CO2 storage and release in the deep Southern Ocean on millennial to centennial timescales.

The cause of changes in atmospheric carbon dioxide (CO2) during the recent ice ages is yet to be fully explained. Most mechanisms for glacial-interglacial CO2 change have centred on carbon exchange with the deep ocean, owing to its large size and relatively rapid exchange with the atmosphere1. The Southern Ocean is thought to have a key role in this exchange, as much of the deep ocean is ventilated to the atmosphere in this region2. However, it is difficult to reconstruct changes in deep Southern Ocean carbon storage, so few direct tests of this hypothesis have been carried out. Here we present deep-sea coral boron isotope data that track the pH-and thus the CO2 chemistry-of the deep Southern Ocean over the past forty thousand years. At sites closest to the Antarctic continental margin, and most influenced by the deep southern waters that form the ocean's lower overturning cell, we find a close relationship between ocean pH and atmospheric CO2: during intervals of low CO2, ocean pH is low, reflecting enhanced ocean carbon storage; and during intervals of rising CO2, ocean pH rises, reflecting loss of carbon from the ocean to the atmosphere. Correspondingly, at shallower sites we find rapid (millennial- to centennial-scale) decreases in pH during abrupt increases in CO2, reflecting the rapid transfer of carbon from the deep ocean to the upper ocean and atmosphere. Our findings confirm the importance of the deep Southern Ocean in ice-age CO2 change, and show that deep-ocean CO2 release can occur as a dynamic feedback to rapid climate change on centennial timescales.

Predicting time to asystole following withdrawal of life-sustaining treatment: a systematic review.

The planned withdrawal of life-sustaining treatment is a common practice in the intensive care unit for patients where ongoing organ support is recognised to be futile. Predicting the time to asystole following withdrawal of life-sustaining treatment is crucial for setting expectations, resource utilisation and identifying patients suitable for organ donation after circulatory death. This systematic review evaluates the literature for variables associated with, and predictive models for, time to asystole in patients managed on intensive care units. We conducted a comprehensive structured search of the MEDLINE and Embase databases. Studies evaluating patients managed on adult intensive care units undergoing withdrawal of life-sustaining treatment with recorded time to asystole were included. Data extraction and PROBAST quality assessment were performed and a narrative summary of the literature was provided. Twenty-three studies (7387 patients) met the inclusion criteria. Variables associated with imminent asystole (<60 min) included: deteriorating oxygenation; absence of corneal reflexes; absence of a cough reflex; blood pressure; use of vasopressors; and use of comfort medications. We identified a total of 20 unique predictive models using a wide range of variables and techniques. Many of these models also underwent secondary validation in further studies or were adapted to develop new models. This review identifies variables associated with time to asystole following withdrawal of life-sustaining treatment and summarises existing predictive models. Although several predictive models have been developed, their generalisability and performance varied. Further research and validation are needed to improve the accuracy and widespread adoption of predictive models for patients managed in intensive care units who may be eligible to donate organs following their diagnosis of death by circulatory criteria.

Denosumab for craniofacial fibrous dysplasia: duration of efficacy and post-treatment effects.

Denosumab has been advocated as a potential treatment for the rare skeletal disorder fibrous dysplasia (FD); however, there is limited data to support safety and efficacy, particularly after drug discontinuation. We report a case of successful treatment of aggressive craniofacial FD with denosumab, highlighting novel insights into the duration of efficacy, surrogate treatment markers, and discontinuation effects. A 13-year-old girl presented with persistent pain and expansion of a maxillary FD lesion, which was not responsive to repeated surgical procedures or bisphosphonates. Pre-treatment biopsy showed high RANKL expression and localization with proliferation markers. Denosumab therapy was associated with improved pain, decreased bone turnover markers, and increased lesion density on computed tomography scan. During 3.5 years of treatment, the patient developed increased non-lesional bone density, and after denosumab discontinuation, she developed hypercalcemia managed with bisphosphonates. Pain relief and lesion stability continued for 2 years following treatment, and symptom recurrence coincided with increased bone turnover markers and decreased lesion density back to pre-treatment levels. This case highlights the importance of considering the duration of efficacy when treating patients with FD and other nonresectable skeletal neoplasms that require long-term management.

Antidepressant medication exposure and 5-HT1A autoreceptor binding in major depressive disorder.

