerns, providing the committees with detailed applications including distress protocols, and offering resources to their ethics committee to learn about conducting research with this population. The researchers navigated recruitment and gatekeeping by clinicians and parents by partnering with clinical agencies and nurturing relationships with practitioners who are supportive of the research, offering to present the findings of the study with continuing education credits, and developing children's, adolescents' and parents' project advisory groups to support recruitment, data collection and analysis. CONCLUSIONS: Simple strategies can be used to overcome barriers to recruitment, providing opportunities for children to be research participants and for their unique perspectives to be heard in palliative care research.

'It's not just all about the fancy words and the adults': Recommendations for practice from a qualitative interview study with children and young people with a parent with a life-limiting illness.

BACKGROUND: Healthcare professionals report challenges in supporting dying patients who have dependent children. These parents are often uncertain how to meet the needs of their children and require appropriate support from professionals. There is limited evidence based guidance for professionals around this issue, which is informed by the views and experiences of children themselves. AIM: To develop an understanding of the perspective of children on living with parental life-limiting illness and inform recommendations for healthcare professionals. DESIGN: Qualitative semi-structured interviews were conducted, with thematic analysis of the data. SETTING/PARTICIPANTS: A diverse sample of 32 children aged 6-17, whose parent was living with life-limiting illness, were recruited from across the United Kingdom. RESULTS: Despite the challenges of living with a parent with a life-limiting illness, the children display agency in their response. The children: feel a responsibility to look after their family; negotiate a relationship with healthcare; employ strategies to maintain some normality; and ensure that the inevitable sadness does not become overwhelming. CONCLUSIONS: Five recommendations for healthcare professionals were developed from the findings. Clinicians should encourage dying parents to: (1) acknowledge the agency of children; (2) recognise children's caregiving roles; (3) engender children's trust in healthcare; (4) maintain some normality; and (5) discuss emotions with their children. Implementing these recommendations will assist parents with a life-limiting illness to provide evidence-based support to their dependent children.

Public health critical race praxis at the intersection of traffic stops and injury epidemiology.

BACKGROUND: Law enforcement traffic stops are one of the most common entryways to the US justice system. Conventional frameworks suggest traffic stops promote public safety by reducing dangerous driving practices and non-vehicular crime with little to no collateral damage to individuals and communities. Critical frameworks interrogate these assumptions, identifying significant individual and community harms that disparately impact Black, Indigenous, and People of Color (BIPOC) and low-income communities. METHODS: The Public Health Critical Race Praxis (PHCRP) and multi-level frameworks from community anti-racist training were combined into a structured diagram to guide intervention and research teams in contrasting conventional and critical perspectives on traffic stops. The diagram divides law enforcement and drivers/residents as two separate agent types that interact during traffic stops. These two agent types have different conventional and critical histories, priorities, and perspectives at multiple levels, including individual, interpersonal, institutional, and cultural levels. Conventional solutions (identifying explicitly racist officers, "meet-a-cop" programs, police interaction training for drivers) are born from conventional frameworks (rewarding crime prevention regardless of cost, the war on drugs saves lives, driver behavior perfectionism). While conventional perspectives focus on individual and interpersonal levels, critical perspectives more deeply acknowledge dynamics at institutional and cultural levels. Critical solutions may be hard to discover without critical frameworks, including that law enforcement creates measurable collateral damage and disparate social control effects; neighborhood patrol priorities can be set without community self-determination or accountability and may trump individual and interpersonal dynamics; and the war on drugs is highly racialized and disproportionally enforced through traffic stop programs. CONCLUSIONS: Traffic stop enforcement and crash prevention programs that do not deeply and critically consider these dynamics at multiple levels, not just law enforcement-driver interactions at the individual and interpersonal levels, may be at increased risk of propagating histories of BIPOC discrimination. In contrast, public health and transportation researchers and practitioners engaged in crash and injury prevention strategies that employ law enforcement should critically consider disparate history and impacts of law enforcement in BIPOC communities. PHCRP, anti-racism frameworks, and the included diagram may assist them in organizing critical thinking about research studies, interventions, and impacts.

