A retrospective observational study of labour ward work Intensity: The challenge of maternity staffing.

BACKGROUND: The UK and Ireland are facing significant challenges in the recruitment and retention of midwifery staff. Deficiencies in staffing, training and leadership have been cited as contributory factors to substandard care in both regional and global independent maternity safety reports. Locally, workforce planning is critical to maintaining 'one to one' care for all women in labor and to meet the peaks of daily birthing suite activity. OBJECTIVES: Analyze the variation in work intensity, defined by the mean number and range of births per midwifery working hours. METHODS: Retrospective observational study of birthing suite activity between 2017 and 2020. 30,550 singleton births were reported during the study period; however, 6529 elective Cesarean sections were excluded as these were performed during normal working hours by a separate operating theatre team. The times of 24,021 singleton births were organized into five proposed midwifery working rosters lasting eight or 12 h; A (00.00-07.59), B (08.00-15.59), C (16.00-23.59), D (20.00-0.759) and E (0.800-19.59). RESULTS: The number of births was comparable between the eight-hour and 12-hour work periods with a mean of five to six babies born per roster (range zero to 15). Work periods D and E lasting 12-hours both recorded a mean of eight births (range zero to 18). Hourly births ranged from a minimum of zero to a maximum of five births per hour (greater than seven times the mean), a number that was achieved 14 times during the study period. CONCLUSIONS: The mean number of births is consistent between normal working hours and unsociable 'on-call' periods, however there is an extreme range of activity within each midwifery roster. Prompt escalation plans remain essential for maternity services to manage unexpected increases in demand and complexity. WHAT IS ALREADY KNOWN ON THIS TOPIC: Shortfalls in staffing and inadequate workforce planning have been frequently cited in recent maternity safety reports as barriers to sustainable and safe maternity care. WHAT THIS STUDY ADDS: Our study shows that the mean number of births in a large tertiary center are consistent across day and night rosters. However, there are large fluctuations in activity during which births can exceed the number of available midwives. HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY: Our study reflects the sentiments of the Ockenden review and APPG report on safe maternity staffing. Investment in services and the workforce to aid recruitment and reduce attrition is essential to establish robust escalation plans, including the deployment of additional staff in the event of extreme service pressures.

Public understandings of potential policy responses to health inequalities: Evidence from a UK national survey and citizens' juries in three UK cities.

A substantial body of research describes the distribution, causes and potential reduction of health inequalities, yet little scholarship examines public understandings of these inequalities. Existing work is dominated by small-scale, qualitative studies of the experiences of specific communities. As a result, we know very little about what broader publics think about health inequalities; and even less about public views of potential policy responses. This is an important gap since previous research shows many researchers and policymakers believe proposals for 'upstream' policies are unlikely to attract sufficient public support to be viable. This mixed methods study combined a nationally representative survey with three two-day citizens' juries exploring public views of health inequalities and potential policy responses in three UK cities (Glasgow, Manchester and Liverpool) in July 2016. Comparing public opinion elicited via a survey to public reasoning generated through deliberative processes offers insight into the formation of public views. The results challenge perceptions that there is a lack of public support for upstream, macro-level policy proposals and instead demonstrate support for proposals aiming to tackle health inequalities via improvements to living and working conditions, with more limited support for proposals targeting individual behavioural change. At the same time, some macro-economic proposals, notably those involving tax increases, proved controversial among study participants and results varied markedly by data source. Our analysis suggests that this results from three intersecting factors: a resistance to ideas viewed as disempowering (which include, fundamentally, the idea that health inequalities exist); the prevalence of individualising and fatalistic discourses, which inform resistance to diverse policy proposals (but especially those that are more 'upstream', macro-level proposals); and a lack of trust in (local and national) government. This suggests that efforts to enhance public support for evidence-informed policy responses to health inequalities may struggle unless these broader challenges are also addressed.

Socioeconomic inequalities and the equity impact of population-level interventions for adolescent health: an overview of systematic reviews.

