Multicomponent superconducting order parameter in UTe2.

An unconventional superconducting state was recently discovered in uranium ditelluride (UTe2), in which spin-triplet superconductivity emerges from the paramagnetic normal state of a heavy-fermion material. The coexistence of magnetic fluctuations and superconductivity, together with the crystal structure of this material, suggests that a distinctive set of symmetries, magnetic properties, and topology underlie the superconducting state. Here, we report observations of a nonzero polar Kerr effect and of two transitions in the specific heat upon entering the superconducting state, which together suggest that the superconductivity in UTe2 is characterized by a two-component order parameter that breaks time-reversal symmetry. These data place constraints on the symmetries of the order parameter and inform the discussion on the presence of topological superconductivity in UTe2.

Association between imaging response and survival following neoadjuvant chemotherapy in patients with resectable colorectal liver metastases: A cohort study.

BACKGROUND: The association between the imaging response (structural or metabolic) to neoadjuvant chemotherapy (neoCT) before colorectal liver metastasis (CRLM) and survival is unclear. METHOD: A total of 201 patients underwent their first CRLM resection. A total of 94 (47%) patients were treated with neoCT. A multivariable, Cox proportional hazard regression analysis was performed to compare overall survival (OS) and progression-free survival (PFS) between response groups. RESULTS: Multivariable regression analysis of the CT/MRI (n = 94) group showed no difference in survival (OS and PFS) in patients who had stable disease/partial response (SD/PR) or complete response (CR) versus patients who had progressive disease (PD) (OS: HR, 0.36 (95% CI: 0.11-1.19) p = .094, HR, 0.78 (95% CI: 0.13-4.50) p = .780, respectively), (PFS: HR, 0.70 (95% CI: 0.36-1.35) p = .284, HR, 0.51 (0.18-1.45) p = .203, respectively). In the FDG-PET group (n = 60) there was no difference in the hazard of death for patients with SD/PR or CR versus patients with PD for OS or PFS except for the PFS in the small CR subgroup (OS: HR, 0.75 (95% CI: 0.11-4.88) p = .759, HR, 1.21 (95% CI: 0.15-9.43) p = .857), (PFS: HR, 0.34% (95% CI: 0.09-1.22), p = .097, HR, 0.17 (95% CI: 0.04-0.62) p = .008, respectively). CONCLUSION: There was no convincing evidence of association between imaging response to neoCT and survival following CRLM resection.

Elective colectomy after acute diverticulitis: an international comparison.

AIM: Routine elective colectomy after acute diverticulitis is not recommended, yet significant numbers are still being performed. Amidst global concern over the rising costs of surgery and the value of healthcare, acute diverticulitis is a disease that is amenable to optimization of strategies for operative intervention. We aim to compare rates of elective colectomy after acute diverticulitis in the USA, England and Australia. METHOD: Index unplanned admissions for acute diverticulitis were found from an international administrative dataset between 2008 and 2012 for hospitals in the USA, England and Australia. Recurrent unplanned admissions for acute diverticulitis and any subsequent elective admissions for colectomy were found between 2008 and 2014 to allow a minimum 2-year follow-up period. The primary outcome measured was elective colectomy rate. Secondary outcomes included rates of emergency operative intervention and recurrence. Multivariable analysis was performed to control for patient and disease factors. RESULTS: There were 7842 index unplanned admissions for acute diverticulitis over 4 years in selected hospitals from the USA, England and Australia. The elective colectomy rates were 13%, 5.4% and 3.4% for the USA, England and Australia, respectively. The propensity for elective colectomy was higher in the USA (OR 4.2, P < 0.001) and England (OR 1.8, P < 0.001) than in Australia. The recurrence rate in all patients with acute diverticulitis was 10% across the countries. CONCLUSION: There is a higher propensity for elective colectomy after acute diverticulitis in the USA than in England and Australia. This highlights the possibilities for a less aggressive surgical approach to reduce resource utilization, but prospective analysis of information on quality of life is required to support this.

Outcomes in emergency general surgery following the introduction of a consultant-led unit.