Staphylococcus aureus and Acinetobacter baumannii Inhibit Osseointegration of Orthopedic Implants.

Bacterial infections routinely cause inflammation and thereby impair osseointegration of orthopedic implants. Acinetobacter spp., which cause osteomyelitis following trauma, on or off the battlefield, were, however, reported to cause neither osteomyelitis nor osteolysis in rodents. We therefore compared the effects of Acinetobacter strain M2 to those of Staphylococcus aureus in a murine implant infection model. Sterile implants and implants with adherent bacteria were inserted in the femur of mice. Bacterial burden, levels of proinflammatory cytokines, and osseointegration were measured. All infections were localized to the implant site. Infection with either S. aureus or Acinetobacter strain M2 increased the levels of proinflammatory cytokines and the chemokine CCL2 in the surrounding femurs, inhibited bone formation around the implant, and caused loss of the surrounding cortical bone, leading to decreases in both histomorphometric and biomechanical measures of osseointegration. Genetic deletion of TLR2 and TLR4 from the mice partially reduced the effects of Acinetobacter strain M2 on osseointegration but did not alter the effects of S. aureus. This is the first report that Acinetobacter spp. impair osseointegration of orthopedic implants in mice, and the murine model developed for this study will be useful for future efforts to clarify the mechanism of implant failure due to Acinetobacter spp. and to assess novel diagnostic tools or therapeutic agents.

Clinical outcomes and bacterial characteristics of carbapenem-resistant Klebsiella pneumoniae complex among patients from different global regions (CRACKLE-2): a prospective, multicentre, cohort study.

BACKGROUND: Carbapenem-resistant Klebsiella pneumoniae (CRKP) is a global threat. We therefore analysed the bacterial characteristics of CRKP infections and the clinical outcomes of patients with CRKP infections across different countries. METHODS: In this prospective, multicentre, cohort study (CRACKLE-2), hospitalised patients with cultures positive for CRKP were recruited from 71 hospitals in Argentina, Australia, Chile, China, Colombia, Lebanon, Singapore, and the USA. The first culture positive for CRKP was included for each unique patient. Clinical data on post-hospitalisation death and readmission were collected from health records, and whole genome sequencing was done on all isolates. The primary outcome was a desirability of outcome ranking at 30 days after the index culture, and, along with bacterial characteristics and 30-day all-cause mortality (a key secondary outcome), was compared between patients from China, South America, and the USA. The desirability of outcome ranking was adjusted for location before admission, Charlson comorbidity index, age at culture, Pitt bacteremia score, and anatomical culture source through inverse probability weighting; mortality was adjusted for the same confounders, plus region where relevant, through multivariable logistic regression. This study is registered at ClinicalTrials.gov, NCT03646227, and is complete. FINDINGS: Between June 13, 2017, and Nov 30, 2018, 991 patients were enrolled, of whom 502 (51%) met the criteria for CRKP infection and 489 (49%) had positive cultures that were considered colonisation. We observed little intra-country genetic variation in CRKP. Infected patients from the USA were more acutely ill than were patients from China or South America (median Pitt bacteremia score 3 [IQR 2-6] vs 2 [0-4] vs 2 [0-4]) and had more comorbidities (median Charlson comorbidity index 3 [IQR 2-5] vs 1 [0-3] vs 1 [0-2]). Adjusted desirability of outcome ranking outcomes were similar in infected patients from China (n=246), South America (n=109), and the USA (n=130); the estimates were 53% (95% CI 42-65) for China versus South America, 50% (41-61) for the USA versus China, and 53% (41-66) for the USA versus South America. In patients with CRKP infections, unadjusted 30-day mortality was lower in China (12%, 95% CI 8-16; 29 of 246) than in the USA (23%, 16-30; 30 of 130) and South America (28%, 20-37; 31 of 109). Adjusted 30-day all-cause mortality was higher in South America than in China (adjusted odds ratio [aOR] 4·82, 95% CI 2·22-10·50) and the USA (aOR 3·34, 1·50-7·47), with the mortality difference between the USA and China no longer being significant (aOR 1·44, 0·70-2·96). INTERPRETATION: Global CRKP epidemics have important regional differences in patients' baseline characteristics and clinical outcomes, and in bacterial characteristics. Research findings from one region might not be generalisable to other regions. FUNDING: The National Institutes of Health.

