A large West Antarctic Ice Sheet explains early Neogene sea-level amplitude.

Early to Middle Miocene sea-level oscillations of approximately 40-60 m estimated from far-field records1-3 are interpreted to reflect the loss of virtually all East Antarctic ice during peak warmth2. This contrasts with ice-sheet model experiments suggesting most terrestrial ice in East Antarctica was retained even during the warmest intervals of the Middle Miocene4,5. Data and model outputs can be reconciled if a large West Antarctic Ice Sheet (WAIS) existed and expanded across most of the outer continental shelf during the Early Miocene, accounting for maximum ice-sheet volumes. Here we provide the earliest geological evidence proving large WAIS expansions occurred during the Early Miocene (~17.72-17.40 Ma). Geochemical and petrographic data show glacimarine sediments recovered at International Ocean Discovery Program (IODP) Site U1521 in the central Ross Sea derive from West Antarctica, requiring the presence of a WAIS covering most of the Ross Sea continental shelf. Seismic, lithological and palynological data reveal the intermittent proximity of grounded ice to Site U1521. The erosion rate calculated from this sediment package greatly exceeds the long-term mean, implying rapid erosion of West Antarctica. This interval therefore captures a key step in the genesis of a marine-based WAIS and a tipping point in Antarctic ice-sheet evolution.

Irish national real-world analysis of the clinical and economic impact of 21-gene oncotype DX® testing in early-stage, 1-3 lymph node-positive, oestrogen receptor-positive, HER2-negative, breast cancer.

PURPOSE: The treatment landscape of Oestrogen receptor-positive (ER-positive) breast cancer is evolving, with declining chemotherapy use as a result of Oncotype DX Breast Recurrence Score® testing. Results from the SWOG S1007 RxPONDER trial suggest that adjuvant chemotherapy may benefit some premenopausal women with ER-positive, HER2-negative disease with 1-3 positive lymph nodes (N1), and a Recurrence Score® (RS) of ≤ 25. Postmenopausal women with similar characteristics did not benefit from adjuvant chemotherapy. We examine the clinical and economic impact of Oncotype DX® testing on treatment decisions in patients with N1 disease in Ireland using real world data. METHODS: From March 2011 to October 2022, a retrospective, cross-sectional observational study was performed of patients with ER-positive, HER2-negative N1 breast cancer, who had Oncotype DX testing across 5 of Ireland's largest cancer centres. Patients were classified into low risk (RS 0-13), intermediate risk (RS 14-25) and high risk (RS > 25). Data were collected via electronic patient records. Information regarding costing was provided primarily by pre-published sources. RESULTS: A total of 828 N1 patients were included in this study. Post Oncotype DX testing, 480 patients (58%) were spared chemotherapy. Of the patients who had a change in chemotherapy recommendation based on Oncotype DX testing, 271 (56%), 205 (43%), 4 (1%) had a RS result of 0-13, 14-25 and > 25 respectively. Use of Oncotype DX testing was associated with a 58% reduction in chemotherapy administration overall. This resulted in estimated savings of over €6 million in treatment costs. Deducting the assay cost, estimated net savings of over €3.3 million were achieved. Changes in the ordering demographics of Oncotype DX tests were identified after RxPONDER data were presented, with increased testing in women ≥ 50 years and a reduction in proportion of tests ordered for women < 50 years. CONCLUSION: Between 2011 and 2022, assay use resulted in a 58% reduction in chemotherapy administration and net savings of over €3.3 million.

A retrospective evaluation of the NHS Health Check Programme in a multi-ethnic population.

BACKGROUND: The NHS Health Check Programme was introduced in 2009 to improve primary prevention of coronary heart disease, stroke, diabetes and chronic kidney disease; however, there has been debate regarding the impact. We present a retrospective evaluation of Leicester City Clinical Commissioning Group. METHODS: Data are reported on diagnosis of type 2 diabetes, hypertension, chronic kidney disease, high risk of type 2 diabetes and high risk of cardiovascular disease. Data on management following the Health Check are also reported. RESULTS: Over a 5-year period, 53 799 health checks were performed, 16 388 (30%) people were diagnosed with at least one condition when diagnosis of being at high risk of cardiovascular disease was defined as ≥20%. This figure increased to 43% when diagnosis of high cardiovascular risk ≥10% was included. Of the 3063 (5.7%) individuals diagnosed with type 2 diabetes, 54% were prescribed metformin and 26% were referred for structured education. Of the 5797 (10.8%) individuals diagnosed at high risk of cardiovascular disease (≥20%), 64% were prescribed statins. CONCLUSIONS: A high proportion of new cases of people at risk of cardiovascular disease were identified by the NHS Health Check Programme. Data suggest that this has translated into appropriate preventative measures.

Programmed intermittent epidural bolus regimen vs continuous epidural infusion: a retrospective study of motor block and obstetric outcomes using the Robson's Ten Group Classification System.

