Heterogeneous melting near the Thwaites Glacier grounding line.

Thwaites Glacier represents 15% of the ice discharge from the West Antarctic Ice Sheet and influences a wider catchment1-3. Because it is grounded below sea level4,5, Thwaites Glacier is thought to be susceptible to runaway retreat triggered at the grounding line (GL) at which the glacier reaches the ocean6,7. Recent ice-flow acceleration2,8 and retreat of the ice front8-10 and GL11,12 indicate that ice loss will continue. The relative impacts of mechanisms underlying recent retreat are however uncertain. Here we show sustained GL retreat from at least 2011 to 2020 and resolve mechanisms of ice-shelf melt at the submetre scale. Our conclusions are based on observations of the Thwaites Eastern Ice Shelf (TEIS) from an underwater vehicle, extending from the GL to 3 km oceanward and from the ice-ocean interface to the sea floor. These observations show a rough ice base above a sea floor sloping upward towards the GL and an ocean cavity in which the warmest water exceeds 2 °C above freezing. Data closest to the ice base show that enhanced melting occurs along sloped surfaces that initiate near the GL and evolve into steep-sided terraces. This pronounced melting along steep ice faces, including in crevasses, produces stratification that suppresses melt along flat interfaces. These data imply that slope-dependent melting sculpts the ice base and acts as an important response to ocean warming.

Reduced hip bone mineral density is associated with high levels of calciprotein particles in patients with Fabry disease.

Calciprotein particles (CPP) are nanoscale mineralo-protein aggregates that help stabilize excess mineral in the circulation. We examined the relationship between CPP and bone mineral density in Fabry disease patients. We found an inverse correlation with total hip and femoral neck density, but none with lumbar spine. PURPOSE: Calciprotein particles (CPP) are colloidal mineral-protein complexes made up primarily of the circulating glycoprotein fetuin-A, calcium, and phosphate. They form in extracellular fluid and facilitate the stabilization, transport, and clearance of excess minerals from the circulation. While most are monomers, they also exist in larger primary (CPP-I) and secondary (CPP-II) form, both of which are reported to be raised in pathological states. This study sought to investigate CPP levels in the serum of patients with Fabry disease, an X-linked systemic lysosomal storage disorder that is associated with generalized inflammation and low bone mineral density (BMD). METHODS: We compared serum CPP-I and CPP-II levels in 59 patients with Fabry disease (37 female) with levels in an age-matched healthy adult cohort (n=28) and evaluated their association with BMD and biochemical data obtained from routine clinical review. RESULTS: CPP-I and CPP-II levels were higher in male Fabry disease patients than female sufferers as well as their corresponding sex- and age-matched controls. CPP-II levels were inversely correlated with BMD at the total hip and femoral neck, but not the lumbar spine. Regression analyses revealed that these associations were independent of common determinants of BMD, but at the femoral neck, a significant association was only found in female patients. CONCLUSION: Low hip BMD was associated with high CPP-II in patients with Fabry disease, but further work is needed to investigate the relevance of sex-related differences and to establish whether CPP measurement may aid assessment of bone disease in this setting.

Giri-nya-la-nha (talk together) to explore acceptability of targeted smoking cessation resources with Australian Aboriginal women.

OBJECTIVES: To engage with health providers and Aboriginal women to understand what educational resources they want and need to support quit smoking attempts during pregnancy in order to develop a comprehensive evidence-based intervention. STUDY DESIGN: Resources were developed in partnership with Aboriginal people, communities and academics with the aim to be inclusive of diverse communities. We then recruited Aboriginal women of various ages for yarning circles (focus groups) held in three Australian states to explore the acceptability of the resources and seeking further guidance as to the needs of Aboriginal women to support smoking cessation during pregnancy. METHODS: Yarning circles were recorded and transcribed, and data were analysed independently by two researchers. Responses were coded using predetermined themes and further general inductive analysis for emergent themes. RESULTS: Twenty-four Aboriginal women reflected on the resources they included: one pregnant woman, 15 mothers and eight elders. Predetermined themes of attraction, comprehension, cultural acceptability, graphics and layout, persuasion and self-efficacy were explored. Women suggested the following: resources need to be visually attractive and interactive to enhance self-efficacy; additional scientific content on health consequences of smoking and combining with non-pharmacological approaches to quitting. CONCLUSION: Indigenous peoples prefer culturally targeted messages. However, developing effective Aboriginal health promotion requires more than a 'culturally appropriate' adaptation of mainstream resources. Consideration needs to be given to the diversity of Aboriginal communities when developing effective, evidence-based interventions. Aboriginal women are calling for innovative and interactive resources that enhance self-efficacy; the use of videos to explain medical and informational brochure content is well received. Requests for non-pharmacological cessation options were reported in New South Wales and Queensland and should be further explored.