OBJECTIVES: Despite robust evidence on health inequalities in adulthood, less attention has been paid to inequalities in adolescence. The aim of this overview was to examine systematic review (SR) evidence on the equity impact of population-level interventions intended to improve health, happiness and wellbeing for adolescents. STUDY DESIGN: An overview (review of systematic reviews). METHODS: Eleven electronic databases were systematically searched to identify SRs of population-level interventions for adolescent health. A secondary data analysis of socioeconomic inequality was conducted to identify whether SRs reported on primary studies in terms of disadvantage, by measures of socioeconomic status (SES) and by differential effects. RESULTS: 35,310 review titles were screened; 566 full texts were retrieved and 140 SRs met the predefined selection criteria. Differential intervention effects were considered in 42/140 (30%) SRs, 18/140 (13%) reported primary studies using an SES measure and 16/140 (11%) explicitly reported differential effects. 15/140 SRs (11%) explicitly focused on socioeconomic inequalities; of these 4/15 reported differential intervention effects in more detail, 7/15 concluded there was insufficient primary evidence to identify the impact of interventions on socioeconomic inequalities and 4/15 planned to examine differential effects by SES, but this was not reported further. CONCLUSIONS: Our overview identifies that there is limited SR evidence on the equity impact of population-level interventions for adolescent health. Strengthening the evidence on whether interventions narrow or widen inequalities for adolescents must be a priority for public health research.

Exposure to liquid sweetness in early childhood: artificially-sweetened and sugar-sweetened beverage consumption at 4-5 years and risk of overweight and obesity at 7-8 years.

BACKGROUND: A significant gap exists in longitudinal evidence on early exposure to artificially sweetened beverages (ASBs) and weight outcomes for paediatric populations. OBJECTIVE: The objective of this study is to examine the relationship between ASB/sugar-sweetened beverage (SSB) consumption at 4-5 years and risk of overweight and obesity at 7-8 years. METHODS: Data from a nationally representative cohort (n = 2986) in Scotland were analysed using logistic regression to evaluate the association between exposure to ASBs/SSBs at 4-5 years and risk of overweight and obesity at 7-8 years. RESULTS: There were positive unadjusted associations between ASB consumption and risk of obesity, and following adjustment for confounders, ASB associations attenuated, and only the middle consumption category (1 to 6 times per week) remained significant (odds ratio 1.57, 95% confidence interval {CI} 1.05-2.36). For SSB consumption, there were no significant unadjusted associations, and following adjustment for confounders, only the middle consumption category was significant (odds ratio 1.65, 95% CI 1.12-2.44). There were no significant associations for risk of overweight. CONCLUSIONS: Longitudinal analysis from 4-5 to 7-8 years demonstrated some evidence of associations between ASBs/SSB consumption and risk of obesity. However, non-linear patterns and wide CIs suggest cautious interpretation and need for future studies with long-term follow-up.

Glucose transporter 1-mediated glucose uptake is limiting for B-cell acute lymphoblastic leukemia anabolic metabolism and resistance to apoptosis.

The metabolic profiles of cancer cells have long been acknowledged to be altered and to provide new therapeutic opportunities. In particular, a wide range of both solid and liquid tumors use aerobic glycolysis to supply energy and support cell growth. This metabolic program leads to high rates of glucose consumption through glycolysis with secretion of lactate even in the presence of oxygen. Identifying the limiting events in aerobic glycolysis and the response of cancer cells to metabolic inhibition is now essential to exploit this potential metabolic dependency. Here, we examine the role of glucose uptake and the glucose transporter Glut1 in the metabolism and metabolic stress response of BCR-Abl+ B-cell acute lymphoblastic leukemia cells (B-ALL). B-ALL cells were highly glycolytic and primary human B-ALL samples were dependent on glycolysis. We show B-ALL cells express multiple glucose transporters and conditional genetic deletion of Glut1 led to a partial loss of glucose uptake. This reduced glucose transport capacity, however, was sufficient to metabolically reprogram B-ALL cells to decrease anabolic and increase catabolic flux. Cell proliferation decreased and a limited degree of apoptosis was also observed. Importantly, Glut1-deficient B-ALL cells failed to accumulate in vivo and leukemic progression was suppressed by Glut1 deletion. Similarly, pharmacologic inhibition of aerobic glycolysis with moderate doses of 2-deoxyglucose (2-DG) slowed B-ALL cell proliferation, but extensive apoptosis only occurred at high doses. Nevertheless, 2-DG induced the pro-apoptotic protein Bim and sensitized B-ALL cells to the tyrosine kinase inhibitor Dasatinib in vivo. Together, these data show that despite expression of multiple glucose transporters, B-ALL cells are reliant on Glut1 to maintain aerobic glycolysis and anabolic metabolism. Further, partial inhibition of glucose metabolism is sufficient to sensitize cancer cells to specifically targeted therapies, suggesting inhibition of aerobic glycolysis as a plausible adjuvant approach for B-ALL therapies.