BACKGROUND: Patients presenting with emergency surgical conditions place significant demands on healthcare services globally. The need to improve emergency surgical care has led to establishment of consultant-led emergency surgery units. The aim of this study was to determine the effect of a changed model of service on outcomes. METHODS: A retrospective observational study of all consecutive emergency general surgical admissions in 2009-2012 was performed. A 2-year time frame before and after the establishment of the emergency general surgery (EGS) service was used to determine the number of admissions and operations, emergency department and hospital length of stay, as well as complication rates. RESULTS: The study included 7233 acute admissions. The EGS service managed 4468 patients (61·6 per cent increase) and performed 1804 operations (41·0 per cent increase). The most common diagnoses during the EGS period included acute appendicitis (532, 11·9 per cent), biliary disease (361, 8·1 per cent) and abdominal pain (561, 12·6 per cent). Appendicectomy (536, 29·7 per cent), cholecystectomy (239, 13·2 per cent) and laparotomy (226, 12·5 per cent) were the most commonly performed procedures. In the EGS period, time in the emergency department was reduced (from 8·0 to 6·0 h; P < 0·001), as was length of hospital stay (from 3·0 to 2·0 days; P < 0·001). The number of complications was reduced by 46·8 per cent, from 172 (6·2 per cent) to 147 (3·3 per cent) (P < 0·001), with a 53 per cent reduction in the number of deaths in the EGS period, from 29 (16·9 per cent) to seven (8 per cent) (P = 0·039). CONCLUSION: The establishment of a consultant-led emergency surgical service has been associated with improved provision of care, resulting in timely management and improved clinical outcomes.

Effect of the introduction of an emergency general surgery service on outcomes from appendicectomy.

BACKGROUND: Appendicectomy is a common general surgical emergency procedure and may be used as a surrogate marker to evaluate quality in surgical management. The aim of this study was to assess the outcomes of appendicectomy before and after the introduction of a consultant-led emergency general surgery (EGS) service at a large metropolitan tertiary referral centre. METHODS: A retrospective historical control study was performed that included all adult patients undergoing appendicectomy during two 18-month periods, before and after the introduction of the EGS service. Data collected included patient demographics, use of radiological investigations, time to surgery, length of hospital stay and histopathology findings. Outcome measures were time to surgery, hospital length of stay, use of radiological investigations, negative appendicectomy rate and perforation rate. RESULTS: A total of 675 patients were identified of whom 276 had an appendicectomy before the EGS service was introduced (2008-2009) and 399 after its introduction (2011-2012). The EGS service resulted in an increase in time to surgery (15 versus 18 h; P < 0.001) with no increase in length of hospital stay (3 days for both periods; P = 0.424). An increase in the rate of appendicectomies performed within office hours was seen (54.3 versus 64.4 per cent; P < 0.001), with no significant increase in negative appendicectomy (13.0 versus 15.8 per cent; P = 0.322) or perforation (8.3 versus 5.5 per cent; P = 0.149) rates. The use of preoperative computed tomography reduced from 38.4 to 26.6 per cent (P = 0.001). CONCLUSION: The introduction of a consultant-led EGS service resulted in a decrease in the use of computed tomography and a greater proportion of appendicectomies performed within office hours, with no increase in length of stay. Overall negative appendicectomy and perforation rates did not change.

Brachial plexopathy in laparoscopic-assisted rectal surgery: a case series.

BACKGROUND: Brachial plexopathy may be caused by malpositioning during surgery when the body's protective mechanism is lost under general anaesthesia. It is the second commonest nerve injury reported in the anaesthetized patient. The exact incidence in colorectal surgery is unclear but there have been numerous cases reported of brachial plexopathy as an adverse event following colorectal surgery. Although it is widely believed that these injuries are preventable by paying special attention to vulnerable areas during patient positioning and by careful intraoperative monitoring, it appears that nerve injury may still occur. METHODS: Patients with post-operative brachial plexopathy in our prospectively kept database were identified. The patient notes were reviewed and documented. RESULTS: In our series, five cases of brachial plexopathy were still observed despite careful precautions taken to prevent nerve injury. The proposed mechanism of nerve injury in our series is most likely due to nerve stretch. All symptoms resolved with the longest taking 7 months before resolution. During this period from 2005 to 2010 our unit performed 548 laparoscopic colorectal resections. The relative incidence of brachial plexopathy in our series is approximately 1 %. CONCLUSION: We recommend certain precautionary steps to follow, as well as predisposing and perioperative factors to be aware of when anticipating a laparoscopic colorectal procedure. These may all contribute to minimising brachial plexopathy which most likely is under-reported in laparoscopic colorectal surgery but is a preventable morbidity to the patient.