Safety and efficacy of a novel short occlusive regimen of imiquimod for selected non-melanotic skin lesions in renal transplant patients.

Australian patients remain at very high risk of non-melanotic skin cancer after renal transplantation. Surgical excision offers a cure but destroys tissue and may jeopardise function and cosmesis. We report excellent safety and efficacy using topical imiquimod in a novel short intensive regimen in 10 renal transplant patients with superficial basal cell carcinomas, Bowen disease or actinic keratosis. Outcomes compare well to those reported with extended-use imiquimod protocols.

Single-dose rituximab in refractory lupus nephritis.

BACKGROUND: Off-label use of rituximab in lupus nephritis is reported to be beneficial. While the optimal dose is unknown, the regimen of four intravenous doses of 375 mg/m(2) is commonly employed, despite expense and potential side-effects. AIM: To investigate the response to single-dose rituximab, added to standard corticosteroids plus additional immunosuppressive agent, in refractory lupus nephritis. METHODS: Consecutive consenting patients with refractory lupus nephritis despite steroids plus either cyclophosphamide, mycophenolate or azathioprine were enrolled in this ethics-approved, open-label, prospective study. After baseline assessment, patients received one intravenous infusion of 375 mg/m(2) rituximab. Clinical, biochemical and serological (DsDNA, complement) responses to this dose were analysed. Complete renal response (CR) was defined as normalisation of creatinine, albumin, proteinuria and urinary RBCs and partial response (PR) as ≥50% improvement in at least one parameter, without deterioration in others. B-cell depletion was defined as peripheral CD19 lymphocyte count ≤0.05 × 10(9) /L. RESULTS: Fourteen patients were enrolled in the study. All were B-cell-depleted until 8 months post-dose. Eleven patients (79%) responded (2CR, 9PR) at a median time of 5 months, with a 6-month probability of renal response of 43%. Five patients (45%) relapsed at a median time of 17 months. DsDNA titres decreased in 69%. Side-effects were minimal. CONCLUSIONS: Single-dose rituximab is effective in relapsed/refractory lupus nephritis. Longevity of B-cell depletion with single-dose rituximab is similar to that of four doses with potentially fewer side-effects.

Adoptive T cell immunotherapy for treatment of ganciclovir-resistant cytomegalovirus disease in a renal transplant recipient.

Cytomegalovirus (CMV) is a significant cause of morbidity, mortality and graft loss in solid organ transplantation (SOT). Treatment options for ganciclovir-resistant CMV are limited. We describe a case of ganciclovir-resistant CMV disease in a renal transplant recipient manifested by thrombotic microangiopathy-associated glomerulopathy. Adoptive T cell immunotherapy using CMV-specific T cells from a donor bank was used as salvage therapy. This report is a proof-of-concept of the clinical and logistical feasibility of this therapy in SOT recipients.

Finding the fifth intercostal space for chest drain insertion: guidelines and ultrasound.

OBJECTIVES: International guidelines exist for chest drain insertion and recommend identifying the fifth intercostal space or above, around the midaxillary line. In a recent study, applying these guidelines in cadavers risked insertion in the 6th intercostal space or below in 80% of cases. However, there are limitations of cadaveric studies and this investigation uses ultrasound to determine the intercostal space identified when applying these guidelines in healthy adult volunteers. METHODS: On each side of the chest wall in 31 volunteers, the position for drain insertion was identified using the European Trauma Course method, Advanced Trauma Life Support (ATLS) method, British Thoracic Society's 'safe triangle' and the 'traditional' method of palpation. Ultrasound imaging was used to determine the relationship of the skin marks with the underlying intercostal spaces. RESULTS: Five methods were assessed on 60 sides. In contrast to the cadaveric study, 94% of skin marks lay over a safe intercostal space. However, the range of intercostal spaces found spanned the second to the seventh space. In 44% of women, the inferior boundary of the 'safe triangle' and the ATLS guidelines located the sixth intercostal space or below. CONCLUSIONS: Current guidelines often identify a safe site for chest drain insertion, although the same site is not reproducibly found. In addition, women appear to be at risk of subdiaphragmatic drain insertion when the nipple is used to identify the fifth intercostal space. Real-time ultrasonography can be used to confirm the intercostal space during this procedure, although a safe guideline is still needed for circumstances in which ultrasound is not possible.