Autophagy is essential to suppress cell stress and to allow BCR-Abl-mediated leukemogenesis.

Hematopoietic cells normally require cell extrinsic signals to maintain metabolism and survival. In contrast, cancer cells can express constitutively active oncogenic kinases such as BCR-Abl that promote these processes independent of extrinsic growth factors. When cells receive insufficient growth signals or when oncogenic kinases are inhibited, glucose metabolism decreases and the self-digestive process of autophagy is elevated to degrade bulk cytoplasm and organelles. Although autophagy has been proposed to provide a cell-intrinsic nutrient supply for mitochondrial oxidative metabolism and to maintain cellular homeostasis through degradation of damaged organelles or protein aggregates, its acute role in growth factor deprivation or inhibition of oncogenic kinases remains poorly understood. We therefore developed a growth factor-dependent hematopoietic cell culture model in which autophagy can be acutely disrupted through conditional Cre-mediated excision of the autophagy-essential gene Atg3. Treated cells rapidly lost their ability to perform autophagy and underwent cell cycle arrest and apoptosis. Although Atg3 was essential for optimal upregulation of mitochondrial oxidative pathways in growth factor withdrawal, this metabolic contribution of autophagy did not appear critical for cell survival, as provision of exogenous pyruvate or lipids could not completely rescue Atg3 deficiency. Instead, autophagy suppressed a stress response that otherwise led to p53 phosphorylation and upregulation of p21 and the pro-apoptotic Bcl-2 family protein Puma. Importantly, BCR-Abl-expressing cells had low basal levels of autophagy, but were highly dependent on this process, and rapidly underwent apoptosis upon disruption of autophagy through Atg3 deletion or treatment with chemical autophagy inhibitors. This dependence on autophagy extended in vivo, as Atg3 deletion also prevented BCR-Abl-mediated leukemogenesis in a cell transfer model. Together these data demonstrate a critical role for autophagy to mitigate cell stress, and that cells expressing the oncogenic kinase BCR-Abl appear particularly dependent on autophagy for cell survival and leukemogenesis.

Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion.

OBJECTIVES: Telomere erosion, a feature of biological ageing, is implicated in a wide range of diseases. Its impact on autoimmune diseases remains unclear although autoantibodies against many telomere nucleoprotein components are prevalent in these diseases. We aimed to assess if telomere biology was abnormal in a cohort of patients with limited cutaneous systemic sclerosis (lcSSc). METHODS: Telomere lengths in peripheral blood leucocytes (PBL) were determined using Southern blotting methods in a cohort of lcSSc subjects (n=43; age range 37-80 years) and a control population (n=107; age range 21-65 years). RESULTS: Telomere lengths in lcSSc subjects were longer than controls (p<0.001), did not show age-related telomere erosion and differed significantly from age-matched controls only after 50 years of age (p<0.001). CONCLUSIONS: This is the first report of maintenance of telomere lengths in an autoimmune disease state. These data indicate aberrant telomere biology and irregular biological ageing from the fifth decade of life. These findings provide insight into compromised DNA damage repair in lcSSc. Whether these observations indicate a causal or consequential relationship requires further investigation. This in turn, may provide potential novel targets for therapeutic intervention.