Risk Factors for and Mechanisms of COlistin Resistance Among Enterobacterales: Getting at the CORE of the Issue.

BACKGROUND: Despite the recent emergence of plasmid-mediated colistin resistance, the epidemiology and mechanisms of colistin-resistant Enterobacterales (CORE) infections remain poorly understood. METHODS: A case-case-control study was conducted utilizing routine clinical isolates obtained at a single tertiary health system in Ann Arbor, Michigan. Patients with CORE isolates from January 1, 2016, to March 31, 2017, were matched 1:1 with patients with colistin-susceptible Enterobacterales (COSE) and uninfected controls. Multivariable logistic regression was used to compare clinical and microbiologic features of patients with CORE and COSE to controls. A subset of available CORE isolates underwent whole-genome sequencing to identify putative colistin resistance genes. RESULTS: Of 16 373 tested clinical isolates, 166 (0.99%) were colistin-resistant, representing 103 unique patients. Among 103 CORE isolates, 103 COSE isolates, and 102 uninfected controls, antibiotic exposure in the antecedent 90 days and age >55 years were predictors of both CORE and COSE. Of 33 isolates that underwent whole-genome sequencing, a large variety of mutations associated with colistin resistance were identified, including 4 mcr-1/mcr-1.1 genes and 4 pmrA/B mutations among 9 Escherichia coli isolates and 5 mgrB and 3 PmrA mutations among 8 Klebsiella pneumoniae isolates. Genetic mutations found in Enterobacter species were not associated with known phenotypic colistin resistance. CONCLUSIONS: Increased age and prior antibiotic receipt were associated with increased risk for patients with CORE and for patients with COSE. Mcr-1, pmrA/B, and mgrB were the predominant colistin resistance-associated mutations identified among E. coli and K. pneumoniae, respectively. Mechanisms of colistin resistance among Enterobacter species could not be determined.

Reflective insights from developing a palliative care children and young people's advisory group.

BACKGROUND: The importance of actively involving patient and public members throughout the different stages of palliative care and health research projects is widely acknowledged, however patient and public involvement work rarely considers insight from children and young people. Although this is becoming increasingly recognised in other areas of research, there is currently no structured guidance on how to best involve children and young people in palliative care research. AIM: To plan and deliver a Young People's Advisory Group in palliative care and health research at a secondary school. FINDINGS: Attending an after-school 'Health and Social Research Methods Club' for 11 weeks benefitted children and researchers. Children were taught about data collection methods, data analysis and ethics in health research and used these skills to provide valuable feedback which has been implemented in current palliative care research projects. Children took part in considered discussions around palliative care topics and enjoyed attending the group. CONCLUSION: This project has equipped researchers with skills and provided a structured template for future Young People's Advisory Groups, ensuring the unique voices of children and young people are considered and valued in future palliative care research.

The perspectives of children and young people affected by parental life-limiting illness: An integrative review and thematic synthesis.