OBJECTIVE: We have previously reported higher brain serotonin 1A (5-HT1A ) autoreceptor binding in antidepressant-naïve patients with Major Depressive Disorder (MDD) compared with healthy volunteers, and a decrease in binding in MDD after selective serotonin reuptake inhibitor (SSRI) treatment. This SSRI effect is also present in rodents administered SSRIs chronically. We therefore sought to determine the duration of antidepressant medication effects on 5-HT1A receptor binding after medication discontinuation. METHODS: Positron emission tomography (PET) imaging with the 5-HT1A receptor radioligand [11 C]WAY-100635 was performed in 66 individuals with current DSM-IV MDD to examine relationships between 5-HT1A binding and time since most recent antidepressant treatment. All subjects were medication-free for at least 2 weeks prior to scanning. Thirty-two additional MDD comparison subjects were antidepressant naïve. RESULTS: No differences in [11 C]WAY-100635 binding were observed between antidepressant naïve and antidepressant exposed MDD groups in 13 a priori cortical and subcortical regions of interest, including raphe autoreceptors, assessed simultaneously in linear mixed effects models. Furthermore, [11 C]WAY-100635 binding did not correlate with time off antidepressants in the antidepressant exposed patients considering these ROIs. The same results were observed when effects of treatment discontinuation of any psychotropic medication used to treat their depression was examined. CONCLUSION: These results indicate that any antidepressant-associated downregulation of 5-HT1A autoreceptor binding reverses within 2 weeks of medication discontinuation. Since this effect is hypothesized to mediate the antidepressant action of SSRIs, and perhaps other antidepressants, it suggests that patients who need ongoing treatment may relapse rapidly when medication is discontinued. Moreover, 2 weeks appears to be a sufficiently long washout of antidepressant medications for a reliable measure of illness-related binding levels.

Pharmacokinetic considerations in selecting optimal antibiotic therapy for Mycoplasma pneumoniae encephalitis.

Effective antimicrobial therapy depends on several factors including degree of activity against the pathogen, antibiotic resistance, and when relevant, optimal tissue penetration factors. Central nervous system (CNS) infections illustrate these points well. The pharmacokinetic (PK) parameters important in antibiotic blood cerebrospinal fluid barrier (BCB) penetration that is important in meningitis are different and do not predict blood brain barrier (BBB) penetration. Recently, we had a case of Mycoplasma pneumoniae encephalitis (MPE) which prompted a review of the antibiotic PK determinants of BBB penetration which differ markedly from those of BCB penetration important in encephalitis. Using MPE as an illustrative example, this article reviews host and drug factors of therapeutic importance in optimally treating MPE.

Side-gated, enhancement mode, InAs nanowire double quantum dot devices-toward controlling transverse electric fields in spin-transport measurements.

A double quantum dot system with a definitive transverse electric field in the plane of the sample is defined by combining a facile side-gating technique with enhancement mode InAs nanowires. Positive bias on the plunger gates enhance quantum dot segments along the nanowire, negative bias on barrier gates deplete regions, and situating gates biased at opposite polarities on opposing sides of the nanowire allows an electric field to be engineered. With sufficiently biased barrier regions stable bias triangle features are observed in the weak interdot coupling regime. The singlet-triplet energy splitting Δ ST in Pauli spin-blockaded features is studied as a function of an external magnetic field applied perpendicular to the sample plane. We interpret an apparent absence of mixing between singlet and triplet states as an indication that the spin-orbit field is oriented out of the sample plane due to the induced electric field. Finally, we discuss the potential of combining advanced gating architectures with enhancement mode nanowires to control the orientation of the spin-orbit field-a prospect that could enable multiple, nanowire-based spin-qubits to be operated on a single chip with a fixed-angle external magnetic field applied.

Achieving short high-quality gate-all-around structures for horizontal nanowire field-effect transistors.

We introduce a fabrication method for gate-all-around nanowire field-effect transistors. Single nanowires were aligned perpendicular to underlying bottom gates using a resist-trench alignment technique. Top gates were then defined aligned to the bottom gates to form gate-all-around structures. This approach overcomes significant limitations in minimal obtainable gate length and gate-length control in previous horizontal wrap-gated nanowire transistors that arise because the gate is defined by wet-etching. In the method presented here gate-length control is limited by the resolution of the electron-beam-lithography process. We demonstrate the versatility of our approach by fabricating a device with an independent bottom gate, top gate, and gate-all-around structure as well as a device with three independent gate-all-around structures with 300, 200, and 150 nm gate length. Our method enables us to achieve subthreshold swings as low as 38 mV dec-1 at 77 K for a 150 nm gate length.

Fever of unknown origin (FUO): CMV infectious mononucleosis or lymphoma?