Recurrent Transmission of a 17q12 Microdeletion and a Variable Clinical Spectrum.

The relatively rare proximal microdeletion of 17q12 (including deletion of the HNF1B gene) is associated with the renal cysts and diabetes syndrome. Recent reports have suggested that there may also be an association between this microdeletion and learning difficulties/autism. This case report describes one of only a few reported families segregating the 17q12 microdeletion, but which highlights the nonpenetrance and variable expressivity of multiple features of this condition.

Care of the migrant obstetric population.

Care of pregnant migrants is a considerable challenge for all health care workers and health systems. Maternal mortality and serious morbidity are both greatly increased among migrants in western countries, particularly in Africans and asylum seekers. While in many instances, migrants are healthier than native populations and have better perinatal outcomes, this is inconsistent and poorer outcomes are described in many groups. The causes of suboptimal outcomes are numerous and are strongly influenced by the health-seeking behaviour of the parturients. Accordingly, improvement in outcome requires a multifaceted approach with a focus on early access to antenatal services and enhanced medical screening and surveillance for detection and optimisation of comorbid conditions. Provision and/or acceptance of analgesia in labour have not been well researched but existing data are sufficient to suggest that some migrant groups do not receive equivalent pain relief during labour. Provision of information and translation services are important components in improvement of standards of care.

Chromosome microarray analysis in a clinical environment: new perspective and new challenge.

The analysis of the human genome has largely been undertaken in a research environment, but recent developments in technology and associated workflow have allowed diagnostic laboratories to interrogate DNA at significantly improved levels of resolution. Principally, whole genome-based analysis of copy number changes using microarrays has led to this method replacing conventional karyotyping as a routine diagnostic workhorse. The resolution offered by microarrays is an improvement of at least an order of magnitude compared to karyotyping, but it comes at a cost in terms of the time spent in data interpretation. Overall, however, the die has been cast and cytogeneticists need to become familiar with the tools use by molecular geneticists and bioinformaticists. The following review provides a brief background to array technology, but uses a series of case studies to illustrate the usefulness and challenges of interpreting array data.

Newborn screening for mucopolysaccharidoses: opinions of patients and their families.

We have conducted a study to assess the opinions of parents of individuals with mucopolysaccharidoses (MPS) and adults with MPS regarding newborn screening (NBS) for this condition, as testing is now technically possible. A questionnaire including a number of hypothetical clinical scenarios about NBS for MPS was distributed to members of MPS support groups from United States and Australia. Questionnaires were returned by 249 members of the US (40% response) and Australian (38% response) support groups. Eleven respondents were adults with MPS and the rest were parents of individuals with MPS. Eighty-six percent of respondents indicated that they would have wanted NBS for their own children. Ninety-seven percent supported the use of NBS for MPS in situations where early treatment that favorably impacts on disease outcome is available, 87% supported NBS when a severe form of MPS was diagnosed, but no treatment is available that improves the long-term outcome and 84% supported NBS for mild MPS where no disease-modifying treatment is available. The most common reason cited in support of NBS was that NBS could avoid a delay in diagnosis and the accompanying distress that delayed diagnosis created. This study has identified strong support for the introduction of NBS for MPS from this group. Psychosocial benefits of screening may outweigh potential harms.

The anticancer drug mithramycin A sensitises tumour cells to apoptosis induced by tumour necrosis factor (TNF).