BACKGROUND: Although the death of a parent during childhood is relatively commonplace, the voices of children affected by parental life-limiting illness are under-represented in research evidence. Guidance for healthcare professionals is largely based upon professional opinion rather than the experience of children themselves. AIM: To synthesise and appraise the literature from primary research with children about their experience of having a parent with a life-limiting illness. DESIGN: Integrative review and thematic synthesis. Registered on PROSPERO (CRD42019094581). DATA SOURCES: PsychINFO, Medline, Embase, Scopus and Web of Science were searched, supplemented by searches of grey literature and systematic reviews. There were no restrictions on publication date, and study quality was appraised using the Hawker checklist. Studies reporting the findings of primary research with participants under 18, whose parent has a life-limiting illness, were eligible for inclusion. RESULTS: Twenty-one papers met the inclusion criteria (n = 13 qualitative; n = 8 quantitative), reporting on n = 18 studies from high-income countries. Findings reveal that throughout parental life-limiting illness, children strive for agency, but are often shielded and excluded by adults. The experience of living with a dying parent is emotionally demanding for children and involves significant caregiving responsibilities. However these children are not passive, developing strategies to cope with the situation and wanting to be involved. CONCLUSIONS: The review has enabled the voices of children affected by parental life-limiting illness to be heard and will inform the development of guidance for parents and professionals.

Bereavement Support on the Frontline of COVID-19: Recommendations for Hospital Clinicians.

Deaths due to COVID-19 are associated with risk factors which can lead to prolonged grief disorder, post-traumatic stress, and other poor bereavement outcomes among relatives, as well as moral injury and distress in frontline staff. Here we review relevant research evidence and provide evidence-based recommendations and resources for hospital clinicians to mitigate poor bereavement outcomes and support staff. For relatives, bereavement risk factors include dying in an intensive care unit, severe breathlessness, patient isolation or restricted access, significant patient and family emotional distress, and disruption to relatives' social support networks. Recommendations include advance care planning; proactive, sensitive, and regular communication with family members alongside accurate information provision; enabling family members to say goodbye in person where possible; supporting virtual communication; providing excellent symptom management and emotional and spiritual support; and providing and/or sign-posting to bereavement services. To mitigate effects of this emotionally challenging work on staff, we recommend an organizational and systemic approach which includes access to informal and professional support.

Re-prioritizing traffic stops to reduce motor vehicle crash outcomes and racial disparities.

BACKGROUND: Law enforcement traffic stops are one of the most common entryways to the US justice system. Conventional frameworks suggest traffic stops promote public safety by reducing dangerous driving practices and non-vehicular crime. Law enforcement agencies have wide latitude in enforcement, including prioritization of stop types: (1) safety (e.g. moving violation) stops, (2) investigatory stops, or (3) economic (regulatory and equipment) stops. In order to prevent traffic crash fatalities and reduce racial disparities, the police department of Fayetteville, North Carolina significantly re-prioritized safety stops. METHODS: Annual traffic stop, motor vehicle crash, and crime data from 2002 to 2016 were combined to examine intervention (2013-2016) effects. Fayetteville was compared against synthetic control agencies built from 8 similar North Carolina agencies by weighted matching on pre-intervention period trends and comparison against post-intervention trends. RESULTS: On average over the intervention period as compared to synthetic controls, Fayetteville increased both the number of safety stops + 121% (95% confidence interval + 17%, + 318%) and the relative proportion of safety stops (+ 47%). Traffic crash and injury outcomes were reduced, including traffic fatalities - 28% (- 64%, + 43%), injurious crashes - 23% (- 49%, + 16%), and total crashes - 13% (- 48%, + 21%). Disparity measures were reduced, including Black percent of traffic stops - 7% (- 9%, - 5%) and Black vs. White traffic stop rate ratio - 21% (- 29%, - 13%). In contrast to the Ferguson Effect hypothesis, the relative de-prioritization of investigatory stops was not associated with an increase in non-traffic crime outcomes, which were reduced or unchanged, including index crimes - 10% (- 25%, + 8%) and violent crimes - 2% (- 33%, + 43%). Confidence intervals were estimated using a different technique and, given small samples, may be asymmetrical. CONCLUSIONS: The re-prioritization of traffic stop types by law enforcement agencies may have positive public health consequences both for motor vehicle injury and racial disparity outcomes while having little impact on non-traffic crime.

Unexpected Precatalyst σ-Ligand Effects in Phenoxyimine Zr-Catalyzed Ethylene/1-Octene Copolymerizations.

