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.

Cancer incidence, treatment, and survival in the prison population compared with the general population in England: a population-based, matched cohort study.

BACKGROUND: The growing and ageing prison population in England makes accurate cancer data of increasing importance for prison health policies. This study aimed to compare cancer incidence, treatment, and survival between patients diagnosed in prison and the general population. METHODS: In this population-based, matched cohort study, we used cancer registration data from the National Cancer Registration and Analysis Service in England to identify primary invasive cancers and cervical cancers in situ diagnosed in adults (aged ≥18 years) in the prison and general populations between Jan 1, 1998, and Dec 31, 2017. Ministry of Justice and Office for National Statistics population data for England were used to calculate age-standardised incidence rates (ASIR) per year and age-standardised incidence rate ratios (ASIRR) for the 20-year period. Patients diagnosed with primary invasive cancers (ie, excluding cervical cancers in situ) in prison between Jan 1, 2012, and Dec 31, 2017 were matched to individuals from the general population and linked to hospital and treatment datasets. Matching was done in a 1:5 ratio according to 5-year age group, gender, diagnosis year, cancer site, and disease stage. Our primary objectives were to compare the incidence of cancer (1998-2017); the receipt of treatment with curative intent (2012-17 matched cohort), using logistic regression adjusted for matching variables (excluding cancer site) and route to diagnosis; and overall survival following cancer diagnosis (2012-17 matched cohort), using a Cox proportional hazards model adjusted for matching variables (excluding cancer site) and route to diagnosis, with stratification for the receipt of any treatment with curative intent. FINDINGS: We identified 2015 incident cancers among 1964 adults (1556 [77·2%] men and 459 [22·8%] women) in English prisons in the 20-year period up to Dec 31, 2017. The ASIR for cancer for men in prison was initially lower than for men in the general population (in 1998, ASIR 119·33 per 100 000 person-years [95% CI 48·59-219·16] vs 746·97 per 100 000 person-years [742·31-751·66]), but increased to a similar level towards the end of the study period (in 2017, 856·85 per 100 000 person-years [675·12-1060·44] vs 788·59 per 100 000 person-years [784·62-792·57]). For women, the invasive cancer incidence rate was low and so ASIR was not reported for this group. Over the 20-year period, the incidence of invasive cancer for men in prison increased (incidence rate ratio per year, 1·05 [95% CI 1·04-1·06], during 1999-2017 compared with 1998). ASIRRs showed that over the 20-year period, overall cancer incidence was lower in men in prison than in men in the general population (ASIRR 0·76 [95% CI 0·73-0·80]). The difference was not statistically significant for women (ASIRR 0·83 [0·68-1·00]). Between Jan 1, 2012, and Dec 31, 2017, patients diagnosed in prison were less likely to undergo curative treatment than matched patients in the general population (274 [32·3%] of 847 patients vs 1728 [41·5%] of 4165; adjusted odds ratio (OR) 0·72 [95% CI 0·60-0·85]). Being diagnosed in prison was associated with a significantly increased risk of death on adjustment for matching variables (347 deaths during 2021·9 person-years in the prison cohort vs 1626 deaths during 10 944·2 person-years in the general population; adjusted HR 1·16 [95% CI 1·03-1·30]); this association was partly explained by stratification by curative treatment and further adjustment for diagnosis route (adjusted HR 1·05 [0·93-1·18]). INTERPRETATION: Cancer incidence increased in people in prisons in England between 1998 and 2017, with patients in prison less likely to receive curative treatments and having lower overall survival than the general population. The association with survival was partly explained by accounting for differences in receipt of curative treatment and adjustment for diagnosis route. Improved routine cancer surveillance is needed to inform prison cancer policies and decrease inequalities for this under-researched population. FUNDING: UK National Institute for Health and Care Research, King's College London, and Strategic Priorities Fund 2019/20 of Research England via the University of Surrey.

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.

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.

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).

AKT signaling promotes DNA damage accumulation and proliferation in polycystic kidney disease.