Conserving large carnivores: dollars and fence.

Conservationists often advocate for landscape approaches to wildlife management while others argue for physical separation between protected species and human communities, but direct empirical comparisons of these alternatives are scarce. We relate African lion population densities and population trends to contrasting management practices across 42 sites in 11 countries. Lion populations in fenced reserves are significantly closer to their estimated carrying capacities than unfenced populations. Whereas fenced reserves can maintain lions at 80% of their potential densities on annual management budgets of $500 km(-2) , unfenced populations require budgets in excess of $2000 km(-2) to attain half their potential densities. Lions in fenced reserves are primarily limited by density dependence, but lions in unfenced reserves are highly sensitive to human population densities in surrounding communities, and unfenced populations are frequently subjected to density-independent factors. Nearly half the unfenced lion populations may decline to near extinction over the next 20-40 years.

A Phase 2 study of migalastat hydrochloride in females with Fabry disease: selection of population, safety and pharmacodynamic effects.

BACKGROUND: Fabry disease (FD) is a genetic disorder resulting from deficiency of the lysosomal enzyme α-galactosidase A (α-Gal A) which leads to globotriaosylceramide (GL-3) accumulation in multiple tissues. We report on the safety and pharmacodynamics of migalastat hydrochloride, an investigational pharmacological chaperone given orally every other day (QOD) to females with FD. METHODS: This was an open-label, uncontrolled, Phase 2 study of 12 weeks with extension to 48 weeks in nine females with FD. Doses of 50mg, 150 mg and 250 mg were given QOD. At multiple time points, α-Gal A activity and GL-3 levels were quantified in blood cells, kidney and skin. GL-3 levels were also evaluated through skin and renal histology. Each individual GLA mutation was retrospectively categorized as being amenable or not to migalastat HCl based on an in vitro α-Gal A transfection assay developed in human embryonic kidney (HEK)-293 cells. RESULTS: Migalastat HCl was generally well tolerated. Patients with amenable mutations seem to demonstrate greater pharmacodynamic response to migalastat HCl compared to patients with non-amenable mutations. The greatest declines in urine GL-3 were observed in the three patients with amenable GLA mutations that were treated with 150 or 250 mg migalastat HCl QOD. Additionally, these three patients all demonstrated decreases in GL-3 inclusions in kidney peri-tubular capillaries. CONCLUSIONS: Migalastat HCl is a candidate oral pharmacological chaperone that provides a potential novel genotype-specific treatment for FD. Treatment resulted in GL-3 substrate decrease in female patients with amenable GLA mutations. Phase 3 studies are ongoing.

Ethnicity and lupus nephritis: an Australian single centre study.

BACKGROUND: The clinical impression of Australian physicians is that systemic lupus erythematosus (SLE) is more prevalent and more severe in Asian patients than in their Caucasian counterparts. The presence and severity of lupus nephritis is a major determinant of prognosis in SLE, and largely determines disease impact. AIM: To analyse the relationships between ethnicity and the prevalence and severity of lupus nephritis (LN) in patients attending a tertiary referral centre (The Royal Melbourne Hospital (RMH)). METHODS: The ethnicity of all known patients with biopsy-proven LN was determined according to three definitions of ethnicity - ancestry, country of origin and primary language spoken. The prevalence of Asian ethnicity in the LN cohort was analysed across severity class, and was compared with the prevalences of Asian ethnicity in the general population within the hospital's geographic area, and with that in the relevant RMH cohorts of inpatients and outpatients, over the same time period. RESULTS: Within this single tertiary centre, Asian patients were disproportionately represented in both the systemic lupus erythematosus (SLE) and the LN patient groups, although the distribution of histological severity of LN was not significantly different from Caucasian patients. CONCLUSION: This study supports the common clinical impression that SLE is more common and more severe in the Asian-Australian population. Asian patients with SLE were more commonly diagnosed with LN. However, the spectrum of histological severity of LN was similar in Asian and Caucasian patients.

Ethanol tolerance in the rat is learned.

