Human plasma cells engineered to secrete bispecifics drive effective in vivo leukemia killing.

Bispecific antibodies are an important tool for the management and treatment of acute leukemias. As a next step toward clinical translation of engineered plasma cells, we describe approaches for secretion of bispecific antibodies by human plasma cells. We show that human plasma cells expressing either fragment crystallizable domain-deficient anti-CD19 × anti-CD3 (blinatumomab) or anti-CD33 × anti-CD3 bispecific antibodies mediate T cell activation and direct T cell killing of B acute lymphoblastic leukemia or acute myeloid leukemia cell lines in vitro. We demonstrate that knockout of the self-expressed antigen, CD19, boosts anti-CD19-bispecific secretion by plasma cells and prevents self-targeting. Plasma cells secreting anti-CD19-bispecific antibodies elicited in vivo control of acute lymphoblastic leukemia patient-derived xenografts in immunodeficient mice co-engrafted with autologous T cells. In these studies, we found that leukemic control elicited by engineered plasma cells was similar to CD19-targeted chimeric antigen receptor-expressing T cells. Finally, the steady-state concentration of anti-CD19 bispecifics in serum 1 month after cell delivery and tumor eradication was comparable with that observed in patients treated with a steady-state infusion of blinatumomab. These findings support further development of ePCs for use as a durable delivery system for the treatment of acute leukemias, and potentially other cancers.

Impact of Humidification Modality on Incidence of Endotracheal Tube Occlusion in COVID-19 Patients.

Background: Endotracheal tube (ETT) occlusion is reported at a higher frequency among coronavirus disease-2019 (COVID-19) patients. Prior to the COVID-19 pandemic, literature examining patient and ventilator characteristics, including humidification, as etiologies of ETT occlusion yielded mixed results. Our study examines the relationship of humidification modality with ETT occlusion in COVID-19 patients undergoing invasive mechanical ventilation (IMV). Methods: We conducted a retrospective chart review of COVID-19 patients requiring IMV at a tertiary care center in New York from April 2020 to April 2021. Teleflex Neptune heated wire heated humidification (HH) and hygroscopic Intersurgical FiltaTherm and Sunmed Ballard 1500 heat and moisture exchangers (HME) were used. Episodes of ETT occlusion were recorded. Univariate and multivariable logistic regression models were used to investigate the relationship between humidification modality and the occurrence of ETT occlusion. Findings: A total of 201 eligible patients were identified. Teleflex HH was utilized in 50.2% of the population and the others Intersurgical and Sunmed HME devices. Median age was 62 years and 78.6% of patients had at least one medical comorbidity. Precisely, 24% of patients experienced an ETT occlusion after a median of 12 days. The HME group was younger (58.5 vs 64 years), predominantly male (75% vs 59.4%), and experienced more total ventilator days than the HH group (24 vs 12). Those using the studied HME devices had significantly higher odds of ETT occlusion (OR 4.4, 95% CI 1.8-10.6, P = .0011). Three patients (6.1%) experienced cardiac arrest as a consequence of their occlusion. There were no deaths directly attributed to ETT occlusion. Conclusions: The studied HME devices were significantly associated with higher odds of ETT occlusion in COVID-19 patients requiring invasive mechanical ventilation. These events are not without significant clinical consequences. Prolonged use of under-performing HME devices remains suspect in the occurrence of ETT occlusions.

The dynamics of colicin E9 release from Escherichia coli in native conditions.

Colicin (Col) plasmid contains colicin encoding genes arranged in an operon controlled by an SOS inducible promoter. Therefore, any external stresses to the host cell can induce the expression of the downstream genes in the Col operon, including a lysis gene. The lysis protein is involved in the extracellular release of colicin through lysis of the producer cells, which causes a decline in culture turbidity. However, it is not yet known that E. coli cells with the native pColE9-J plasmid hold the same level of cell death at the population level following a set of induced conditions. In this study, using a mitomycin C sensitivity assay along with a live dead staining method of detection, we showed that the native pColE9-J plasmid, which unusually carries an extended Col operon (ColE9) containing two lysis genes, did not confer a rapid decline in the culture turbidity following induction with mitomycin C. Interestingly a subset of the cells suffered perturbation of their outer membrane, which was not observed from single lysis mutant (∆celE or ∆celI) cells. This observed heterogeneity in the colicin E9 release leading to differential outer membrane perforation may bring a competitive advantage to these cells in a mixed population.

