Safety and efficacy of reperfusion therapies in acute ischemic stroke related to left ventricular thrombus: A retrospective cohort study.

BACKGROUND: Left ventricular thrombus (LVT) is a source of cardiogenic embolic stroke. Conflicting data exist in the literature regarding the utilization of intravenous thrombolysis (IVT) at the acute phase of stroke in presence of LVT. We sought to assess the efficacy and safety of reperfusion therapies (IVT and/or thrombectomy) in patients with LVT. METHODS: We retrospectively analyzed patients with acute ischemic stroke and proven LVT and divided them in two groups: an intervention group with patients treated by reperfusion therapies and a control group with untreated patients. RESULTS: Between 2009 and 2021, 3890 patients were treated by reperfusion therapies in the Lyon stroke center, 33 of whom (0.9%) had LVT. We identified 27 control patients. There were more embolic recurrences at six months in the intervention group than in the control group (nine recurrences versus three, P=0.03, OR=13.56, 95% CI [1.5;195]). Only two early embolic recurrences (< 24h) occurred, both in the IVT group. There was a 4.8-fold decrease in the median NIHSS score between baseline and 24h follow-up in the intervention group (P<0.0001), and the two groups exhibited similar six-month mortality. At stroke onset, cardiopathy was known in 70% of patients, while LVT was known in 30%. CONCLUSION: Acute reperfusion therapies seem to be effective in the context of stroke in patients with LVT. However, further studies are needed to support the hypothesis that stroke recurrence might be related to the use of IVT.

Monitoring of older HIV-1-positive adults by HIV clinics in the United Kingdom: a national quality improvement initiative.

OBJECTIVES: The aim of the study was to describe a UK-wide process to assess adherence to guidelines for the routine investigation and monitoring of HIV-positive adults aged ≥ 50 years and provide clinical services with individual feedback to support improvement in quality of care. METHODS: The British HIV Association (BHIVA) invited HIV clinical care sites to provide retrospective data from case notes of up to 40 adults aged ≥ 50 years with HIV-1 infection attending the clinic for care during 2017 and/or 2018, using a structured dynamic online questionnaire. RESULTS: A total of 4959 questionnaires from 141 clinical services were returned. Regarding the key targets specified in the BHIVA monitoring guidelines, 97% of patients on antiretroviral therapy (ART) had had their viral load measured in the last 9 months, or 15 months if on a protease inhibitor, and 94% had had all medications recorded in the last 15 months. Only 67% of patients on ART without cardiovascular disease (CVD) had had a 10-year CVD risk calculated in the last 3 years. It was reported that 80% and 92% had had their smoking status documented in the last 2 years and blood pressure checked in the last 15 months, respectively. HIV services had communicated with the general practitioners of 90% of consenting individuals, but consulted electronic primary care records for only 10%. CONCLUSIONS: Nationally, targets were met for viral load and blood pressure monitoring but not for CVD risk assessment, smoking status documentation and recording of comedication. There was variable performance in relation to other outcomes; adherence and laboratory measurements were carried out more regularly than lifestyle and wellbeing assessments.

Cell cycle-dependent ubiquitylation and destruction of NDE1 by CDK5-FBW7 regulates ciliary length.

Primary cilia start forming within the G1 phase of the cell cycle and continue to grow as cells exit the cell cycle (G0). They start resorbing when cells re-enter the cell cycle (S phase) and are practically invisible in mitosis. The mechanisms by which cilium biogenesis and disassembly are coupled to the cell cycle are complex and not well understood. We previously identified the centrosomal phosphoprotein NDE1 as a negative regulator of ciliary length and showed that its levels inversely correlate with ciliogenesis. Here, we identify the tumor suppressor FBW7 (also known as FBXW7, CDC4, AGO, or SEL-10) as the E3 ligase that mediates the destruction of NDE1 upon entry into G1. CDK5, a kinase active in G1/G0, primes NDE1 for FBW7-mediated recognition. Cells depleted of FBW7 or CDK5 show enhanced levels of NDE1 and a reduction in ciliary length, which is corrected in cells depleted of both FBW7 or CDK5 and NDE1. These data show that cell cycle-dependent mechanisms can control ciliary length through a CDK5-FBW7-NDE1 pathway.

BRG1 (Brahma-Related Gene 1) Promotes Endothelial Mrtf Transcription to Establish Embryonic Capillary Integrity.