Rats were trained to walk on a treadmill to avoid foot shock. The animals developed tolerance for ethanol if given subsequent practice while ethanol intoxicated. Rats given equivalent doses of ethanol after practice did not develop tolerance, nor did saline-treated controls. These results challenge the hypothesis that mere repeated doses of ethanol are sufficient to induce tolerance. It seems that tolerance does not develop unless the response used to measure tolerance is performed while the subject is intoxicated.

Thrombotic thrombocytopenic purpura is associated with a high relapse rate after plasma exchange: a single-centre experience.

BACKGROUND: Thrombotic thrombocytopenic purpura (TTP) is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, renal and/or neurological dysfunction secondary to microvascular or macrovascular thrombosis. Despite advances in treatment, TTP remains a serious condition with significant morbidity and mortality. METHODS: We undertook an audit of patients with TTP over 14 years to assess remission, relapse, survival and factors predictive of outcome using current therapy based on plasma exchange with fresh-frozen plasma. RESULTS: Forty patients were identified between January 1992 and December 2005. Thirty-one (82%) achieved complete response (CR) to therapy using plasma exchange with fresh-frozen plasma (median 11 exchanges) and steroids. Twelve (37%) relapsed a median of 14 days following cessation of therapy, with multiple relapses occurring in two patients. TTP-related death occurred in four patients during their initial presentation and in two during subsequent relapse. Four patients were only partially responsive to first-line therapy. The absence of neurological features at presentation was the only factor predicting a sustained CR to first-line therapy (P = 0.027, log-rank analysis). The mean duration of inpatient treatment was 18 days (range 4-38 days) with 30% of patients requiring intensive care admission. Thirty-four per cent of patients acquired central venous line infection, with a median of two episodes of line sepsis per patient. CONCLUSION: Our results indicate the need for better treatments to reduce the high early relapse rate and significant mortality associated with current therapy.

Management of refractory lupus nephritis: challenges and solutions.

Refractory lupus nephritis, broadly defined as failure to attain clinical remission after appropriate induction immunosuppressive therapy, is associated with an increased risk of progression to end-stage kidney disease and mortality. This is a challenging issue in clinical practice, as modern induction therapy despite proven efficacy can still be associated with treatment failure. Moreover, newer therapies have failed in recent years to displace or even match existing protocols for effective induction of remission. Refractory disease is generally assessed on the basis of clinical parameters, which may be unreliable, and renal biopsy, which is often not performed in a standard or timely fashion. Persisting histological inflammation in 30%-50% of patients who have attained clinical remission highlights the disparity between clinical and immunological response to therapy. The lack of an international consensus regarding what constitutes refractory lupus nephritis compounds clinician indecision regarding optimal management for these patients. Moreover, non-adherence to prescribed therapy versus primary treatment failure can be challenging to discriminate, and the time point at which non-response becomes treatment failure is unclear. In this review, we assess the key published evidence for the treatment of refractory lupus nephritis and provide practical recommendations based around the use of adjunctive therapies. These agents include rituximab and calcineurin inhibitors, with evidence consisting largely of observational or uncontrolled studies, as well as some of the biologic therapies currently under investigation through prospective clinical trials. The poor prognosis of refractory lupus nephritis demands regular review of patient response and the flexibility to switch or augment therapy.

Physical Conditions of Fast Glacier Flow: 3. Seasonally-Evolving Ice Deformation on Store Glacier, West Greenland.

Temporal variations in ice sheet flow directly impact the internal structure within ice sheets through englacial deformation. Large-scale changes in the vertical stratigraphy within ice sheets have been previously conducted on centennial to millennial timescales; however, intra-annual changes in the morphology of internal layers have yet to be explored. Over a period of 2 years, we use autonomous phase-sensitive radio-echo sounding to track the daily displacement of internal layers on Store Glacier, West Greenland, to millimeter accuracy. At a site located ∼30 km from the calving terminus, where the ice is ∼600 m thick and flows at ∼700 m/a, we measure distinct seasonal variations in vertical velocities and vertical strain rates over a 2-year period. Prior to the melt season (March-June), we observe increasingly nonlinear englacial deformation with negative vertical strain rates (i.e., strain thinning) in the upper half of the ice column of approximately -0.03 a-1, whereas the ice below thickens under vertical strain reaching up to +0.16 a-1. Early in the melt season (June-July), vertical thinning gradually ceases as the glacier increasingly thickens. During late summer to midwinter (August-February), vertical thickening occurs linearly throughout the entire ice column, with strain rates averaging 0.016 a-1. We show that these complex variations are unrelated to topographic setting and localized basal slip and hypothesize that this seasonality is driven by far-field perturbations in the glacier's force balance, in this case generated by variations in basal hydrology near the glacier's terminus and propagated tens of kilometers upstream through transient basal lubrication longitudinal coupling.