Analysis of 20 Years of Ethics Consultations at a U.S. Children's Hospital.

AbstractEmpirical studies of pediatric clinical ethics cases are scant in the biomedical and bioethics literature. In this study, more than 100 detailed records of clinical ethics consultations spanning from 2000 to 2020 at a moderately sized U.S. Mid-Atlantic children's hospital were abstracted and analyzed. Findings of the analysis were generally consistent with other studies in pediatric clinical ethics, with additional insight into aspects of moral distress associated with cases, family engagement with consultations, and other characteristics of interest also documented. Over the 20-year time frame, ethics consults were completed on average twice a year, with a detectable upward trend. Consultations were requested across the spectrum of services and units within the hospital, with critical care environments represented most frequently and genetic and neurological conditions being the most common primary diagnoses. Ethical analysis most commonly related to questions around the principles of autonomy and beneficence.

Baeckea frutescens L. Promotes wound healing by upregulating expression of TGF-ß, IL-1 ß, VEGF and MMP-2.

Baeckea frutescens L. has been traditionally used for treating snakebites and is known to possess antifebrile and hemostatic properties. These properties are closely related to wound healing. This study aimed to evaluate the wound healing properties of B. frutescens leaves extract (BFLE) in vitro and in vivo. The in vitro study focused on proliferation, migration, and expression of TGF-ß, IL-1ß, VEGF, and MMP-2 genes and proteins. The in vivo study included excisional wound healing, histology, and tensile strength studies. The ethanolic extract of B. frutescens (BFLE) was tested for its effects on proliferation and migration using keratinocytes (HaCaT) and fibroblasts (BJ) cells. Gene and protein expression related to wound healing were analyzed using real-time PCR and Western blot assays. The wound healing properties of BFLE were evaluated in vivo using Wistar albino rats, focusing on excisional wound healing, histology, and tensile strength studies. The BFLE displayed significant proliferative and migratory effects on keratinocytes and fibroblasts cells, while upregulating the expression of TGF-ß, IL-1ß, VEGF, and MMP-2 genes and proteins. BFLE also exhibited significant wound healing effects on Wistar albino rats' excisional wounds and improved the overall tensile strength. The results suggest that BFLE has strong wound healing properties, as demonstrated by its ability to increase keratinocytes and fibroblasts proliferation and migration, upregulate genes and proteins involved in the wound healing process, and improve wound healing rates and tensile strength. The findings of this study provide important insights into the potential use of B. frutescens as a natural wound healing agent.

Bringing people together through shared purpose and identity: lessons learnt from NHS Providers CEO Sir Julian Hartley.

INTRODUCTION: The healthcare sector is facing increased demand with reduced resources, yet despite these challenges, leaders such as NHS Providers CEO Sir Julian Hartley have created cultures where the workforce can realise shared values, through a focus on staff engagement. This article describes Julian's journey, through the eyes of a doctor-in-training working in an organisation he has led, to understand what we can learn from his approach to leadership. NARRATIVE: As a manager, Julian saw how many different people it takes to make the NHS work, and decided the role of an NHS leader was to bring people together, through a strong sense of shared purpose and identity. As CEO of Trusts in Blackpool and Leeds, he put this focus on staff engagement into practice to great success. Julian then introduced lean methods that flourished in the culture he had created, and when external factors such as COVID-19 began to erode that culture, returned to refresh that underpinning shared purpose. REFLECTION: Julian has developed a toolkit of behaviours and approaches, refined through experience and reflection, to help him elucidate and bring to life both the values and goals of the workforce. Because he shares these values, he has been able to lead with authenticity, creating engaged workforces, empowered to drive continuous improvement. We can reflect on Julian's approach as leaders ourselves: how can we align the values and visions of our staff, and ensure they are empowered to realise both?

Participation in staff engagement campaigns at large healthcare organisations: a focus group study.