Altered sirtuin expression is associated with node-positive breast cancer.

Sirtuins are genes implicated in cellular and organismal ageing. Consequently, they are speculated to be involved in diseases of ageing including cancer. Various cancers with widely differing prognosis have been shown to have differing and characteristic expression of these genes; however, the relationship between sirtuin expression and cancer progression is unclear. In order to correlate cancer progression and sirtuin expression, we have assessed sirtuin expression as a function of primary cell ageing and compared sirtuin expression in normal, 'nonmalignant' breast biopsies to breast cancer biopsies using real-time polymerase chain reaction (PCR). Levels of SIRT7 expression were significantly increased in breast cancer (P<0.0001). Increased levels of SIRT3 and SIRT7 transcription were also associated with node-positive breast cancer (P<0.05 and P<0.0001, respectively). This study has demonstrated differential sirtuin expression between nonmalignant and malignant breast tissue, with consequent diagnostic and therapeutic implications.

Chlamydia pneumoniae infection promotes the transmigration of monocytes through human brain endothelial cells.

We have investigated the effects of Chlamydia pneumoniae on human brain endothelial cells (HBMECs) and human monocytes as a mechanism for breaching the blood-brain barrier (BBB) in Alzheimer's disease (AD). HBMECs and peripheral blood monocytes may be key components in controlling the entry of C. pneumoniae into the human brain. Our results indicate that C. pneumoniae infects blood vessels and monocytes in AD brain tissues compared with normal brain tissue. C. pneumoniae infection stimulates transendothelial entry of monocytes through HBMECs. This entry is facilitated by the up-regulation of VCAM-1 and ICAM-1 on HBMECs and a corresponding increase of LFA-1, VLA-4, and MAC-1 on monocytes. C. pneumoniae infection in HBMECs and THP-1 monocytes up-regulates monocyte transmigration threefold in an in vitro brain endothelial monolayer. In this way, C. pneumoniae infection in these cell types may contribute to increased monocyte migration and promote inflammation within the CNS resulting from infection at the level of the vasculature. Thus, infection at the level of the vasculature may be a key initiating factor in the pathogenesis of neurodegenerative diseases such as sporadic AD.

Large-scale quarantine following biological terrorism in the United States: scientific examination, logistic and legal limits, and possible consequences.

Concern for potential bioterrorist attacks causing mass casualties has increased recently. Particular attention has been paid to scenarios in which a biological agent capable of person-to-person transmission, such as smallpox, is intentionally released among civilians. Multiple public health interventions are possible to effect disease containment in this context. One disease control measure that has been regularly proposed in various settings is the imposition of large-scale or geographic quarantine on the potentially exposed population. Although large-scale quarantine has not been implemented in recent US history, it has been used on a small scale in biological hoaxes, and it has been invoked in federally sponsored bioterrorism exercises. This article reviews the scientific principles that are relevant to the likely effectiveness of quarantine, the logistic barriers to its implementation, legal issues that a large-scale quarantine raises, and possible adverse consequences that might result from quarantine action. Imposition of large-scale quarantine-compulsory sequestration of groups of possibly exposed persons or human confinement within certain geographic areas to prevent spread of contagious disease-should not be considered a primary public health strategy in most imaginable circumstances. In the majority of contexts, other less extreme public health actions are likely to be more effective and create fewer unintended adverse consequences than quarantine. Actions and areas for future research, policy development, and response planning efforts are provided.

Direct evidence that leukemic cells present HLA-associated immunogenic peptides derived from the BCR-ABL b3a2 fusion protein.