Polycystic kidney disease (PKD) results in the formation of renal cysts that can impair function leading to renal failure. DNA damage accumulates in renal epithelial cells in PKD, but the molecular mechanisms are unclear and are investigated here. Phosphoinositide 3-kinase (PI3K)/AKT signaling activates mammalian target of rapamycin complex 1 (mTORC1) and hyperactivation of mTORC1 is a common event in PKD; however, mTORC1 inhibitors have yielded disappointing results in clinical trials. Here, we demonstrate AKT and mTORC1 hyperactivation in two representative murine PKD models (renal epithelial-specific Inpp5e knockout and collecting duct-specific Pkd1 deletion) and identify a downstream signaling network that contributes to DNA damage accumulation. Inpp5e- and Pkd1-null renal epithelial cells showed DNA damage including double-stranded DNA breaks associated with increased replication fork numbers, multinucleation and centrosome amplification. mTORC1 activated CAD, which promotes de novo pyrimidine synthesis, to sustain cell proliferation. AKT, but not mTORC1, inhibited the DNA repair/replication fork origin firing regulator TOPBP1, which impacts on DNA damage and cell proliferation. Notably, Inpp5e- and Pkd1-null renal epithelial cell spheroid formation defects were rescued by AKT inhibition. These data reveal that AKT hyperactivation contributes to DNA damage accumulation in multiple forms of PKD and cooperates with mTORC1 to promote cell proliferation. Hyperactivation of AKT may play a causal role in PKD by regulating DNA damage and cell proliferation, independent of mTORC1, and AKT inhibition may be a novel therapeutic approach for PKD.

Towards an artificial human lung: modelling organ-like complexity to aid mechanistic understanding.

Respiratory diseases account for over 5 million deaths yearly and are a huge burden to healthcare systems worldwide. Murine models have been of paramount importance to decode human lung biology in vivo, but their genetic, anatomical, physiological and immunological differences with humans significantly hamper successful translation of research into clinical practice. Thus, to clearly understand human lung physiology, development, homeostasis and mechanistic dysregulation that may lead to disease, it is essential to develop models that accurately recreate the extraordinary complexity of the human pulmonary architecture and biology. Recent advances in micro-engineering technology and tissue engineering have allowed the development of more sophisticated models intending to bridge the gap between the native lung and its replicates in vitro Alongside advanced culture techniques, remarkable technological growth in downstream analyses has significantly increased the predictive power of human biology-based in vitro models by allowing capture and quantification of complex signals. Refined integrated multi-omics readouts could lead to an acceleration of the translational pipeline from in vitro experimental settings to drug development and clinical testing in the future. This review highlights the range and complexity of state-of-the-art lung models for different areas of the respiratory system, from nasal to large airways, small airways and alveoli, with consideration of various aspects of disease states and their potential applications, including pre-clinical drug testing. We explore how development of optimised physiologically relevant in vitro human lung models could accelerate the identification of novel therapeutics with increased potential to translate successfully from the bench to the patient's bedside.

Oncology Patient Smoking Cessation Treatment Preferences: Perceptions Across Former and Current Cigarette Smokers.

Although the benefits of smoking cessation following a cancer diagnosis have been well-established, up to 50% of cancer patients continue to smoke. Continued smoking through oncology treatment leads to increased risk of adverse events including reduced effectiveness of treatment, recurrence of additional malignancies, and reduced survival rates. Upon the cancer diagnosis, oncology healthcare providers become the primary trusted source of information and support, which represents a great opportunity to assist these patients to quit smoking. However, it remains unclear how oncology healthcare providers can best address smoking cessation from a patient-centered perspective. The present study surveyed oncology patients from Birmingham, AL, classified as either former (n = 174) or current smokers (n = 81) to identify their perceptions regarding the role of oncology healthcare providers in their smoking cessation efforts. Current smokers were more likely to be younger, received their cancer diagnosis within the past 3 years, and have a cancer diagnosis with high smoking-related public awareness (i.e., head, neck, or lung) compared to former smokers. Additionally, 81% of current smokers reported experiencing smoking cessation discussions with their oncology healthcare providers with the most prominent recommendations being use of nicotine replacement therapies (46.9%) and medication (35.8%). These smoking cessation experiences align with patient preferences. However, despite the frequency of smoking cessation discussions, current smokers demonstrated an ambivalence in understanding the risks of continued smoking during their medical treatment. Overall, this study highlights the important role of oncology healthcare providers on implementing smoking cessation intervention for their patients who continue to smoke.