INTRODUCTION: Healthcare organisations work better with an engaged workforce, and staff-engagement campaigns offer a method to build this engagement. Leeds Teaching Hospitals NHS Trust (LTHT), one of the UK's largest Trusts, provides an example of where an organisation-wide engagement intervention has been used in a healthcare setting. This study aimed to understand why staff participate, or do not participate, in staff-engagement campaigns, supporting healthcare leaders to increase participation in future campaigns. METHODS: Scenario-based focus groups were carried out across five different organisational units within LTHT. The data from these were transcribed, coded and analysed using reflective thematic analysis. RESULTS: Participation in staff-engagement campaigns is dependent on campaign awareness, staff perceptions of the campaign and the practicalities associated with participation. Perceptions of the campaign are further subdivided into the campaign's perceived effectiveness, purpose and relevance. CONCLUSIONS: Staff engagement was a powerful driver of participation, which presents a conundrum: how do you encourage participation in staff-engagement campaigns, if engagement is a prerequisite for participation? The answer lies in taking advantage of organisational belongingness and visible leadership, supported by communications that take control of the narrative around the campaign. Behavioural science models may guide leaders across the organisation in mapping where these approaches can have the greatest impact within their existing spheres of influence. Further, considering inequalities around participation across different groups may help target action to the areas of greatest need. Accordingly, the research provides pragmatic guidance for leaders in thinking about how to use staff-engagement campaigns more effectively.

Who, What, Where, and How? The State of Family Science in Pediatric Palliative Care.

CONTEXT: Families are vital providers and recipients of pediatric palliative care (PPC) services. Understanding the scope and nature of evidence at the intersection of family science and PPC research is necessary to develop family-focused interventions that enhance child and family health. OBJECTIVES: Explore and describe the family-level impact of pediatric serious illness. METHODS: We conducted a librarian-assisted scoping review using Arskey and O'Malley's approach. We searched PubMed, Scopus, CINAHL, and EMBASE databases for empirical publications from 2016 to 2021 that focused on families navigating serious pediatric illness published in English. Two reviewers assessed eligibility, with discrepancies resolved by a third. We used Covidence and REDCap for data management and extraction. RESULTS: We screened 10,983 abstracts; 309 abstracts were included in full text screening. The final group of 52 citations was analyzed by the entire team. Most research was conducted in Western Europe and North America. The perspectives of parents of children with cancer were most frequently described; voices of seriously ill youth and their siblings were less often presented. Most of the research was descriptive qualitative, followed by descriptive quantitative. Few studies were mixed methods, inferential, or interpretive. Studies most often described parent, youth, and family experience with illness and less often explored family processes and relationships. Irrespective of the approach (i.e., qualitative, quantitative), few studies focused on families as the analytic unit or used family-level analysis techniques. Study participants were usually from local dominant populations and less often from historically marginalized communities. CONCLUSION: The robust, descriptive, and individual-level evidence describing family impact of serious pediatric illness provides a solid foundation for future research priorities. Stronger integration of family techniques and diverse family voices in pediatric palliative care research can clarify family processes, illuminate structural barriers, and inform interventions that are responsive to family needs. These steps will enhance the education, policy, and clinical provision of PPC to all who would benefit, thereby advancing health equity for children living with serious illness and their families.

Failure of Pavlik Harness Treatment in Infants Under 6 Months Old with Dislocated Hips: Short- and Intermediate-Term Results of Subsequent Treatment Modalities.

Objective: This study aimed to determine the short- and medium-term outcomes of hip dislocation in infants who failed Pavlik harness therapy and were subsequently treated with brace, closed reduction (CR) or open reduction (OR) before 6 months of age. Methods: Fifty infants (66 hip dislocations) who failed Pavlik harness therapy between 2000 and 2018 and were treated with a rigid abduction brace or undergoing a CR or OR/cast were evaluated. All demographic data obtained from the medical system, developments and complications during the follow-up and treatment process were recorded and evaluated. Results: Fifty infants (66 hips) with dislocated hips failed Pavlik harness therapy. Of these, 9 infants (12 hips) underwent rigid abduction splint therapy: 9 hips were successful, 2 hips had CR and 1 had OR. Thirty-eight infants (51 hips) had index CR, of which 3 (3 hips) failed and had OR. Radiographs of 49 hips (44 patients) were normal at the final evaluation. Pavlik harness therapy starting after 3 weeks (P = 0.028) and unilateral dislocations (P = 0.028) increased the risk of needing operating room. There was an association between OR and avascular necrosis (P = 0.025), but not between OR and other complications-dysplasia and re-dislocation/subluxation (P = 0.257 and P = 0.508, respectively). Conclusion: Closed treatment of hip dislocation is possible in most babies who fail Pavlik treatment. Babies who are started on Pavlik therapy after 3 weeks of age may be at increased risk of needing an operating room. Level of Evidence: IV.