Fever of unknown origin (FUO) refers to fevers of > 101 °F that persist for > 3 weeks and remain undiagnosed after a focused inpatient or outpatient workup. FUO may be due to infectious, malignant/neoplastic, rheumatic/inflammatory, or miscellaneous disorders. The FUO category determines the focus of the diagnostic workup. In the case presented of an FUO in a young woman, there were clinical findings of both CMV infectious mononucleosis or a lymphoma, e.g., highly elevated ESR, elevated ferritin levels, and elevated ACE level, ß-2 microglobulins. The indium scan showed intense splenic uptake. Lymph node biopsy, PET scan, and flow cytometry were negative for lymphoma. CMV infectious mononucleosis was the diagnosis, and she made a slow recovery.

Study of the radiologic features of Legionnaires' disease with mediastinal adenopathy: Legionella or lymphoma?

An index case of Legionnaires's disease with mediastinal adenopathy prompted us to review our recent experience with Legionnaires' disease to determine the incidence of mediastinal adenopathy of this finding in Legionnaires' disease. We reviewed the radiographic findings of 90 hospitalized adults with Legionnaires' disease from 2015 to 2017. Excluded were 11 patients with mediastinal adenopathy due to non-Legionnaires' disease causes, e.g., lymphoma. Thirty-seven of the remaining patients had both chest films and chest computed tomography (CT) scans. Of the 37 Legionnaires' disease cases, 13/37 (35%) had mediastinal adenopathy and 8/27 (24%) also had unilateral hilar adenopathy. These chest CT findings were not seen on chest films. Chest CT scans are needed to detect mediastinal adenopathy in Legionnaires' disease. Mediastinal adenopathy may be due to Legionnaires' disease or a malignancy. Some findings in Legionnaires' disease are also present in mediastinal adenopathy due to lymphomas, e.g., highly elevated erythrocyte sedimentation rate (ESR), lactate dehydrogenase (LDH), and ferritin. Hospitalized adults with Legionnaires' disease and mediastinal adenopathy should have serial chest CT scans to monitor resolution of the mediastinal adenopathy. In hospitalized adults with otherwise unexplained persistent mediastinal adenopathy, they should be considered as being due to another etiology, e.g., lymphoma, until proven otherwise.

Lessons learned from splenic infarcts with fever of unknown origin (FUO): culture-negative endocarditis (CNE) or malignancy?

Culture negative endocarditis (CNE) is a common concern in patients with fever, heart murmur, cardiac vegetation, and negative blood cultures. The diagnosis of CNE is not based only on negative blood cultures and a cardiac vegetation. The clinical definition of CNE is based on negative blood cultures plus the findings of culture positive infective endocarditis (IE), e.g., fever, cardiac vegetation, splenomegaly, peripheral manifestations. Because embolic splenic infarcts may occur with culture positive IE, some may assume that splenic infarcts are a sign of CNE. Previously, CNE was due to fastidious and non-culturable organisms. With current diagnostic methods, fastidious organisms grow in 2-3 days. Therefore, fastidious IE are a subset of culture positive IE, but do not represent true CNE. We describe a case of an elderly female who presented with a fever of unknown origin (FUO) and multiple splenic infarcts thought by some to represent CNE. An extensive workup for CNE pathogens was negative. The final cause of her splenic infarcts was a diffuse large B-cell lymphoma (DLBCL). Review of the literature, as well as this case, confirms that splenic infarcts are not a feature of CNE. In patients with fever, splenic infarcts, and negative blood cultures, physicians should search for an alternate explanation rather than CNE, e.g., malignancy and hypercoaguable state (lupus anticoagulant).

Hybrid Nanowire Ion-to-Electron Transducers for Integrated Bioelectronic Circuitry.

A key task in the emerging field of bioelectronics is the transduction between ionic/protonic and electronic signals at high fidelity. This is a considerable challenge since the two carrier types exhibit intrinsically different physics and are best supported by very different materials types-electronic signals in inorganic semiconductors and ionic/protonic signals in organic or bio-organic polymers, gels, or electrolytes. Here we demonstrate a new class of organic-inorganic transducing interface featuring semiconducting nanowires electrostatically gated using a solid proton-transporting hygroscopic polymer. This model platform allows us to study the basic transducing mechanisms as well as deliver high fidelity signal conversion by tapping into and drawing together the best candidates from traditionally disparate realms of electronic materials research. By combining complementary n- and p-type transducers we demonstrate functional logic with significant potential for scaling toward high-density integrated bioelectronic circuitry.

Legionnaires' disease.