BACKGROUND: Use of a programmed intermittent epidural bolus (PIEB) regimen during labour is associated with several benefits over a continuous epidural infusion (CEI), including reduced local anaesthetic consumption and reduced risk of motor block. We hypothesise that the benefits of a PIEB regimen may vary according to the Robson Ten Group Classification System (TGCS). The aim of this study was to determine if introduction of a PIEB regimen was associated with reduced incidence of motor block. We also wished to examine changes in obstetric outcomes following PIEB introduction across the Robson TGCS. METHODS: This was a single-centre retrospective cohort study. Data were collected over two three-month periods before and after PIEB introduction. The primary outcome was the incidence of motor block. Maternal and obstetric outcomes across Robson Groups 1-4 were analysed. RESULTS: Introduction of PIEB was associated with reduced incidence of motor block (28.4% (95% CI 25.7% to 31.3%) vs 22.4%, (95% CI 19.9% to 25.2%), difference 5.9% (95% CI 1.0% to 21.1%), P=0.003), with no association with changes in rates of caesarean section, operative vaginal delivery or other obstetric outcomes. Use of a PIEB regimen was associated with reduced incidence of motor block in Robson Group 4a (20.3% (16.0%, 28.0%) vs 12.0%, (7.6%, 16.4%), difference 9.9% (95% CI -17.4% to -2.4%) P=0.009). There were no significant changes in other outcomes assessed across Robson TGCS. CONCLUSION: Introduction of PIEB for maintenance of labour analgesia was associated with reduced incidence of motor block in our institution compared with CEI. Presenting results according to Robson's TGCS in future studies may allow better elucidation of the impact of neuraxial analgesia on maternal and obstetric outcomes.

The efficacy and safety of bronchial thermoplasty in severe persistent asthma on extended follow-up.

BACKGROUND: Asthma is a common condition and there remains a subset of patients who are poorly controlled on maximal therapy. Bronchial thermoplasty (BT) is a bronchoscopic therapy using radiofrequency energy to reduce airway smooth muscle, which has been shown to improve asthma control although further evidence regarding long-term efficacy and safety is required. AIM: We aimed to demonstrate safety and efficacy of BT on extended follow-up. Our initial experience with this group was previously reported in 2016, where patients were shown to have a significant improvement in asthma control test (ACT) scores 1-year post-treatment. DESIGN: We carried out a retrospective observational study of seven patients who underwent BT between 2012 and 2013 in an Irish severe asthma centre. The primary endpoint was change in ACT scores from baseline to present. METHODS: Seven patients underwent BT at a tertiary referral centre in Ireland. ACT scores and data on hospital admissions, exacerbations, maintenance corticosteroid requirements, rescue bronchodilator use and forced expiratory volume for 1 s (FEV1) prior to the procedure and on extended follow-up were collected. Mean follow-up was 49.42 months. RESULTS: A trend towards improvement was seen in median hospitalisations (respective values for median over 12 months 3, 1 P = 0.059) and ACT scores, from 9 to 13 (P = 0.249). Mean FEV1 was 1.68 l prior to treatment and 1.46 l 4 years post-treatment (P = 0.237). There was no mortality among the group. CONCLUSIONS: These data support the safety of BT and suggest extended efficacy.

Anaesthesia for phaeochromocytoma and sickle cell disease in pregnancy.

A 33-year-old woman (G(1)P(0)) presented to a maternity hospital at 36 weeks' gestation. She suffered from sickle cell disease with three acute crises in the previous five months of her pregnancy. She also had a phaeochromocytoma with inadequately controlled hypertension. This report describes the multi-disciplinary work-up and peri-operative management necessary to optimise her medical condition before caesarean section at 39 weeks' gestation and subsequent removal of a malignant phaeochromocytoma.

Prejunctional actions of N-ethyl-maleimide and phenoxybenzamine in rat vas deferens.

In studies of electrically evoked isometric contractions of rat vas deferens, N-ethyl-maleimide (30 microM) pretreatment significantly reduced the prejunctional inhibitory potencies of xylazine and 5-hydroxytryptamine but failed to affect the potency of the alpha 1-adrenoceptor agonist amidephrine. Phenoxybenzamine (1 microM) or N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) (10 microM) produced significant shifts in the potency of xylazine and significantly reduced the maximum inhibition, but the combination of phenoxybenzamine or EEDQ and N-ethyl-maleimide (30 microM) produced no further alteration in the effects of xylazine. In displacement studies, N-ethyl-maleimide displaced the binding of [3H]MK 912 ((2S,12bS)1',3'-dimethylspiro- (1,3,4,5',6,6',7,12b-octahydro-2H-benzo[b]furo[2,3-a]quinazoline)- 2,4'- pyrimidin-2'one) to rat renal cortex membranes with a Ki of 466 +/- 133 microM (n = 5), and so does not bind to alpha 2-adrenoceptors in the concentration range in which it affects prejunctional receptor mediated responses. This may suggest that N-ethyl-maleimide has actions other than inactivation of G-proteins or that the irreversible alpha 2-adrenoceptor antagonists phenoxybenzamine and EEDQ inactivate G-proteins sensitive to N-ethyl-maleimide in concentrations at which they bind to alpha 2-adrenoceptors.