Betanin dye extracted from ayrampo (Opuntia soehrensii) seeds to develop dye-sensitized solar cells.

Pigments extracted from ayrampo seeds of the Peruvian-native prickly pear (Opuntia soehrensii) were used in dye-sensitized solar cells with promising efficiencies. The performance of the solar cells was then improved via the addition of citric acid to stabilise the photosensitive dye, and an efficiency of 1.41% was achieved with current output remaining stable after 7 days. Upon testing in low-light conditions, the solar conversion efficiency of devices increased to 4%. This paper not only highlights the potential of natural sensitizers in DSSCs but also shows that simple extraction and gentle handling methods can contribute to the device performance.

Have outcomes of trauma in centenarians changed in the last 15 years?

BACKGROUND: Centenarians are an often forgotten and under-reported group. Trauma in this population is a substantial cause of morbidity and mortality. 15 years ago, a small observational study examined the outcomes of trauma in centenarians in a single trauma unit, concluding that age alone should not be a determinant of treatment. Following implementation of national standards of care for trauma patients in older adults, this study re-examined outcomes in centenarians admitted secondary to trauma to assess if outcomes have changed. MATERIALS AND METHODS: We performed a retrospective cohort study examining patients aged over 100 years who had been admitted with trauma to an acute district general hospital and trauma unit. Patients were admitted from January 2020 to January 2022. Outcomes investigated included duration of hospital stay, complications, and mortality at three timepoints (inpatient, 30 days, 12 months). We compared this cohort to the cohort 15 years ago to assess for changes in outcomes. RESULTS: 29 patients met our eligibility criteria in this cohort. Common presenting injuries included hip fracture (13), pelvic ring fractures (8) and head injuries (8). There was significantly higher inpatient mortality within our cohort between patients who underwent operative versus non-operative treatment, but no significant difference in duration of hospital stay. There was no significant change in duration of hospital stay, inpatient mortality, or mortality at 30 days and 12 months between this cohort and 15 years ago. CONCLUSIONS: Outcomes of centenarians admitted secondary to trauma have been maintained but not improved in the last 15 years in our centre. Following this we must consider if more must be done to improve outcomes in this underreported but growing patient demographic.

BCR signaling is required for posttransplant lymphoproliferative disease in immunodeficient mice receiving human B cells.

Posttransplant lymphoproliferative disease (PTLD) is a major therapeutic challenge that has been difficult to study using human cells because of a lack of suitable models for mechanistic characterization. Here, we show that ex vivo-differentiated B cells isolated from a subset of healthy donors can elicit pathologies similar to PTLD when transferred into immunodeficient mice. The primary driver of PTLD-like pathologies were IgM-producing plasmablasts with Epstein-Barr virus (EBV) genomes that expressed genes commonly associated with EBV latency. We show that a small subset of EBV+ peripheral blood-derived B cells expressing self-reactive, nonmutated B cell receptors (BCRs) expand rapidly in culture in the absence of BCR stimulation. Furthermore, we found that in vitro and in vivo expansion of EBV+ plasmablasts required BCR signaling. Last, treatment of immunodeficient mice with the BCR pathway inhibitor, ibrutinib, delays onset of PTLD-like pathologies in vivo. These data have implications for the diagnosis and care of transplant recipients who are at risk of developing PTLD.

Molecular epidemiology of recurrent zoonotic transmission of mpox virus in West Africa.