Since first identified in early 1977, bacteria of the genus Legionella are recognised as a common cause of community-acquired pneumonia and a rare cause of hospital-acquired pneumonia. Legionella bacteria multisystem manifestations mainly affect susceptible patients as a result of age, underlying debilitating conditions, or immunosuppression. Water is the major natural reservoir for Legionella, and the pathogen is found in many different natural and artificial aquatic environments such as cooling towers or water systems in buildings, including hospitals. The term given to the severe pneumonia and systemic infection caused by Legionella bacteria is Legionnaires' disease. Over time, the prevalence of legionellosis or Legionnaires' disease has risen, which might indicate a greater awareness and reporting of the disease. Advances in microbiology have led to a better understanding of the ecological niches and pathogenesis of the condition. Legionnaires' disease is not always suspected because of its non-specific symptoms, and the diagnostic tests routinely available do not offer the desired sensitivity. However, effective antibiotics are available. Disease notification systems provide the basis for initiating investigations and limiting the scale and recurrence of outbreaks. This report reviews our current understanding of this disease.

Fibrous dysplasia of bone: craniofacial and dental implications.

Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase and elevated levels of cyclic AMP, which act on downstream signaling pathways and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings, and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.

A systematic review of the effectiveness of alcohol brief interventions for the UK military personnel moving back to civilian life.

BACKGROUND: Higher levels of alcohol consumption have been observed in the UK armed forces compared with the general population. For some, this may increase the risk of using alcohol as a coping strategy when adjusting to multiple life events occurring when moving back into civilian life. METHOD: A systematic review was conducted to determine the effectiveness of alcohol brief interventions for military personnel during transition. Electronic databases including Medline, Central, Healthcare Management Information Consortium (HMIC) and Embase, and grey literature, were searched. Two reviewers independently assessed potential studies for inclusion, extracted data and assessed quality of selected articles using an established instrument. RESULTS: Ten studies met criteria for inclusion. Studies were synthesised narratively. Interventions were heterogeneous, and bias within studies may have acted to increase or decrease their reported effectiveness. The findings suggest some evidence for effectiveness of self-administered web-based interventions, involving personalised feedback over a number of sessions, and system-level electronic clinical reminders. All studies were from the USA. Delivery of interventions by a clinician during motivational interviews was most effective for those with post-traumatic stress disorder symptoms. CONCLUSIONS: A UK trial of web-based interventions with personalised feedback is recommended.

Fever of unknown origin (FUO) in a renal transplant recipient due to drug fever from sirolimus.

INTRODUCTION: A variety of medications may cause drug fever. Drug fevers may persist for days to weeks until diagnosis is considered. The diagnosis of drug fever is confirmed when there is resolution of fever within 3 days after the medication is discontinued. Only rarely do undiagnosed drug fevers persist for over 3 weeks to meet fever of unknown origin (FUO) criteria. FUOs due to drug fever are uncommon, and drug fevers due to immunosuppressive drugs are very rare. CASE REPORT: This is a case of a 58-year-old female renal transplant recipient who presented with FUO that remained undiagnosed for over 8 weeks. DISCUSSION: We believe this is the first reported case of an FUO due to drug fever from sirolimus in a renal transplant recipient.

Psychosocial aspects of spinal cord injury pain: a meta-analysis.

STUDY DESIGN: Meta-analysis. OBJECTIVES: Although the association between modifiable psychosocial factors and spinal cord injury (SCI) pain has been identified, the full range of psychological and social difficulties for those who experience acute and/or persistent pain remains unclear. This meta-analysis consolidates the available evidence, using the International Classification of Functioning, Disability and Health (ICF) as a reference framework. METHODS: Nineteen studies that examined persistent neuropathic, nociceptive or mixed pain subtypes in adults with a SCI (newly acquired and chronic; Nparticipants=2934) were identified from electronic database searches. Standardised mean differences between SCI pain and no-pain groups on self-reported psychosocial outcomes were calculated, along with 95% confidence intervals, fail-safe Ns and heterogeneity statistics. RESULTS: Twenty individual outcomes were grouped into nine ICF-related categories. Emotional functions were the most frequent (100%) psychosocial outcomes assessed, with pain contributing to heightened stress (d=-0.85), depression (d=-2.49) anxiety (d range=-0.85 to -1.45), poor self-efficacy (d=-0.77), lowered wellbeing (d range=-0.67 to -1.02) and decreased use of adaptive coping, such as illness acceptance (d=-0.85). Activity limitations and participation restriction were examined by seven studies (43%), although these findings were largely characterised by single studies. CONCLUSIONS: Multicomponent treatments that target mood disturbance and foster community connections are important in SCI pain management. However, to improve the comparability of future studies, SCI pain research must adopt definitions of pain consistent with the International Spinal Cord Injury Pain Classification along with validated outcomes that map onto the ICF framework.