Cardiovascular testing in Fabry disease: exercise capacity reduction, chronotropic incompetence and improved anaerobic threshold after enzyme replacement.

AIM: The aim of this study was to document exercise capacity and serial electrocardiogram and echocardiograph findings in a cohort of Australian patients with Fabry disease, in relation to their history of enzyme replacement therapy (ERT). BACKGROUND: Fabry disease has multifactorial effects on the cardiovascular system. Most previous studies have focused on electrocardiographic and echocardiographic parameters. Exercise capacity can be used as an integrated measure of cardiovascular function and allows the effects of treatment to be monitored. METHODS: A total of 38 patients (30 men and 8 women) with Fabry disease were monitored by 12-lead electrocardiograms every 6-12 months, and by annual standardized-protocol echocardiograms. Bicycle stress tests with VO(2) max measurement and once-only 6 minutes' walk tests were also carried out in subsets of patients whose general health status allowed testing. RESULTS: Seventy per cent of patients met electrocardiogram criteria for left ventricular hypertrophy. Left ventricular hypertrophy on echocardiograph was present in 64% of patients (80% of men). Exercise capacity was reduced in patients with Fabry disease compared with that predicted from normative population data. Mild improvement in anaerobic threshold was seen in the first year of ERT (14.1 +/- 3.0 to 15.8 +/- 3.0, P = 0.02), but no consistent further increase was seen beyond the first year. Most patients had resting bradycardia, with impaired ability to increase heart rate during exercise. Serial testing on ERT showed an improvement in anaerobic threshold but no significant change in VO(2) max. CONCLUSIONS: Male patients with Fabry disease were unable to attain predicted maximal heart rate on exercise or to achieve normal exercise levels. ERT was associated with a small improvement in anaerobic threshold over the first year.

Fabry disease: baseline medical characteristics of a cohort of 1765 males and females in the Fabry Registry.

The Fabry Registry is a global observational research platform established to define outcome data on the natural and treated course of this rare disorder. Participating physicians submit structured longitudinal data to a centralized, confidential database. This report describes the baseline demographic and clinical characteristics of the first 1765 patients (54% males (16% aged < 20 years) and 46% females (13% < 20 years)) enrolled in the Fabry Registry. The median ages at symptom onset and diagnosis were 9 and 23 years (males) and 13 and 32 years (females), respectively, indicating diagnostic delays in both sexes. Frequent presenting symptoms in males included neurological pain (62%), skin signs (31%), gastroenterological symptoms (19%), renal signs (unspecified) (17%), and ophthalmological signs (11%). First symptoms in females included neurological pain (41%), gastroenterological symptoms (13%), ophthalmological (12%), and skin signs (12%). For those patients reporting renal progression, the median age at occurrence was 38 years for both sexes, but onset of cerebrovascular and cardiovascular events was later in females (median 43 and 47 years, respectively) than in males (38 and 41 years, respectively). This paper demonstrates that in spite of the considerable burden of disease in both sexes that begins to manifest in childhood or adolescence, the recognition of the underlying diagnosis is delayed by 14 years in males and 19 years in females. The Fabry Registry provides data that can increase awareness of common symptoms in all age groups, as well as insight into treated and untreated disease course, leading to improved recognition and earlier treatment, and possibly to improved outcomes for affected individuals.

Anti-CD20 antibody in thrombotic thrombocytopenic purpura refractory to plasma exchange.

Thrombotic thrombocytopenic purpura is a rare condition characterized by microangiopathic haemolytic anaemia, thrombocytopenia, altered neurology, renal impairment and fever. While plasma exchange has reduced mortality from more than 90% to between 10 and 30%, a proportion of cases fail to respond. Rituximab may be efficacious in the management of refractory cases of thrombotic thrombocytopenic purpura. We present two cases in which rituximab was used with successful outcomes. Treatment resulted in resolution of severe clinical and haematological abnormalities in both patients. There has been no relapse after 16 months follow up. Our experience supports the use of rituximab in difficult cases of TTP. Ongoing evaluation of its use is in progress at our institution.