Survey of the publics' preferences for communication of medical radiation risk.

To comply with the Ionising Radiations (Medical Exposures) Regulations 2017, patients need to be adequately informed of medical radiation risks prior to exposure. This study used a survey developed in partnership with patients and members of the public to explore patient preferences for radiation risk communication. It was distributed through social media between 28/4/2020 and 18/7/2020. All respondents (N= 376) wanted to be informed about radiation risk, though the threshold at which they wished to be informed varied. The current practice of displaying posters in waiting areas does not meet the expressed preference of the patients if used in isolation. Only 6% of respondents were satisfied with the commonly used statement that the 'risk is low' if used in isolation. The majority of respondents (73%) said they would not be concerned about an increase in the risk of cancer of less than 1 in 10 000. The level of risk at which patients express a concern and the methodology for risk communication has been evaluated and based on these findings, and pre-existing literature, a graded approach to radiation risk communication based on modality is proposed. Patients must be involved throughout the evolution of this practice.

Being assigned a clinical nurse specialist is associated with better experiences of cancer care: English population-based study using the linked National Cancer Patient Experience Survey and Cancer Registration Dataset.

OBJECTIVE: This study aimed to examine whether being given the name of a clinical nurse specialist (CNS) is associated with better cancer patients' experiences across different points along their cancer care pathway. METHODS: We identified 100,885 colorectal, lung, breast and prostate cancer patients who responded to the National Cancer Patient Experience Survey between 2010 and 2014. We compared experiences of four key aspects of cancer care among patients who reported being given a CNS name with those who did not, adjusting for age, sex, socio-economic deprivation, ethnicity, route to diagnosis and disease stage. RESULTS: Across all cancers, patients who reported being given the name of a CNS reported better experiences with involvement in treatment decisions, care coordination, treatment with more respect and dignity, and overall care experience. Experience of being involved in treatment decisions was the aspect of care most strongly associated with being given a CNS name (colorectal: OR 2.69, 95% CI: 2.45-2.96; lung: OR 2.41, 95% CI: 2.07-2.78; breast: OR 2.68, 95% CI: 2.47-2.92; and prostate: OR 2.11, 95% CI: 1.92-2.32). CONCLUSION: These findings may provide new evidence of the vital contribution CNS make to cancer care and suggest their input and support should be available to all patients after the diagnosis.

Involvement of the epidermal growth factor receptor in IL-13-mediated corticosteroid-resistant airway inflammation.

BACKGROUND: Effective treatment for severe asthma is a significant unmet need. While eosinophilic inflammation caused by type 2 cytokines is responsive to corticosteroid and biologic therapies, many severe asthmatics exhibit corticosteroid-unresponsive mixed granulocytic inflammation. OBJECTIVE: Here, we tested the hypothesis that the pro-allergic cytokine, IL-13, can drive both corticosteroid-sensitive and corticosteroid-resistant responses. RESULTS: By integration of in vivo and in vitro models of IL-13-driven inflammation, we identify a role for the epidermal growth factor receptor (EGFR/ERBB1) as a mediator of corticosteroid-unresponsive inflammation and bronchial hyperresponsiveness driven by IL-13. Topological data analysis using human epithelial transcriptomic data from the U-BIOPRED cohort identified severe asthma groups with features consistent with the presence of IL-13 and EGFR/ERBB activation, with involvement of distinct EGFR ligands. Our data suggest that IL-13 may play a dual role in severe asthma: on the one hand driving pathologic corticosteroid-refractory mixed granulocytic inflammation, but on the other hand underpinning beneficial epithelial repair responses, which may confound responses in clinical trials. CONCLUSION AND CLINICAL RELEVANCE: Detailed dissection of those molecular pathways that are downstream of IL-13 and utilize the ERBB receptor and ligand family to drive corticosteroid-refractory inflammation should enhance the development of new treatments that target this sub-phenotype(s) of severe asthma, where there is an unmet need.

Inpp5e suppresses polycystic kidney disease via inhibition of PI3K/Akt-dependent mTORC1 signaling.