OBJECTIVE: The chromatin remodeling enzyme BRG1 (brahma-related gene 1) transcriptionally regulates target genes important for early blood vessel development and primitive hematopoiesis. However, because Brg1 deletion in vascular progenitor cells results in lethal anemia by embryonic day 10.5 (E10.5), roles for BRG1 in embryonic vascular development after midgestation are unknown. In this study, we sought to determine whether endothelial cell BRG1 regulates genes important for vascular development or maintenance later in embryonic development. APPROACH AND RESULTS: Using mice with temporally inducible deletion of endothelial BRG1 (Brg1fl/fl;Cdh5(PAC)-CreERT2 ), we found that Brg1 excision between E9.5 and 11.5 results in capillary dilation and lethal hemorrhage by E14.5. This phenotype strongly resembles that seen when the SRF (serum response factor) transcription factor is deleted from embryonic endothelial cells. Although expression of Srf and several of its known endothelial cell target genes are downregulated in BRG1-depleted endothelial cells, we did not detect binding of BRG1 at these gene promoters, indicating that they are not direct BRG1 target genes. Instead, we found that BRG1 binds to the promoters of the SRF cofactors Mrtfa and Mrtfb (myocardin-related transcription factors A and B) in endothelial cells, and these genes are downregulated in Brg1-deficient endothelial cells. CONCLUSIONS: BRG1 promotes transcription of endothelial Mrtfa and Mrtfb, which elevates expression of SRF and SRF target genes that establish embryonic capillary integrity. These data highlight a new and temporally specific role for BRG1 in embryonic vasculature and provide novel information about epigenetic regulation of Mrtf expression and SRF signaling in developing blood vessels.

Activating mutations in STIM1 and ORAI1 cause overlapping syndromes of tubular myopathy and congenital miosis.

Signaling through the store-operated Ca(2+) release-activated Ca(2+) (CRAC) channel regulates critical cellular functions, including gene expression, cell growth and differentiation, and Ca(2+) homeostasis. Loss-of-function mutations in the CRAC channel pore-forming protein ORAI1 or the Ca(2+) sensing protein stromal interaction molecule 1 (STIM1) result in severe immune dysfunction and nonprogressive myopathy. Here, we identify gain-of-function mutations in the cytoplasmic domain of STIM1 (p.R304W) associated with thrombocytopenia, bleeding diathesis, miosis, and tubular myopathy in patients with Stormorken syndrome, and in ORAI1 (p.P245L), associated with a Stormorken-like syndrome of congenital miosis and tubular aggregate myopathy but without hematological abnormalities. Heterologous expression of STIM1 p.R304W results in constitutive activation of the CRAC channel in vitro, and spontaneous bleeding accompanied by reduced numbers of thrombocytes in zebrafish embryos, recapitulating key aspects of Stormorken syndrome. p.P245L in ORAI1 does not make a constitutively active CRAC channel, but suppresses the slow Ca(2+)-dependent inactivation of the CRAC channel, thus also functioning as a gain-of-function mutation. These data expand our understanding of the phenotypic spectrum of dysregulated CRAC channel signaling, advance our knowledge of the molecular function of the CRAC channel, and suggest new therapies aiming at attenuating store-operated Ca(2+) entry in the treatment of patients with Stormorken syndrome and related pathologic conditions.

Cerebrovascular events as presenting manifestations of Myeloproliferative Neoplasm.

AIM: To determine the incidence and main characteristics of cerebrovascular events as the presenting manifestations of myeloproliferative neoplasm (MPN). METHODS: The Hematology in Lyon (HEMILY) registry is a prospective database (763 patients) of all cases of MPN diagnosed since 2005 in the Rhône-Alpes district of France. The MPN cases were divided into four groups: polycythemia vera (PV); essential thrombocythemia (ET); myelofibrosis (MF); and atypical MPN. The ischemic stroke subtype was classified according to TOAST criteria. RESULTS: A stroke history revealed MPN in 35 (4.3%) patients: 22 (63%) had an ischemic stroke; eight (23%) had a transient ischemic attack; four (11%) had cerebral venous thrombosis; and one (3%) had hemorrhagic stroke. All patients had hemoglobin and/or platelet count abnormalities. In addition, 12 (34%) patients had PV, 21 (60%) had ET, one (3%) had MF and one (3%) had atypical/unclassified MPN. The JAK2 V617F mutation was found in 83% of patients. In 18 (51%) patients, an additional mechanism of stroke was present (atherosclerosis in 10 patients, atrial fibrillation in one patient and dissection in another). The median NIHSS score at entry was 2, and the median modified Rankin Scale score at 3 months was 0. Compared with the general MPN population, stroke-MPN patients presented with significantly higher levels of hemoglobin (P<0.001) and were more frequently positive for the JAK2 V617F mutation (P=0.044). CONCLUSION: Stroke revealing MPN is rare. However, careful attention should still be paid to blood counts even in patients with obvious stroke etiologies, as early diagnosis permits prompt treatment and decreases the risk of recurrence, thus limiting morbidity and mortality.

People with diagnosed HIV infection not attending for specialist clinical care: UK national review.