In this report we show that mithramycin considerably increases the direct cytotoxic effect of tumour necrosis factor (TNF) on tumour cells in vitro. Sensitisation to TNF-induced apoptosis was prevented by the broad caspase inhibitor zVAD-fmk, whereas overexpression of Bcl-2 had no effect. Mithramycin also potentiated cell death induced by Fas agonistic antibodies. In contrast, mithramycin reduced the percentage of cells undergoing apoptosis due to factor withdrawal. TNF-induced activation of NF-kappaB (NF-kappaB)-dependent gene expression was not modulated by mithramycin treatment. Concomitantly with the increased sensitivity, the protein level of the short-spliced cFLIP variant was downregulated. These results indicate that mithramycin enhances TNF-induced cell death in an NF-kappaB-independent manner, and suggest that the Fas-associated death domain protein plays a crucial role in the TNF-sensitising effect of mithramycin.

Microarray analysis of eosinophils reveals a number of candidate survival and apoptosis genes.

The increase in eosinophils at the site of antigen challenge has been used as evidence to suggest that this cell type plays a role in the pathophysiology of asthma. Aberrant production of several different cytokines, particularly interleukin (IL)-5, has been shown to result in eosinophilia. IL-5 influences the development and maturation of eosinophils in a number of different ways. Of note is the ability of IL-5 to act as a survival factor for eosinophils specifically inhibiting apoptosis. The precise mechanism by which IL-5 exerts its effect remains obscure. We used microarray technologies to investigate the changes in the messenger RNA expression profile of eosinophils after treatment with IL-5. Using the Affymetrix Hu6800 chip, a total of 80 genes were observed to be regulated by 2-fold or greater. Many of the genes previously identified as regulated by IL-5 were regulated in our microarray experiments. Of the 73 genes found to be upregulated, many were shown to play a role in adhesion, migration, activation, or survival of eosinophils or hematopoietic cells, whereas the function of others was unknown. To facilitate the identification of genes that govern the apoptosis and survivability of eosinophils, we used an alternative cellular model, TF1.8 cells, whose survival was also dependent on IL-5. Comparison of these models identified four genes, Pim-1, DSP-5 (hVH3, B23), CD24, and SLP-76, whose regulation was similarly coordinated in both systems. Identification of Pim-1 and SLP-76 as regulated by IL-5 led us to suggest a direct role for these proteins in the IL-5 signaling pathway in eosinophils. The tissue distribution of these genes demonstrated that Pim-1 and SLP-76 were relatively restricted to the eosinophil compared with their expression in brain, bone marrow, kidney, liver, and lung. By contrast, DSP-5 and CD24 were confirmed as ubiquitous in their expression by microarray.

Analysis of cellular adhesion by microarray expression profiling.

Microarrays of oligonucleotides or cDNAs can be used to establish the expression profiles of numerous genes in a single experiment. We have established a microarray platform to identify genes in a number of different pathological conditions, particularly those with an inflammation component. This platform utilised the output of an eosinophil sequencing project in which 1069 sequences were identified that were not represented in the public domain. An eosinophil model cell line, AML14.3D10, was used to investigate cell adhesion. The transcription profile of adhered and non-adhered AML 14.3D10 cells was shown to be both technically and biologically reproducible. A number of genes were found differentially expressed in the adhered vs. non-adhered populations. In the adhered population, the expression of these genes was restricted compared to brain, lung, kidney and especially bone marrow. However, the differentially regulated genes were not among those genes most restricted to eosinophils. We discuss the implications of transcription profiling on gene annotation and its potential utility for the identification of targets for drug intervention.

Differentiating embryonal stem cells are a rich source of haemopoietic gene products and suggest erythroid preconditioning of primitive haemopoietic stem cells.