Polycystic kidney disease (PKD) is a common cause of renal failure with few effective treatments. INPP5E is an inositol polyphosphate 5-phosphatase that dephosphorylates phosphoinositide 3-kinase (PI3K)-generated PI(3,4,5)P3 and is mutated in ciliopathy syndromes. Germline Inpp5e deletion is embryonically lethal, attributed to cilia stability defects, and is associated with polycystic kidneys. However, the molecular mechanisms responsible for PKD development upon Inpp5e loss remain unknown. Here, we show conditional inactivation of Inpp5e in mouse kidney epithelium results in severe PKD and renal failure, associated with a partial reduction in cilia number and hyperactivation of PI3K/Akt and downstream mammalian target of rapamycin complex 1 (mTORC1) signaling. Treatment with an mTORC1 inhibitor improved kidney morphology and function, but did not affect cilia number or length. Therefore, we identify Inpp5e as an essential inhibitor of the PI3K/Akt/mTORC1 signaling axis in renal epithelial cells, and demonstrate a critical role for Inpp5e-dependent mTORC1 regulation in PKD suppression.

Short-term breast cancer survival in relation to ethnicity, stage, grade and receptor status: national cohort study in England.

BACKGROUND: In the re-organisation of cancer registration in England in 2012, a high priority was given to the recording of cancer stage and other prognostic clinical data items. METHODS: We extracted 86 852 breast cancer records for women resident in England and diagnosed during 2012-2013. Information on age, ethnicity, socio-economic status, comorbidity, tumour stage, grade, morphology and oestrogen, progesterone and HER2 receptor status was included. The two-year cumulative risk of death from any cause was estimated with the Kaplan-Meier method, and univariate and multivariate Cox proportional hazards regressions were used to estimate hazard ratios (HR) and their 95% confidence intervals (95% CI). The follow-up ended on 31 December 2014. RESULTS: The completeness of registration for prognostic variables was generally high (around 80% or higher), but it was low for progesterone receptor status (41%). Women with negative receptor status for each of the oestrogen, progesterone and HER2 receptors (triple-negative cancers) had an adjusted HR for death of 2.00 (95%CI 1.84-2.17). Black women had an age-adjusted HR of 1.77 (1.48-2.13) compared with White women. CONCLUSIONS: The excess mortality of Black women with breast cancer has contributions from socio-economic factors, stage distribution and tumour biology. The study illustrates the richness of detail in the national cancer registration data. This allows for analysis of cancer outcomes at a high level of resolution, and may form the basis for risk stratification.

Stable Phenotypic Changes of the Host T Cells Are Essential to the Long-Term Stability of Latent HIV-1 Infection.

UNLABELLED: The extreme stability of the latent HIV-1 reservoir in the CD4(+) memory T cell population prevents viral eradication with current antiretroviral therapy. It has been demonstrated that homeostatic T cell proliferation and clonal expansion of latently infected T cells due to viral integration into specific genes contribute to this extraordinary reservoir stability. Nevertheless, given the constant exposure of the memory T cell population to specific antigen or bystander activation, this reservoir stability seems remarkable, unless it is assumed that latent HIV-1 resides exclusively in memory T cells that recognize rare antigens. Another explanation for the stability of the reservoir could be that the latent HIV-1 reservoir is associated with an unresponsive T cell phenotype. We demonstrate here that host cells of latent HIV-1 infection events were functionally altered in ways that are consistent with the idea of an anergic, unresponsive T cell phenotype. Manipulations that induced or mimicked an anergic T cell state promoted latent HIV-1 infection. Kinome analysis data reflected this altered host cell phenotype at a system-wide level and revealed how the stable kinase activity changes networked to stabilize latent HIV-1 infection. Protein-protein interaction networks generated from kinome data could further be used to guide targeted genetic or pharmacological manipulations that alter the stability of latent HIV-1 infection. In summary, our data demonstrate that stable changes to the signal transduction and transcription factor network of latently HIV-1 infected host cells are essential to the ability of HIV-1 to establish and maintain latent HIV-1 infection status. IMPORTANCE: The extreme stability of the latent HIV-1 reservoir allows the infection to persist for the lifetime of a patient, despite completely suppressive antiretroviral therapy. This extreme reservoir stability is somewhat surprising, since the latently HIV-1 infected CD4(+) memory T cells that form the structural basis of the viral reservoir should be exposed to cognate antigen over time. Antigen exposure would trigger a recall response and should deplete the reservoir, likely over a relatively short period. Our data demonstrate that stable and system-wide phenotypic changes to host cells are a prerequisite for the establishment and maintenance of latent HIV-1 infection events. The changes observed are consistent with an unresponsive, anergy-like T cell phenotype of latently HIV-1 infected host cells. An anergy-like, unresponsive state of the host cells of latent HIV-1 infection events would explain the stability of the HIV-1 reservoir in the face of continuous antigen exposure.

