LKB1 depletion-mediated epithelial-mesenchymal transition induces fibroblast activation in lung fibrosis.

The factors that determine fibrosis progression or normal tissue repair are largely unknown. We previously demonstrated that autophagy inhibition-mediated epithelial-mesenchymal transition (EMT) in human alveolar epithelial type II (ATII) cells augments local myofibroblast differentiation in pulmonary fibrosis by paracrine signalling. Here, we report that liver kinase B1 (LKB1) inactivation in ATII cells inhibits autophagy and induces EMT as a consequence. In IPF lungs, this is caused by downregulation of CAB39L, a key subunit within the LKB1 complex. 3D co-cultures of ATII cells and MRC5 lung fibroblasts coupled with RNA sequencing (RNA-seq) confirmed that paracrine signalling between LKB1-depleted ATII cells and fibroblasts augmented myofibroblast differentiation. Together these data suggest that reduced autophagy caused by LKB1 inhibition can induce EMT in ATII cells and contribute to fibrosis via aberrant epithelial-fibroblast crosstalk.

Ibrutinib as first-line therapy for mantle cell lymphoma: a multicenter, real-world UK study.

ABSTRACT: During the COVID-19 pandemic, ibrutinib with or without rituximab was approved in England for initial treatment of mantle cell lymphoma (MCL) instead of immunochemotherapy. Because limited data are available in this setting, we conducted an observational cohort study evaluating safety and efficacy. Adults receiving ibrutinib with or without rituximab for untreated MCL were evaluated for treatment toxicity, response, and survival, including outcomes in high-risk MCL (TP53 mutation/deletion/p53 overexpression, blastoid/pleomorphic, or Ki67 ≥ 30%). A total of 149 patients from 43 participating centers were enrolled: 74.1% male, median age 75 years, 75.2% Eastern Cooperative Oncology Group status of 0 to 1, 36.2% high-risk, and 8.9% autologous transplant candidates. All patients received ≥1 cycle ibrutinib (median, 8 cycles), 39.0% with rituximab. Grade ≥3 toxicity occurred in 20.3%, and 33.8% required dose reductions/delays. At 15.6-month median follow-up, 41.6% discontinued ibrutinib, 8.1% due to toxicity. Of 104 response-assessed patients, overall (ORR) and complete response (CR) rates were 71.2% and 20.2%, respectively. ORR was 77.3% (low risk) vs 59.0% (high risk) (P = .05) and 78.7% (ibrutinib-rituximab) vs 64.9% (ibrutinib; P = .13). Median progression-free survival (PFS) was 26.0 months (all patients); 13.7 months (high risk) vs not reached (NR) (low risk; hazard ratio [HR], 2.19; P = .004). Median overall survival was NR (all); 14.8 months (high risk) vs NR (low risk; HR, 2.36; P = .005). Median post-ibrutinib survival was 1.4 months, longer in 41.9% patients receiving subsequent treatment (median, 8.6 vs 0.6 months; HR, 0.36; P = .002). Ibrutinib with or without rituximab was effective and well tolerated as first-line treatment of MCL, including older and transplant-ineligible patients. PFS and OS were significantly inferior in one-third of patients with high-risk disease and those unsuitable for post-ibrutinib treatment, highlighting the need for novel approaches in these groups.

The role of tocilizumab in the treatment of post-transfusion hyperhaemolysis.

Hyperhaemolysis syndrome (HHS) is a serious complication of transfusion mostly reported in patients with sickle cell disease. HHS is characterised by the destruction of both donor and autologous red blood cells. Tocilizumab is a recombinant humanised monoclonal antibody that inhibits the binding of interleukin-6 and has been used in the treatment of severe/critical coronavirus disease 2019 infection but also some cases of HHS. We describe two further cases of HHS successfully treated with tocilizumab and propose a decision aid for when to consider this treatment.

CWTCH in the community: improving education to reduce adverse outcomes for patients who fall in nursing homes.