Nigeria and Cameroon reported their first mpox cases in over three decades in 2017 and 2018 respectively. The outbreak in Nigeria is recognised as an ongoing human epidemic. However, owing to sparse surveillance and genomic data, it is not known whether the increase in cases in Cameroon is driven by zoonotic or sustained human transmission. Notably, the frequency of zoonotic transmission remains unknown in both Cameroon and Nigeria. To address these uncertainties, we investigated the zoonotic transmission dynamics of the mpox virus (MPXV) in Cameroon and Nigeria, with a particular focus on the border regions. We show that in these regions mpox cases are still driven by zoonotic transmission of a newly identified Clade IIb.1. We identify two distinct zoonotic lineages that circulate across the Nigeria-Cameroon border, with evidence of recent and historic cross border dissemination. Our findings support that the complex cross-border forest ecosystems likely hosts shared animal populations that drive cross-border viral spread, which is likely where extant Clade IIb originated. We identify that the closest zoonotic outgroup to the human epidemic circulated in southern Nigeria in October 2013. We also show that the zoonotic precursor lineage circulated in an animal population in southern Nigeria for more than 45 years. This supports findings that southern Nigeria was the origin of the human epidemic. Our study highlights the ongoing MPXV zoonotic transmission in Cameroon and Nigeria, underscoring the continuous risk of MPXV (re)emergence.

Genomic epidemiology uncovers the timing and origin of the emergence of mpox in humans.

Five years before the 2022-2023 global mpox outbreak Nigeria reported its first cases in nearly 40 years, with the ongoing epidemic since driven by sustained human-to-human transmission. However, limited genomic data has left questions about the timing and origin of the mpox virus' (MPXV) emergence. Here we generated 112 MPXV genomes from Nigeria from 2021-2023. We identify the closest zoonotic outgroup to the human epidemic in southern Nigeria, and estimate that the lineage transmitting from human-to-human emerged around July 2014, circulating cryptically until detected in September 2017. The epidemic originated in Southern Nigeria, particularly Rivers State, which also acted as a persistent and dominant source of viral dissemination to other states. We show that APOBEC3 activity increased MPXV's evolutionary rate twenty-fold during human-to-human transmission. We also show how Delphy, a tool for near-real-time Bayesian phylogenetics, can aid rapid outbreak analytics. Our study sheds light on MPXV's establishment in West Africa before the 2022-2023 global outbreak and highlights the need for improved pathogen surveillance and response.

Informing the pandemic response: the role of the WHO's COVID-19 Weekly Epidemiological Update.

On 31 December 2019, the Municipal Health Commission of Wuhan, China, reported a cluster of atypical pneumonia cases. On 5 January 2020, the WHO publicly released a Disease Outbreak News (DON) report, providing information about the pneumonia cases, implemented response interventions, and WHO's risk assessment and advice on public health and social measures. Following 9 additional DON reports and 209 daily situation reports, on 17 August 2020, WHO published the first edition of the COVID-19 Weekly Epidemiological Update (WEU). On 1 September 2023, the 158th edition of the WEU was published on WHO's website, marking its final issue. Since then, the WEU has been replaced by comprehensive global epidemiological updates on COVID-19 released every 4 weeks. During the span of its publication, the webpage that hosts the WEU and the COVID-19 Operational Updates was accessed annually over 1.4 million times on average, with visits originating from more than 100 countries. This article provides an in-depth analysis of the WEU process, from data collection to publication, focusing on the scope, technical details, main features, underlying methods, impact and limitations. We also discuss WHO's experience in disseminating epidemiological information on the COVID-19 pandemic at the global level and provide recommendations for enhancing collaboration and information sharing to support future health emergency responses.

Tracking online searches for gambling activities and operators in the United Kingdom during the COVID-19 pandemic: A Google Trends™ analysis.

Background: Whilst some research has explored the impact of COVID-19 on gambling behaviour, little is yet known about online search behaviours for gambling during this period. The current study explored gambling-related online searches before, during and after the outbreak of the COVID-19 pandemic in the UK. We also assessed whether search trends were related to Gambling Commission behavioural data over the same period. Methods: Google Trends™ search data, covering thirty months from January 2020 to June 2022, for five gambling activities and five gambling operators were downloaded. Graphical displays of the weekly relative search values over this period were then produced to visualise trends in search terms, with key dates in COVID-19 policy and sporting events highlighted. Cross-correlations between seasonally adjusted monthly search data and behavioural indices were conducted. Results: Sharp increases in internet searches for poker, slots, and bingo were evident during the first lockdown in the UK, with operator searches sharply decreasing over this period. No changes in gambling activity searches were highlighted during subsequent lockdowns, although small increases in operator-based searches were detected. Strong positive correlations were found between search data and industry data for sports betting and poker but not for slots. Conclusions: Google Trends™ data may act as an indicator of population-level gambling behaviour. Substitution of preferred gambling activities for others may have occurred during the first lockdown when opportunities for sports betting were limited. Further research is needed to assess the effectiveness of internet search data in predicting gambling-related harm.