Recent decades have witnessed intense research efforts aimed at developing new homogeneous olefin polymerization catalysts, with a primary focus on metal-Cl or metal-hydrocarbyl precursors. Curiously, metal-NR2 precursors have received far less attention. In this contribution, the Zr-amido complex FI2ZrX2 (FI = 2,4-di- tert-butyl-6-((isobutylimino)methyl)phenolate, X = NMe2) is found to exhibit high ethylene polymerization activity and relatively high 1-octene coenchainment selectivity (up to 7.2 mol%) after sequential activation with trimethylaluminum, then Ph3C+B(C6F5)4-. In sharp contrast, catalysts with traditional hydrocarbyl ligands such as benzyl and methyl give low 1-octene incorporation (0-1.0 mol%). This unexpected selectivity persists under scaled/industrial operating conditions and was previously inaccessible with traditional metal-Cl or -hydrocarbyl precursors. NMR, X-ray diffraction, and catalytic control experiments indicate that in this case an FI ligand is abstracted from FI2Zr(NMe2)2 by trimethylaluminum in the activation process to yield a catalytically active cationic mono-FIZr species. Heretofore this process was believed to serve only as a major catalyst deactivation pathway to be avoided. This work demonstrates the importance of investigating diverse precatalyst monodentate σ-ligands in developing new catalyst systems, especially for group 4 olefin polymerization catalysts.

Targeting Multidrug-Resistant Acinetobacter spp.: Sulbactam and the Diazabicyclooctenone ß-Lactamase Inhibitor ETX2514 as a Novel Therapeutic Agent.

Multidrug-resistant (MDR) Acinetobacter spp. poses a significant therapeutic challenge in part due to the presence of chromosomally encoded ß-lactamases, including class C Acinetobacter-derived cephalosporinases (ADC) and class D oxacillinases (OXA), as well as plasmid-mediated class A ß-lactamases. Importantly, OXA-like ß-lactamases represent a gap in the spectrum of inhibition by recently approved ß-lactamase inhibitors such as avibactam and vaborbactam. ETX2514 is a novel, rationally designed, diazabicyclooctenone inhibitor that effectively targets class A, C, and D ß-lactamases. We show that addition of ETX2514 significantly increased the susceptibility of clinical Acinetobacterbaumannii isolates to sulbactam. AdeB and AdeJ were identified to be key efflux constituents for ETX2514 in A. baumannii The combination of sulbactam and ETX2514 was efficacious against A. baumannii carrying blaTEM-1, blaADC-82, blaOXA-23, and blaOXA-66 in a neutropenic murine thigh infection model. We also show that, in vitro, ETX2514 inhibited ADC-7 (k2/Ki 1.0 ± 0.1 × 106 M-1 s-1) and OXA-58 (k2/Ki 2.5 ± 0.3 × 105 M-1 s-1). Cocrystallization of ETX2514 with OXA-24/40 revealed hydrogen bonding interactions between ETX2514 and residues R261, S219, and S128 of OXA-24/40 in addition to a chloride ion occupied in the active site. Further, the C3 methyl group of ETX2514 shifts the position of M223. In conclusion, the sulbactam-ETX2514 combination possesses a broadened inhibitory range to include class D ß-lactamases as well as class A and C ß-lactamases and is a promising therapeutic candidate for infections caused by MDR Acinetobacter spp.IMPORTANCE The number and diversity of ß-lactamases are steadily increasing. The emergence of ß-lactamases that hydrolyze carbapenems poses a significant threat to our antibiotic armamentarium. The explosion of OXA enzymes that are carbapenem hydrolyzers is a major challenge (carbapenem-hydrolyzing class D [CHD]). An urgent need exists to discover ß-lactamase inhibitors with class D activity. The sulbactam-ETX2514 combination demonstrates the potential to become a treatment regimen of choice for Acinetobacter spp. producing class D ß-lactamases.