Falls in nursing homes (NH) are common and cause significant morbidity and mortality. We proposed that by improving staff education, the volume of emergency calls, hospital conveyance and adverse patient outcomes could be reduced. An analysis of the volume of emergency calls coded as Falls from January 2020 to February 2022, with 4907 calls in total, 866 were falls (17.65%), further 1032 potential falls (21.07%). A survey was sent to NH to evaluate how staff treated residents who fell and showed that 47% of NH do not have any guidelines for falls and emergency services, are contacted 88.24% of the time. Education was delivered focusing on the negative consequences of falls. The package used the acronym "CWTCH" translated from the Welsh language as a hug. Education was offered to all NH (177 staff) and Feedback showed 100% felt more confident and found the session helpful with 90.96% less likely to contact emergency services. Falls remain a significant burden on emergency services, with clear opportunity to improve patient outcomes and experience. A referral pathway was developed diverting calls, showing a significant change in conveyance to hospital (p < 0.05).

Diabetes management in older adults who fall: a study amongst older adults presenting to the emergency department.

INTRODUCTION: Type 2 diabetes mellitus (T2D) is associated with poor health outcomes whilst tight glycaemic targets are questionable in those aged over 70 years with increased frailty. Our aim was to examine whether people with T2D admitted to hospital with a fall, were more likely to have greater frailty, increased mortality and co-morbidity burden, or risk factors for falls than people without T2D, and whether these differences were associated with medications used for the treatment of T2D. METHODS: The Older Persons Assessment Service (OPAS) is a local emergency department (ED) service, which accepts patients on frailty criteria. The OPAS accepts patients primarily aged over 70 years who present with frailty and geriatric syndromes such as falls, with retrieval from the ED department directly to the service from triage. The OPAS databank was analysed for people with T2D admitted with a fall between June 2020-September 2022. We examined clinical outcomes relating to medication, age, Charlson co-morbidity index (CCI) and clinical frailty score (CFS). RESULTS: 1081 patients were included: 294 (27.2%) with T2D and a mean HbA1c of 53.9 (± 15.8) mmol/mol [7.1%]. People with T2D had a similar mean CFS and age compared to those without T2D, but higher mean CCI (7.0 ± 2.2 vs 5.9 ± 2.1, p < 0.001). Of those people with T2D, 175 (59.5%) and 240 (81.6%) had a HbA1c ≤ 53 mmol/mol [7.0%] and ≤ 64 mmol/mol [8.0%], respectively. In total, 48 (16.3%) people with T2D were identified to have a capillary blood glucose below 4.0 mmol/L on admission to the ED. At 12 months' follow-up, 831 (76.9%) patients were alive and 250 (23.1%) had died. People with T2D treated with insulin and/or gliclazide had a greater 1-year mortality (36.6% vs 23.6%, p < 0.05), greater frequency of hypoglycaemia (35.4% vs 11.8%, p < 0.001), and greater HbA1c (65.5 ± 17.2 mmol/mol [8.2] vs 48.9 ± 12.1 mmol/mol [6.6%]) compared to those who used other agents. Logistic regression confirmed a diagnosis of T2D was associated with 1-year mortality, but mortality was not significantly associated with hypoglycaemic-inducing agents. People with T2D were not more likely to live in deprived areas. CONCLUSIONS: A diagnosis of T2D is associated with greater 1-year mortality, and may be influenced by use of hypoglycaemia-inducing diabetes medications. Clinician awareness can support de-prescribing for patients with frailty and HbA1c < 64 mmol/mol.

Phosphoinositides in New Spaces.

Phosphoinositides (PIs) are phospholipids derived from phosphatidylinositol. PIs are regulated via reversible phosphorylation, which is directed by the opposing actions of PI kinases and phosphatases. PIs constitute a minor fraction of the total cellular lipid pool but play pleiotropic roles in multiple aspects of cell biology. Genetic mutations of PI regulatory enzymes have been identified in rare congenital developmental syndromes, including ciliopathies, and in numerous human diseases, such as cancer and metabolic and neurological disorders. Accordingly, PI regulatory enzymes have been targeted in the design of potential therapeutic interventions for human diseases. Recent advances place PIs as central regulators of membrane dynamics within functionally distinct subcellular compartments. This brief review focuses on the emerging role PIs play in regulating cell signaling within the primary cilium and in directing transfer of molecules at interorganelle membrane contact sites and identifies new roles for PIs in subcellular spaces.

The Omicron Sub-Variant BA.4 Displays a Remarkable Lack of Clinical Signs in a Golden Syrian Hamster Model of SARS-CoV-2 Infection.