The effect of perioperative beta-blockade on the pulmonary function of patients undergoing major arterial surgery.

INTRODUCTION: Concern about the potential detrimental side-effects of beta-blockade on pulmonary function often dissuades against their perioperative use in patients undergoing major arterial surgery (especially in those with chronic obstructive pulmonary disease (COPD)). In this study we aimed to establish prospectively the clinical relevance of these concerns. METHODS: After ethics committee approval and individual informed consent, the pulmonary function of twenty patients (mean age 68.7 years (range 43-82), 11 males) scheduled to undergo non-emergency major vascular surgery was studied by recording symptoms and spirometry before and after institution of effective beta-blockade. Fifteen patients (75%) had significant smoking histories (mean pack years/patient=50), while 12 (60%) had COPD. RESULTS: All patients tolerated effective beta-blockade satisfactorily without developing either subjective deterioration in symptoms or significant change on spirometry. The mean change in FEV1 following adequate beta-blockade was 0.05+/-0.24 liters (95% CI -0.06 to +1.61), p=0.35, giving a mean percentage change of 3.18%+/-11.66 (95% CI -2.26 to 8.62). CONCLUSIONS: Previously held concerns about worsening pulmonary function through the short-term use of beta-blockers should not dissuade their perioperative usage in patients with peripheral vascular disease. Furthermore, the accuracy of pulmonary function tests in preoperative assessment and risk stratification also appears unaffected by this therapy.

A pregnant woman with previous anaphylactic reaction to local anesthetics: a case report.

A 43-year-old woman with a history of lidocaine allergy required dermatologic surgery during pregnancy. To accomplish this without the use of general anesthesia, intradermal allergy testing was performed. This information enabled appropriate anesthetic care for a tissue biopsy at 29 weeks' gestation and subsequent labor analgesia and obstetric management at term.

Adrenal failure in the critically ill.

Three critically ill patients suffered multiple organ failure secondary to sepsis. Despite adequate supportive therapy and appropriate antibiotic cover, they failed to improve and required inappropriate inotrope support. They had not been treated with steroids or other drugs known to suppress adrenal function. Adrenal insufficiency was suspected. A random cortisol concentration and a short synacthen test demonstrated concentrations below the range expected in all three cases. High-dose steroid therapy was commenced with marked improvement in the short-term. However, in each case sepsis eventually caused death.

Sexism and medical care in a jail setting.

As part of a study on health conditions in women's prisons, comparisons were made of outcomes of clinic visits by male and female prisoners in New York City jails on Rikers' Island. Despite a basic similarity in health problems, significant differences were found between the sexes in terms of number of clinicians with whom they had interaction, access to a physician, and access to treatment of any sort. Men were four times as likely to be seen by a physician and twice as likely to receive treatment. A general pattern of sex bias was determined to exist. Staffing patterns, clinic access and diagnostic bias are examined as possible explanations for the differences in care.

Identification of polysubstance abuse in the parturient.

Illicit drugs are widely used by inner city patients and their use by pregnant women has increased in recent years. The aim of this study was to determine the prevalence of polysubstance abuse among parturients at our institution who received no prenatal care ('unbooked') and to determine the accuracy of the Ontrak TesTcup an in vitro immunodiagnostic assay. We prospectively analysed urine from 50 'unbooked' parturients and found that 26 (52%) tested positive for cocaine. Of these, six patients (23%) were also positive for morphine. All TesTcup results were confirmed by the hospital laboratory using alternate chemical methods. When comparing TesTcup to the hospital laboratory, there were no false positive or negative results. Given the high frequency of concomitant opioid abuse in cocaine-abusing parturients, anyone suspected of cocaine abuse should be tested for other illicit substances. TesTcup is a clinically accurate test that allows the rapid assessment of several drugs of abuse, which may impact on anaesthetic care.

Limits on the cosmological abundance of supermassive compact objects from a search for multiple imaging in compact radio sources.

Using very long baseline interferometry we have searched a sample of 300 compact radio sources for examples of multiple imaging produced by gravitational lensing; no multiple images were found with separations in the angular range 1.5--50 milliarcsec. This null result allows us to place a limit on the cosmological abundance of intergalactic supermassive compact objects in the mass range approximately 10(6)M( middle dot in circle) to approximately 10(8)M( middle dot in circle); such objects cannot make up more than approximately 1% of the closure density ( 95% confidence). A uniformly distributed population of supermassive black holes forming soon after the big bang does not, therefore, contribute significantly to the dark matter content of the Universe.

Constraints on cosmological parameters from the analysis of the cosmic lens all sky survey radio-selected gravitational lens statistics.

We derive constraints on cosmological parameters and the properties of the lensing galaxies from gravitational lens statistics based on the final Cosmic Lens All Sky Survey data. For a flat universe with a classical cosmological constant, we find that the present matter fraction of the critical density is Omega(m)=0.31(+0.27)(-0.14) (68%)+0.12-0.10 (syst). For a flat universe with a constant equation of state for dark energy w=p(x)(pressure)/rho(x)(energy density), we find w<-0.55(+0.18)(-0.11) (68%).