InAs Nanowire Transistors with Multiple, Independent Wrap-Gate Segments.

We report a method for making horizontal wrap-gate nanowire transistors with up to four independently controllable wrap-gated segments. While the step up to two independent wrap-gates requires a major change in fabrication methodology, a key advantage to this new approach, and the horizontal orientation more generally, is that achieving more than two wrap-gate segments then requires no extra fabrication steps. This is in contrast to the vertical orientation, where a significant subset of the fabrication steps needs to be repeated for each additional gate. We show that cross-talk between adjacent wrap-gate segments is negligible despite separations less than 200 nm. We also demonstrate the ability to make multiple wrap-gate transistors on a single nanowire using the exact same process. The excellent scalability potential of horizontal wrap-gate nanowire transistors makes them highly favorable for the development of advanced nanowire devices and possible integration with vertical wrap-gate nanowire transistors in 3D nanowire network architectures.

A Case of Pneumonia Caused by Pneumocystis Jirovecii and Cryptococcus Neoformans in a Patient with HTLV-1 Associated Adult T- Cell Leukemia/Lymphoma: Occam's Razor Blunted.

Adult T-cell leukemia/lymphoma (ATLL) is usually preceded by infection with human T-cell lymphotropic virus I (HTLV-I). Patients with ATLL frequently get opportunistic infections of the lungs, intestines, and central nervous system. Pneumocystis pneumonia is commonly known as an AIDS defining illness. Grocott's methenamine silver stain of bronchoalveolar lavage (BAL) samples obtained via bronchoscopy remain the gold standard for diagnosis. Pulmonary cryptococcosis is seen in patients with T-cell deficiencies and a diagnosis is made by culture of sputum, BAL, or occasionally of pleural fluid. We present the second case of coinfection with these two organisms in a patient with ATLL who was successfully treated with trimethoprim-sulfamethoxazole, corticosteroids, and fluconazole. We illustrate the need for high clinical vigilance for seeking out an additional diagnosis, especially in immunocompromised patients if they are not improving despite receiving appropriate treatment.

Life events: a complex role in the timing of suicidal behavior among depressed patients.

Suicidal behavior is often conceptualized as a response to overwhelming stress. Our model posits that given a propensity for acting on suicidal urges, stressors such as life events or major depressive episodes (MDEs) determine the timing of suicidal acts. Depressed patients (n=415) were assessed prospectively for suicide attempts and suicide, life events and MDE over 2 years. Longitudinal data were divided into 1-month intervals characterized by MDE (yes/no), suicidal behavior (yes/no) and life event scores. Marginal logistic regression models were fit, with suicidal behavior as the response variable and MDE and life event score in either the same or previous month, respectively, as time-varying covariates. Among 7843 person-months, 33% had MDE and 73% had life events. MDE increased the risk for suicidal behavior (odds ratio (OR)=4.83, P⩽0.0001). Life event scores were unrelated to the timing of suicidal behavior (OR=1.06 per 100 point increase, P=0.32), even during a MDE (OR=1.12, P=0.15). However, among those without borderline personality disorder (BPD), both health- and work-related life events were key precipitants, as was recurrent MDE, with a 13-fold effect. The relationship of life events to suicidal behavior among those with BPD was more complex. Recurrent MDE was a robust precipitant for suicidal behavior, regardless of BPD comorbidity. The specific nature of life events is key to understanding the timing of suicidal behavior. Given unanticipated results regarding the role of BPD and study limitations, these findings require replication. Of note, that MDE, a treatable risk factor, strongly predicts suicidal behaviors is cause for hope.

Pulmonary mycobacterial spindle cell pseudotumor in a lung transplant patient: progression without therapy and response to therapy.

Mycobacterial spindle cell pseudotumor (MSP) represents a rare, non-malignant, mass-forming reaction to various mycobacterial infections, typically occurring in immunocompromised patients. It is characterized by the proliferation of spindle-shaped fibrohistiocytic cells without the formation of epithelioid granulomas. Without staining for acid-fast bacilli, histological distinction from other spindle cell lesions, including malignancy, can be difficult. Most of the MSP cases reported in the literature have involved lymph nodes, skin, spleen, or bone marrow, but rarely involve the lung. MSP predominately occurs in patients who are immunosuppressed. We present a patient with MSP of the transplanted lung caused by non-tuberculous mycobacteria, in whom both the natural course of the untreated pseudotumor as well as the response to antimycobacterial treatments were observed.