The ongoing emergence of SARS-CoV-2 virus variants remains a source of concern because it is accompanied by the potential for increased virulence as well as evasion of immunity. Here we show that, although having an almost identical spike gene sequence as another Omicron variant (BA.5.2.1), a BA.4 isolate lacked all the typical disease characteristics of other isolates seen in the Golden Syrian hamster model despite replicating almost as effectively. Animals infected with BA.4 had similar viral shedding profiles to those seen with BA.5.2.1 (up to day 6 post-infection), but they all failed to lose weight or present with any other significant clinical signs. We hypothesize that this lack of detectable signs of disease during infection with BA.4 was due to a small (nine nucleotide) deletion (∆686-694) in the viral genome (ORF1ab) responsible for the production of non-structural protein 1, which resulted in the loss of three amino acids (aa 141-143).

Syrian hamster convalescence from prototype SARS-CoV-2 confers measurable protection against the attenuated disease caused by the Omicron variant.

The mutation profile of the SARS-CoV-2 Omicron (lineage BA.1) variant posed a concern for naturally acquired and vaccine-induced immunity. We investigated the ability of prior infection with an early SARS-CoV-2 ancestral isolate (Australia/VIC01/2020, VIC01) to protect against disease caused by BA.1. We established that BA.1 infection in naïve Syrian hamsters resulted in a less severe disease than a comparable dose of the ancestral virus, with fewer clinical signs including less weight loss. We present data to show that these clinical observations were almost absent in convalescent hamsters challenged with the same dose of BA.1 50 days after an initial infection with ancestral virus. These data provide evidence that convalescent immunity against ancestral SARS-CoV-2 is protective against BA.1 in the Syrian hamster model of infection. Comparison with published pre-clinical and clinical data supports consistency of the model and its predictive value for the outcome in humans. Further, the ability to detect protection against the less severe disease caused by BA.1 demonstrates continued value of the Syrian hamster model for evaluation of BA.1-specific countermeasures.

PI(4,5)P2-dependent regulation of endothelial tip cell specification contributes to angiogenesis.

Dynamic positioning of endothelial tip and stalk cells, via the interplay between VEGFR2 and NOTCH signaling, is essential for angiogenesis. VEGFR2 activates PI3K, which phosphorylates PI(4,5)P2 to PI(3,4,5)P3, activating AKT; however, PI3K/AKT does not direct tip cell specification. We report that PI(4,5)P2 hydrolysis by the phosphoinositide-5-phosphatase, INPP5K, contributes to angiogenesis. INPP5K ablation disrupted tip cell specification and impaired embryonic angiogenesis associated with enhanced DLL4/NOTCH signaling. INPP5K degraded a pool of PI(4,5)P2 generated by PIP5K1C phosphorylation of PI(4)P in endothelial cells. INPP5K ablation increased PI(4,5)P2, thereby releasing ß-catenin from the plasma membrane, and concurrently increased PI(3,4,5)P3-dependent AKT activation, conditions that licensed DLL4/NOTCH transcription. Suppression of PI(4,5)P2 in INPP5K-siRNA cells by PIP5K1C-siRNA, restored ß-catenin membrane localization and normalized AKT signaling. Pharmacological NOTCH or AKT inhibition in vivo or genetic ß-catenin attenuation rescued angiogenesis defects in INPP5K-null mice. Therefore, PI(4,5)P2 is critical for ß-catenin/DLL4/NOTCH signaling, which governs tip cell specification during angiogenesis.

The decrease in diurnal oxygen production in Elodea under the influence of high geomagnetic variability: the role of light, temperature and atmospheric pressure.

Epidemiological studies have indicated adverse effects of geomagnetic disturbance on human health, including increased mortality. There is evidence from plant and animal studies that help to elucidate this interaction. This study tests the hypothesis that geomagnetic disturbance affects living systems, by modifying the metabolic process of photosynthesis, in the natural environment.Continuous 24-h measurements of dissolved oxygen in flasks containing Holtfreiter's solution and strands of healthy Elodea were recorded from May 1996, until September 1998, in an electromagnetically quiet, purpose built, garden shed environment, without mains electricity. Sensormeter recordings of oxygen, light, temperature and air pressure were uploaded weekly to a PC. The hourly total geomagnetic field measurements were obtained from the nearest observatory.Significant decrease in oxygen (diurnal volume of oxygen divided by plant mass and diurnal light), (O/WL), was found on days of high geomagnetic field variability throughout 11 recorded months of the year 1997. This result was independent of temperature and atmospheric pressure. No significant decrease in O/WL during high geomagnetic variability was found for the 7 months recorded in 1996. The 1996 and 1997 data both showed a significant decrease in the diurnal time lag between peak light and peak oxygen for diurnal high geomagnetic variability compared with low geomagnetic variability. Cross correlation analysis for 1997 and 1998 data showed a decrease in positive correlation of oxygen with light in high geomagnetic variability, compared with low geomagnetic variability, and increased positive correlation with the geomagnetic field instead. These experiments support a hypothesis of high geomagnetic field variability as a weak zeitgeber, and a metabolic depressant for photosynthetic oxygen production in plants.