The BCR-ABL oncogene is central in the pathogenesis of chronic myeloid leukemia (CML). Here, tandem nanospray mass spectrometry was used to demonstrate cell surface HLA-associated expression of the BCR-ABL peptide KQSSKALQR on class I-negative CML cells transfected with HLA-A*0301, and on primary CML cells from HLA-A3-positive patients. These patients mounted a cytotoxic T-lymphocyte response to KQSSKALQR that also killed autologous CML cells, and tetramer staining demonstrated the presence of circulating KQSSKALQR-specific T cells. The findings are the first demonstration that CML cells express HLA-associated leukemia-specific immunogenic peptides and provide a sound basis for immunization studies against BCR-ABL.

Mitosis and differentiation in T-cells under cytotoxic action of Echinococcus granulosus hydatid fluid.

In the T-cell line, D10, thymidine uptake was used to measure the proportion of cells in S-phase, and the MTT assay to measure the number of viable cells. The effect of Echinococcus granulosus hydatid fluid (HF) on the lymphocytes was assayed in 3-day cultures of the T-cell line, D10, in increasing concentrations of HF. Apparent cytotoxic effects of HF were recorded as a log-linear decline in S-phase activity, which was reduced by the presence of IL-1, IL-2, or a combination of the two. In the presence of IL-2, however, mitogenic treatment with concanavalin A increased the cytotoxic effect in 3-day cultures, while in day-2 cultures, HF itself showed mitogenic effect. HF-induced decline in S-phase activity was not matched by a parallel decline in viable cells, suggesting that the apparent cytotoxicity of HF could result from cell-cycle arrest. Depending on its origin, HF enhanced membrane expression of CD25 and CD38 on human peripheral blood lymphoblasts, and diminished that of CD28. Taken together, these changes suggest that HF can induce T-cell mitosis and reduce co-stimulation with subsequent T-cell anergy or apoptosis.

Echinococcus granulosus: regulation of leukocyte growth by living protoscoleces from horses, sheep, and cattle.

To determine whether living hydatid tissue can, like hydatid fluid, regulate leukocyte growth, T-cell, B-cell, and macrophage lines were cocultured with protoscoleces of Echinococcus granulosus and their growth was compared with that of control cultures by thymidine uptake estimates and chemiluminescent assays of cell number. Protoscoleces supported mitosis of IL-1-deprived D10 T cells, but did not increase D10 count. The action of protoscoleces was affected by the species and organ of their origin and the length of time in culture. Unusually marked mitotic reaction, unaffected by parasite age and origin, was recorded in the B-cell line, BSM, also without commensurate count increase, indicating that induced mitosis resulted in cell loss. It is concluded that protoscoleces can induce mitosis in B and T cells of particular lineages and that this is a potential means of producing the pathological proliferation and depletion of B- and T-cell areas which characterize local reaction to hydatids.

Growth kinetics of leukocyte cell lines cultured with hydatid fluid of Echinococcus granulosus equinus.

Oxidation of 3,(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and tritiated thymidine uptake were used to measure, respectively, the viable cell count and the S-phase activity of D10, B9, A20 and p388d leukocytic cell lines cultured in the presence of varying concentrations of fluid from fertile and infertile hydatid cysts of Echinococcus granulosus equinus. Exposure to hydatid fluid raised or lowered the entry of D10 cells into S-phase depending on the concentration of the fluid and of the supporting cytokines. Enlargement of the S-phase population was unaccompanied by increase in viable count indicating that the mitotic cycles induced by hydatid products were not completed. A similar conclusion was reached in respect of the p388d monocytic line, and both changes appear consistent with those occurring in histopathology in vivo. By contrast, the main effect on B9 and A20 B cells was inhibition of entry into S-phase.

Echinococcus granulosus: assays for hydatid immunoregulatory factors using established lymphoid cell lines.