The difficulties associated with studying molecular mechanisms important in hemopoietic stem cell (HSC) function such as the problems of purifying homogeneous stem cell populations, have prompted us to adapt the murine ES cell system as an in vitro model of HSC generation and function. We now report that careful analysis of the time course of HSC generation in differentiating ES cells allows them to be used as a source of known and novel hemopoietic gene products. We have generated a subtracted library using cDNA from ES cells collected just prior to and just following the emergence of HSCs. Analysis of this library shows it to be a rich source of known hemopoietic and hemopoietic related gene products with 44% of identifiable cDNAs falling into these camps. We have demonstrated the value of this system as a source of novel genes of relevance to HSC function by characterizing a novel membrane protein encoding cDNA that is preferentially expressed in primitive hemopoietic cells. Intriguingly, further analysis of the known components of the subtracted library is suggestive of erythroid preconditioning of the ES cell-derived HSC. We have used dot-blot and in situ analysis to indicate that this erythroid preconditioning is probably restricted to primitive but not definitive HSC.

Epidemiological studies of large resistance plasmids in Haemophilus.

The distribution of large conjugative Haemophilus influenzae plasmids in the nasopharyngeal haemophili of a group of people and in a large collection of 541 H. influenzae type b (Hib) isolates was studied. A newly developed PCR-based assay was used to detect the plasmids. The target sequences were chosen from sequence analysis of part of p1056, a large multiresistance plasmid isolated from a clinical Hib isolate, 1056. Fifty-nine per cent of people were found to carry beta-lactamase-positive (beta-lac(+)), ampicillin-resistant (ampR) haemophili with detectable plasmid sequences. Of these, 83% were in Haemophilus parainfluenzae and 17% were in H. influenzae. In the collection of 541 Hib, antibiotic resistance [beta-lac(+)ampR, beta-lac(+)ampR plus tetracycline resistance (tetR) or tetR] was highly correlated with large plasmids. It was found that 2.3% of the isolates contained large cryptic plasmids (i.e. these isolates were susceptible to antibiotics). The distribution of plasmids between invasive and carried Hib did not differ significantly (25 of 245 and 23 of 276, respectively). Isolates with large plasmids occur at high frequency in the nasopharynx of the normal human population and consist of two populations in Hib, one associated with specific antibiotic resistance traits and the other cryptic. These plasmids do not appear to influence the invasiveness of Hib.

Human vascular smooth muscle cells express receptors for CC chemokines.

Arteriosclerotic lesions are characterized by the accumulation of T lymphocytes and monocytes and the proliferation of intimal smooth muscle cells. Expression of the chemokine monocyte chemoattractant protein-1 (MCP- 1) has been observed in arteriosclerotic plaques and has been proposed to mediate the transendothelial migration of mononuclear cells. More recently, MCP-1 has been proposed to affect the proliferation and migration of vascular smooth muscle cells (VSMCs). We have used reverse transcription-polymerase chain reaction (RT-PCR) to investigate chemokine mRNA expression in human arteriosclerotic lesions obtained from surgical biopsy of diseased vascular tissue and show, in addition to MCP-1, expression of the chemokine macrophage inflammatory protein-1alpha (MIP-1alpha) at higher levels than in "normal" aortic tissue. We have also used RT-PCR to characterize the expression of known chemokine receptors by primary human VSMCs. Messenger RNA for the MIP-1alpha/RANTES receptor, CCR-1, and the MCP-1/MCP-3 receptor, CCR-2, was expressed by unstimulated VSMCs grown under serum-free culture conditions for 24 hours. The receptors CCR-3, CCR-4, CCR-5, CXCR-1, and CXCR-2 were not expressed by VSMCs. The presence of functionally coupled receptors for MIP-1alpha on VSMCs was demonstrated by specific binding of biotinylated MIP-1alpha and increases in intracellular Ca2+ levels after exposure to this chemokine. Taken together, these results suggest that chemokines are likely to be involved in arteriosclerosis and may play a role in modulating the function of VSMCs in vivo.

Malignant melanoma of the toenail apparatus.