SARS-CoV-2 Disease Severity in the Golden Syrian Hamster Model of Infection Is Related to the Volume of Intranasal Inoculum.

The golden Syrian hamster (Mesocricetus auratus) is now commonly used in preclinical research for the study of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the assessment of vaccines, drugs and therapeutics. Here, we show that hamsters inoculated via the intranasal route with the same infectious virus dose of prototypical SARS-CoV-2 administered in a different volume present with different clinical signs, weight loss and viral shedding, with a reduced volume resulting in reduced severity of disease similar to that obtained by a 500-fold reduction in the challenge dose. The tissue burden of the virus and the severity of pulmonary pathology were also significantly affected by different challenge inoculum volumes. These findings suggest that a direct comparison between the severity of SARS-CoV-2 variants or studies assessing the efficacy of treatments determined by hamster studies cannot be made unless both the challenge dose and inoculation volume are matched when using the intranasal route. Additionally, analysis of sub-genomic and total genomic RNA PCR data demonstrated no link between sub-genomic and live viral titres and that sub-genomic analyses do not provide any information beyond that provided by more sensitive total genomic PCR.

The Influence of Ethnicity on Survival from Malignant Primary Brain Tumours in England: A Population-Based Cohort Study.

BACKGROUND: In recent years, the completeness of ethnicity data in the English cancer registration data has greatly improved. Using these data, this study aims to estimate the influence of ethnicity on survival from primary malignant brain tumours. METHODS: Demographic and clinical data on adult patients diagnosed with malignant primary brain tumour from 2012 to 2017 were obtained (n = 24,319). Univariate and multivariate Cox proportional hazards regression analyses were used to estimate hazard ratios (HR) for the survival of the ethnic groups up to one year following diagnosis. Logistic regressions were then used to estimate odds ratios (OR) for different ethnic groups of (1) being diagnosed with pathologically confirmed glioblastoma, (2) being diagnosed through a hospital stay that included an emergency admission, and (3) receiving optimal treatment. RESULTS: After an adjustment for known prognostic factors and factors potentially affecting access to healthcare, patients with an Indian background (HR 0.84, 95% CI 0.72-0.98), Any Other White (HR 0.83, 95% CI 0.76-0.91), Other Ethnic Group (HR 0.70, 95% CI 0.62-0.79), and Unknown/Not Stated Ethnicity (HR 0.81, 95% CI 0.75-0.88) had better one-year survivals than the White British Group. Individuals with Unknown ethnicity are less likely be diagnosed with glioblastoma (OR 0.70, 95% CI 0.58-0.84) and less likely to be diagnosed through a hospital stay that included an emergency admission (OR 0.61, 95% CI 0.53-0.69). CONCLUSION: The demonstrated ethnic variations associated with better brain tumour survival suggests the need to identify risk or protective factors that may underlie these differences in patient outcomes.

Non-traumatic extraocular muscle haemorrhage associated with anticoagulation use.

We present a case of a unilateral extraocular muscle haematoma in an adult female patient who was compliant with life-long oral anticoagulation for recurrent deep vein thrombosis. The patient presented with symptoms of sudden-onset left-sided headache radiating to the temporal region, which started 2 days prior. No obvious triggering factors were identified. Cranial and ocular examinations were within normal limits. Imaging revealed a haemorrhage related to the lateral rectus muscle of the left eye. Conservative management was employed with abstinence from anticoagulation for 2 weeks and a weaning regime of oral steroids. Under the clinical review of ophthalmology and interval radiological monitoring, symptoms were reduced with reduction of haemorrhage size. Anticoagulation was reinstated after 2 weeks. To our knowledge, this is the first case of a non-traumatic extraocular muscle haematoma to be reported in a patient on anticoagulation.