Comparing the case mix and survival of women receiving breast cancer care from one private provider with other London women with breast cancer: pilot data exchange and analyses.

BACKGROUND: Data from providers of private cancer care are not yet formally included in English cancer registration data. This study aimed to test the exchange of breast cancer data from one Hospital Corporation of America International (HCAI) hospital in London with the cancer registration system and assess the suitability of these data for comparative analyses of case mix and adjusted survival. METHODS: Data on 199 London women receiving 'only HCAI care', 278 women receiving 'some HCAI care' (HCAI and other services), and 31,234 other London women diagnosed between 2005 and 2011 could be identified and compared. Overall survival was estimated using the Kaplan-Meier method, and Cox regression was used to adjust for age, socioeconomic deprivation, year of diagnosis, stage of disease and recorded treatment. RESULTS: Women receiving 'only HCAI care' were younger, lived in areas of higher affluence (47.8 % vs 27.6 %) and appeared less likely to be recorded as having screen-detected (2.5 % vs 25.0 %) disease than other London women. Women receiving 'some HCAI care' were more similar to 'HCAI only' women. Although HCAI stage of disease data completeness improved during the study period, this was less complete overall than cancer registration data and limited the comparative survival analyses. An apparent survival advantage for 'HCAI only' women compared with other London women (hazard ratio 0.48, 95 % confidence interval (CI): 0.32-0.74) was attenuated and no longer statistically significant after adjustment (0.79, 95 % CI: 0.51-1.21). Women receiving 'some HCAI care' appeared to have higher survival (hazard ratio 0.24, 95 % CI 0.14-0.41) which was attenuated to 0.48 (95 % CI: 0.28-0.80) in the fully adjusted model. CONCLUSIONS: Exchange of data between the private cancer sector and the English cancer registration service can identify patients who receive all or some private care. The better survival of women receiving only or some HCAI breast cancer care appears to be at least partly explained by demographic, disease, and treatment factors. However, larger studies using similarly quality assured datasets and more complete staging data from the private sector are needed to produce definitive comparative results.

The PtdIns(3,4)P(2) phosphatase INPP4A is a suppressor of excitotoxic neuronal death.

Phosphorylated derivatives of phosphatidylinositol, collectively referred to as phosphoinositides, occur in the cytoplasmic leaflet of cellular membranes and regulate activities such as vesicle transport, cytoskeletal reorganization and signal transduction. Recent studies have indicated an important role for phosphoinositide metabolism in the aetiology of diseases such as cancer, diabetes, myopathy and inflammation. Although the biological functions of the phosphatases that regulate phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P(3)) have been well characterized, little is known about the functions of the phosphatases regulating the closely related molecule phosphatidylinositol-3,4-bisphosphate (PtdIns(3,4)P(2)). Here we show that inositol polyphosphate phosphatase 4A (INPP4A), a PtdIns(3,4)P(2) phosphatase, is a suppressor of glutamate excitotoxicity in the central nervous system. Targeted disruption of the Inpp4a gene in mice leads to neurodegeneration in the striatum, the input nucleus of the basal ganglia that has a central role in motor and cognitive behaviours. Notably, Inpp4a(-/-) mice show severe involuntary movement disorders. In vitro, Inpp4a gene silencing via short hairpin RNA renders cultured primary striatal neurons vulnerable to cell death mediated by N-methyl-d-aspartate-type glutamate receptors (NMDARs). Mechanistically, INPP4A is found at the postsynaptic density and regulates synaptic NMDAR localization and NMDAR-mediated excitatory postsynaptic current. Thus, INPP4A protects neurons from excitotoxic cell death and thereby maintains the functional integrity of the brain. Our study demonstrates that PtdIns(3,4)P(2), PtdIns(3,4,5)P(3) and the phosphatases acting on them can have distinct regulatory roles, and provides insight into the unique aspects and physiological significance of PtdIns(3,4)P(2) metabolism. INPP4A represents, to our knowledge, the first signalling protein with a function in neurons to suppress excitotoxic cell death. The discovery of a direct link between PtdIns(3,4)P(2) metabolism and the regulation of neurodegeneration and involuntary movements may aid the development of new approaches for the treatment of neurodegenerative disorders.