Mitosis, mitochondrial metabolic rate and proliferation were measured in established lymphoid cell lines exposed to chromatographic fractions of equine Echinococcus granulosus hydatid fluid. In several cell lines, one or more of the three parameters were modified by the exposure. As an assay for potential immunoregulatory activity, the method was simple and repeatable. The following novel observations were made: (1) Mitotic reaction was found among lines of T-cell, B-cell and macrophage origin; (2) mitosis was accompanied by proliferation in the B-cell lines, B9 and A20, and in the macrophage lines, HL-60 and P388d. With mitotically responsive T-cells, proliferation was slight in CTLL-2 and absent in D10, implying cell-cycle modification; (3) mitotic responsiveness tended to occur in cell lines with mature characteristics; (4) among cytokine-dependent cell lines, hydatid fluid FPLC fraction 1 mimicked IL-1 and several fractions mimicked IL-2 and IL-6 in the maintenance of mitosis; and (5) there was significant statistical interaction between the influences of mammalian cytokines and hydatid fluid fractions, implying that the propensity of antigenically unprimed lymphoid cells to be regulated by E. granulosus is conditioned by cytokine activity.

Weapons of mass destruction events with contaminated casualties: effective planning for health care facilities.

Biological and chemical terrorism is a growing concern for the emergency preparedness community. While health care facilities (HCFs) are an essential component of the emergency response system, at present they are poorly prepared for such incidents. The greatest challenge for HCFs may be the sudden presentation of large numbers of contaminated individuals. Guidelines for managing contaminated patients have been based on traditional hazardous material response or military experience, neither of which is directly applicable to the civilian HCF. We discuss HCF planning for terrorist events that expose large numbers of people to contamination. Key elements of an effective HCF response plan include prompt recognition of the incident, staff and facility protection, patient decontamination and triage, medical therapy, and coordination with external emergency response and public health agencies. Controversial aspects include the optimal choice of personal protective equipment, establishment of patient decontamination procedures, the role of chemical and biological agent detectors, and potential environmental impacts on water treatment systems. These and other areas require further investigation to improve response strategies.

Accuracy of the clinical diagnoses of Lewy body disease, Parkinson disease, and dementia with Lewy bodies: a clinicopathologic study.

BACKGROUND: Whether Parkinson disease (PD) and dementia with Lewy bodies (DLB) represent 2 distinct nosologic entities or are diverse phenotypes of Lewy body disease is subject to debate. OBJECTIVES: To determine the accuracy of the diagnoses of Lewy body disease, PD, and DLB by validating the clinical diagnoses of 6 neurologists with the neuropathologic findings and to identify early predictors of the diagnoses. METHODS: Six raters who were unaware of the neuropathologic diagnoses analyzed 105 clinical vignettes corresponding to 29 cases of Lewy body disease (post hoc analysis of 15 patients with PD and 14 with DLB) and 76 patients without PD or DLB whose cases were confirmed through autopsy findings. MAIN OUTCOME MEASURES: Sensitivity and positive predictive value (PPV) were chosen as validity measures and the K statistic as a reliability measure. RESULTS: Interrater reliability for the diagnoses of Lewy body disease and PD was moderate for the first visit and substantial for the last, whereas agreement for diagnosis of DLB was fair for the first visit and slight for the last. Median sensitivity for diagnosis of Lewy body disease was 56.9% for the first visit and 67.2% for the last; median PPV was 60.0% and 77.4%, respectively. Median sensitivity for the diagnosis of PD was 73.3% for the first visit and 80.0% for the last; median PPV was 45.9% and 64.1%, respectively. Median sensitivity for the diagnosis of DLB was 17.8% for the first visit and 28.6% for the last; median PPV was 75.0% for the first visit and 55.8% for the last. The raters' results were similar to those of the primary neurologists. Several features differentiated PD from DLB, predicted each disorder, and could be used as clinical pointers. CONCLUSIONS: The low PPV with relatively high sensitivity for the diagnosis of PD suggests overdiagnosis. Conversely, the extremely low sensitivity for the diagnosis of DLB suggests underdiagnosis. Although the case mix included in the study may not reflect the frequency of these disorders in practice, limiting the clinical applicability of the validity measures, the raters' results were similar to those of the primary neurologists who were not exposed to such limitations. Overall, our study confirms features suggested to predict these disorders, except for the early presence of postural imbalance, which is not indicative of either disorder.