BACKGROUND: Subungual melanoma is an unpredictable and aggressive tumor with a propensity to metastasize widely. Because it is an uncommon condition, statistical analysis of its behavior patterns is difficult, factors that determine its prognosis are unclear, and optimal management is ill defined. STUDY DESIGN: A detailed review was undertaken of the clinical and histologic features of subungual melanomas arising from the toenail apparatus in 25 patients treated at the Sydney Melanoma Unit during a 40-year period. Treatment and outcomes were analyzed. RESULTS: Most of the lesions were situated on the great toe in elderly patients of Anglo-Celtic extraction. Antecedent trauma to the toe was frequently reported and delayed diagnosis was usual. There was great variation in Breslow thickness and Clark's level, but these indices were found to have less prognostic significance than for other forms of cutaneous melanoma. CONCLUSIONS: The treatment of subungual melanoma of the toenail apparatus is primarily surgical, by amputation at or proximal to the metatarsophalangeal joint. Even if there is no clinical evidence of metastatic disease in regional lymph nodes, radical node dissection is desirable. The condition is most appropriately managed at a specialist center.

Managing Staphylococcus aureus catheter infection in continuous ambulatory peritoneal dialysis patients.

A case of Staphylococcus aureus catheter infection in a patient on peritoneal dialysis is presented and discussed by nephrologists, a social worker, a nurse specializing in the care of peritoneal dialysis patients, and the patient involved. The focus of the multidisciplinary case discussion concerns the management of S aureus catheter infections, including catheter removal, psychosocial issues and the patient's response to the need for catheter removal, the risk factors and prevention of S aureus catheter infections in peritoneal dialysis patients, and exit site care practices.

Factors confounding blockade of cardiac afferents by intrapericardial procaine in conscious rabbits.

Intrapericardial procaine has been used by several groups to block cardiac afferent nerves to study effects of cardiogenic reflexes. In eight conscious rabbits, procaine (17-113 mg ipc; median 32) blocked cardiac efferents. Procaine (17-113 mg ipc; median 39) abolished the reflex depressor effects of the cardiac C-fiber excitant 1-phenylbiguanide (PBG), and in four of eight rabbits prevented the hypotensive phase 2 of acute central hypovolemia, which has been attributed to a signal from the heart. However, in three of the rabbits respiratory incoordination and blood gas abnormalities developed. In another study of four rabbits, procaine (165-335 mg ipc; median 235) invariably caused phrenic nerve blockade and underventilation. In three rabbits, after intrapericardial (250 mg) or subcutaneous (50 mg) procaine, plasma procaine levels rose to 9.4 and 4.8 micrograms/ml, respectively. During intravenous infusion of procaine, the PBG chemoreflex was abolished at plasma levels > 3.1 micrograms/ml, and phase 2 of acute hypovolemia at levels > or = 4.3 micrograms/ml. There is a narrow margin between a dose of intrapericardial procaine that blocks cardiac nerves and one that can produce confounding effects from phrenic nerve blockade or absorption into the bloodstream.

Does the haemodynamic response to acute central hypovolaemia depend on the rate of fall of cardiac output?

1. In published studies of the effects of acute blood loss in conscious rabbits, the rates of haemorrhage have ranged for 3-9% of blood volume/min. This is potentially a confounding factor when it comes to comparing the results of different studies. We have therefore tested whether the haemodynamic response to acute central hypovolaemia depends on the rate of fall of cardiac output. 2. Cardiac output in six conscious rabbits was reduced by 4, 8 and 12% of baseline levels per min by gradual inflation of a cuff around the thoracic inferior vena cava. These rates correspond approximately to blood loss at rates of 3, 6 and 9% of blood volume/min. 3. The haemodynamic responses were biphasic. In Phase I (compensatory) there was progressive systemic vasoconstriction and tachycardia, and only a small fall in blood pressure. In Phase II (decompensatory), systemic vasoconstriction failed abruptly, arterial pressure plummeted and heart rate declined. 4. We could detect no effect of rate of fall of cardiac output on the pattern of the haemodynamic responses in either Phase I or Phase II. 5. We conclude that the rate of blood loss in different studies of haemorrhage in conscious rabbits, within the range 3 to 9 per cent of blood volume per minute, need not be regarded as a confounding factor when it comes to interpreting the results. It is likely that this conclusion can be generalized to studies of haemorrhage in other mammalian species.