The varying influence of socioeconomic deprivation on breast cancer screening uptake in London.

BACKGROUND: We assessed the relationship between screening uptake and socioeconomic deprivation for London women aged 50-52 invited to their first routine screening appointment between 2006 and 2009. METHODS: We examined uptake for London overall and within six screening areas, using deprivation quintile, based on post code of residence. RESULTS: After adjustment for age, area and ethnicity, overall uptake decreased with increasing deprivation (adjusted odds ratio (OR) = 0.95, P < 0.001). However, in two screening areas with lower uptake, women living in deprived areas had higher uptake than women from affluent areas. CONCLUSIONS: These potential inequalities in early diagnosis across London require further investigation.

A qualitative investigation of the motivations, experiences and views of female sunbed users under the age of 18 in England.

OBJECTIVE: To explore the motivations, experiences and views of female regular sunbed users aged 15-17 and consider the implications of legislation seeking to restrict sunbed use among the under-18s. Design Qualitative study of 12 focus groups. METHOD: Participants were recruited opportunistically through community and social networks, around tanning salons, leisure and educational facilities in six English towns and cities. Interviews were transcribed, a thematic framework generated and a validation exercise conducted. Setting Urban communities in England. Participants Sixty-nine female regular sunbed users aged 15-18. RESULTS: Respondents consistently valued tanning and attached considerable personal and social importance to it. They showed an awareness of the risks of sunbed use that they accepted, downplayed and/or ignored. While experiences and responses to supervision varied, respondents were resistant to any measures that restricted their use and expressed willingness to find ways around such restrictions. CONCLUSIONS: The sunbed users interviewed in this study attached considerable significance to tanning, rationalized the risks of sunbed use and expressed their determination to continue using them. The impact of legislation to limit sunbed access may be weakened without requirements to ensure supervision of salons.

Breast Cancer in Women in Gaza: A Review of Clinical Characteristics and Short-Term Survival.

PURPOSE: To understand how breast cancer is diagnosed in Gaza, and disease stage distribution, treatment, and survival. MATERIALS AND METHODS: A clinical record case series study of women diagnosed in 2017 and 2018 was conducted with follow-up until December 31, 2020. Breast cancer crude incidence rates and age-specific incidence rates were calculated. Clinical characteristics, including investigation, diagnosis, and treatment methods by year of diagnosis, were compared using the chi-square test. The 2-year cumulative risk of death from any cause was estimated using the Kaplan-Meier method, and univariate and multivariate Cox proportional hazard regressions estimated hazard ratios and their 95% CIs. RESULTS: Five hundred twenty-four new diagnoses (mean age, 53 years; range, 23-100) were recorded, giving a crude annual incidence rate of 27 per 100,000 population. Six percent (32/524) were diagnosed at stage I, 35% (185/524) at stage II, 33% (171/524) at stage III, and 19% (99/524) at stage IV. More than one half (52%, 271/524) underwent modified radical mastectomy. Seventy-seven percent (405/524) received chemotherapy, 70% (368/524) hormone therapy, and 39% (204/524) radiotherapy. Data on key prognostic factors were mostly available-stage (93%), estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2; 82%), tumor grade (77%), and tumor size (70%). The overall survival was 95.4% at 1 year and 86.6% at 2 years. CONCLUSION: Women with breast cancer in Gaza have a high short-term survival after diagnosis. However, one half were diagnosed with advanced disease, and their investigations were incomplete. Better reporting on family history, tumor grade, size, and ER, PR, and HER2 receptor status is needed for future studies.