Impact of pre-existing mental health disorders on the receipt of guideline recommended cancer treatments: A systematic review.

OBJECTIVE: Disparities in cancer outcomes for individuals with pre-existing mental health disorders have already been identified, particularly for cancer screening and mortality. We aimed to systematically review the influence on the time from cancer diagnosis to cancer treatment, treatment adherence, and differences in receipt of guideline recommended cancer treatment. METHODS: We included international studies published in English from 1 January 1995 to 23 May 2022 by searching MEDLINE, Embase, and APA PsycInfo. RESULTS: This review identified 29 studies with 27 being published in the past decade. Most studies focused on breast, non-small cell lung and colorectal cancer and were of high or medium quality as assessed by the Newcastle Ottawa Scale. All studies were from high-income countries, and mostly included patients enrolled in national health insurance systems. Five assessed the impact on treatment delay or adherence, and 25 focused on the receipt of guideline recommended treatment. 20/25 studies demonstrated evidence that patients with pre-existing mental health disorders were less likely to receive guideline recommended therapies such as surgery or radiotherapy. In addition, there was a greater likelihood of receiving less intensive or modified treatment including systemic therapy. CONCLUSIONS: Across different cancer types and treatment modalities there is evidence of a clear disparity in the receipt of guideline recommended cancer treatment for patients with pre-existing mental health disorders. The effect of pre-existing mental health disorders on treatment delay or adherence is under-researched. Future research needs to include low- and middle-income countries as well as qualitative investigations to understand the reasons for disparities in cancer treatment.

Factors affecting delay in the presentation of breast cancer symptoms among women in Gaza, occupied Palestinian territory: a cross-sectional survey.

OBJECTIVE: To identify factors related to women's delay in presenting with breast cancer symptoms to improve diagnosis in the occupied Palestinian territory (oPt). DESIGN: Cross-sectional. SETTING: Two government cancer hospitals. PARTICIPANTS: A consecutive sample of 130 Palestinian women living in Gaza with newly diagnosed breast cancer were approached in the waiting rooms of cancer hospitals in Gaza between 1 January 2017 and 31 December 2017. 120 women took part and returned the completed questionnaire. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical information about breast cancer was collected from hospital cancer records. An interval of 3 months or more between women's self-discovery of symptoms and their first presentation to a medical provider was considered as a delay. RESULTS: 94% (122/130) of women attending cancer hospitals in Gaza agreed to take part in the study. Their mean age was 51 years (range: 23-72), 33.6% (31/122) had a family history of breast cancer and 74.5% (41/55) of those whose cancer stage was known had been diagnosed at stage III or IV. Around one-half (62/122) said they had not recognised the seriousness of their breast changes but only 20% (24/122) of women delayed seeking healthcare by 3 months and more. The two only factors associated to late presentation were that the woman considered their symptoms not serious (p<0.001) and lack of pain (p=0.012). Lower socioeconomic status, older age, lower education and negative family history of breast cancer were not statistically associated with women's delay. CONCLUSIONS: Women's awareness about the seriousness of breast changes and the critical importance of seeking prompt diagnosis needs to be improved using context-relevant and evidence-based awareness campaigns. This should be accompanied with training of female nurses on promoting early detection and improvement in diagnostic facilities to ensure timely diagnosis of cancer in the oPt.

Spatially resolved deconvolution of the fibrotic niche in lung fibrosis.

A defining pathological feature of human lung fibrosis is localized tissue heterogeneity, which challenges the interpretation of transcriptomic studies that typically lose spatial information. Here we investigate spatial gene expression in diagnostic tissue using digital profiling technology. We identify distinct, region-specific gene expression signatures as well as shared gene signatures. By integration with single-cell data, we spatially map the cellular composition within and distant from the fibrotic niche, demonstrating discrete changes in homeostatic and pathologic cell populations even in morphologically preserved lung, while through ligand-receptor analysis, we investigate cellular cross-talk within the fibrotic niche. We confirm findings through bioinformatic, tissue, and in vitro analyses, identifying that loss of NFKB inhibitor zeta in alveolar epithelial cells dysregulates the TGFß/IL-6 signaling axis, which may impair homeostatic responses to environmental stress. Thus, spatially resolved deconvolution advances understanding of cell composition and microenvironment in human lung fibrogenesis.