The Clinical Application of Platelet-Rich Plasma in the Female Reproductive System: A Narrative Review.

Platelet-rich plasma is an autologous plasma containing platelets prepared from fresh whole blood drawn from a peripheral vein. Through processing, it can be prepared to contain supraphysiologic levels of platelets at three to five times greater than the level of normal plasma. PRP has been explored both in vivo and ex vivo in the human endometrium model in its ability to harness the intrinsic regenerative capacity of the endometrium. Intrauterine autologous PRP infusions have been shown to increase endometrial thickness and reduce the rate of intrauterine adhesions. In the setting of recurrent implantation failure, intrauterine infusion of PRP has been shown to increase clinical pregnancy rate. PRP also appears to hold a potential role in select patients with premature ovarian insufficiency, poor ovarian responders and in improving outcomes following frozen-thawed transplantation of autologous ovarian tissue. Further studies are required to explore the potential role of PRP in reproductive medicine further, to help standardise PRP protocols and evaluate which routes of administration are most effective.

Interaction between apolipoprotein E genotypes, excessive daytime sleepiness, and cognitive function in obstructive sleep apnea patients / Interação entre genótipos da apolipoproteína E, sonolência excessiva diurna e função cognitiva em pacientes com apneia obstrutiva do sono

Abstract Background Some studies show an association between the apolipoprotein E ε4 allele (ApoEε4) and obstructive sleep apnea syndrome (OSAS), and other studies, an association between ApoEε4 and excessive daytime sleepiness (EDS), but there are no data in the literature on the interaction between EDS, cognitive function, and ApoEε4 in patients with OSA. Objective To examine the cognitive function of adults with and without EDS and with and without ApoEε4. Methods A total of 21 male and female patients aged between 33 and 79 years, underwent a clinical interview, ApoE genotyping, neuropsychological evaluation, polysomnography, and the application of the Epworth Sleepiness Scale. Results Excessive daytime sleepiness was associated with lower intelligence quotient (IQ; total performance) and worse immediate visual memory, regardless of the ApoE genotype. Patients carrying the ApoEε3/ε4 genotype had a worse performance in divided attention, constructional praxis, perceptual organization, and cognitive flexibility. A combination of the ε4 allele and EDS potentiates the negative effect on cognition, except for immediate visual memory. In this case, patients had a worse performance in terms of processing speed, selective attention, and visuomotor coordination. Conclusions Excessive daytime sleepiness and the ApoEε3/ε4 genotype are associated with worse cognitive performance in OSA patients. The combination of EDS and ε4 allele potentiates cognitive impairment.

Resumo Antecedentes Alguns estudos mostram uma associação entre o alelo ε4 da apolipoproteina E (ApoEε4) e a síndrome da apneia obstrutiva do sono (SAOS), e outros, entre ApoEε4 e a sonolência excessiva diurna (SED), mas não há dados na literatura sobre a interação entre SED, função cognitiva e ApoEε4 em pacientes com SAOS. Objetivo Avaliar a função cognitiva em adultos com SAOS com e sem SED e com e sem ApoEε4. Métodos Ao todo, 21 pacientes, de 33 a 79 anos, homens e mulheres, foram avaliados clinicamente, e submetidos a genotipagem ApoE, avaliação neuropsicológica, polissonografia, e aplicação da Escala de Sonolência de Epworth. Resultados A SED esteve associada com menor quociente de inteligência (QI; desempenho geral) e pior memória visual imediata, independentemente do genótipo ApoE. Pacientes com genótipo ApoEε3/ε4 apresentaram pior desempenho na atenção dividida, praxe construcional, organização perceptiva e flexibilidade cognitiva. A combinação do alelo ε4 com a SED potencializa esse efeito deletério na cognição, exceto na memória visual imediata. Nesse caso, os pacientes tiveram uma menor velocidade de processamento cognitivo, e piores atenção seletiva e coordenação visiomotora. Conclusões A SED e o genótipo ApoEε3/ε4 estão associados a um pior desempenho cognitivo em pacientes com SAOS. A combinação de SED e do alelo ε4 potencializa esse efeito.