BACKGROUND: Regular clinical care is important for the well-being of people with HIV. We sought to audit and describe the characteristics of adults with diagnosed HIV infection not reported to be attending for clinical care in the UK. METHODS: Public Health England (PHE) provided clinics with lists of patients diagnosed or seen for specialist HIV care in 2010 but not linked to a clinic report or known to have died in 2011. Clinics reviewed case-notes of these individuals and completed questionnaires. A nested case-control analysis was conducted to compare those who had remained in the UK in 2011 while not attending care with individuals who received specialist HIV care in both 2010 and 2011. RESULTS: Among 74,418 adults living with diagnosed HIV infection in the UK in 2010, 3510 (4.7%) were not reported as seen for clinical care or died in 2011. Case note reviews and outcomes were available for 2255 (64%) of these: 456 (20.2%) remained in the UK and did not attend care; 590 (26.2%) left UK; 508 (22.6%) received care in the UK: 73 (3.2%) died and 628 (27.8%) had no documented outcome. Individuals remaining in the UK and not attending care were more likely to be treatment naïve than those in care, but duration since HIV diagnosis was not significant. HIV/AIDS related hospitalisations were observed among non-attenders. CONCLUSION: Retention in UK specialist HIV care is excellent. Our audit indicates that the 'true' loss to follow up rate in 2011 was <2.5% with no evidence of health tourism. Novel interventions to ensure high levels of clinic engagement should be explored to minimise disease progression among non-attenders.

A TRPC1 protein-dependent pathway regulates osteoclast formation and function.

Ca(2+) signaling is essential for bone homeostasis and skeletal development. Here, we show that the transient receptor potential canonical 1 (TRPC1) channel and the inhibitor of MyoD family, I-mfa, function antagonistically in the regulation of osteoclastogenesis. I-mfa null mice have an osteopenic phenotype characterized by increased osteoclast numbers and surface, which are normalized in mice lacking both Trpc1 and I-mfa. In vitro differentiation of pre-osteoclasts derived from I-mfa-deficient mice leads to an increased number of mature osteoclasts and higher bone resorption per osteoclast. These parameters return to normal levels in osteoclasts derived from double mutant mice. Consistently, whole cell currents activated in response to the depletion of intracellular Ca(2+) stores are larger in pre-osteoclasts derived from I-mfa knock-out mice compared with currents in wild type mice and normalized in cells derived from double mutant mice, suggesting a cell-autonomous effect of I-mfa on TRPC1 in these cells. A new splice variant of TRPC1 (TRPC1ε) was identified in early pre-osteoclasts. Heterologous expression of TRPC1ε in HEK293 cells revealed that it is unique among all known TRPC1 isoforms in its ability to amplify the activity of the Ca(2+) release-activated Ca(2+) (CRAC) channel, mediating store-operated currents. TRPC1ε physically interacts with Orai1, the pore-forming subunit of the CRAC channel, and I-mfa is recruited to the TRPC1ε-Orai1 complex through TRPC1ε suppressing CRAC channel activity. We propose that the positive and negative modulation of the CRAC channel by TRPC1ε and I-mfa, respectively, fine-tunes the dynamic range of the CRAC channel regulating osteoclastogenesis.

Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients.

Body surface area (BSA)-based dosing leads to wide inter-individual variations in drug pharmacokinetics and pharmacodynamics, whereas body composition has been shown to be a more robust determinant of efficacy and toxicity of certain chemotherapeutic agents. We correlated various parameters of body composition with doxorubicin pharmacokinetics and hematologic toxicities in Asian patients with locally advanced or metastatic breast cancer. Our analysis included 84 patients from two studies who received pre- or post-operative single-agent doxorubicin; pharmacokinetic parameters were available for 44 patients. Body composition parameters were derived from CT cross-sectional images and population pharmacokinetic analysis was conducted using mixed-effects modeling. Higher intra-abdominal fat volume and fat ratio (intra-abdominal:total abdominal fat volume) correlated with greater incidence of grade 4 leukopenia on cycle 1 day 15 (mean intra-abdominal fat volume: 97.4 ± 46.5 cm(3) vs 63.4 ± 30.9 cm(3), p = 0.014; mean fat ratio: 0.43 ± 0.11 vs 0.33 ± 0.09, p = 0.012, grade 4 vs grade 0-3 leukopenia). On subset analysis, this relationship was maintained even in underweight patients. Concordantly, there were positive correlations between doxorubicin AUC and intra-abdominal fat volume as well as total abdominal fat volume (r (2) = 0.324 and 0.262, respectively, all p < 0.001). BSA and muscle volume did not predict for doxorubicin pharmacokinetics or toxicities. High-intra-abdominal fat volume but not BSA predicted for greater doxorubicin exposure and hematologic toxicities, suggesting that body composition is superior to BSA in determining doxorubicin pharmacokinetics and pharmacodynamics. Body composition has an emerging role in chemotherapy dose determination.

Consensus guidelines from The American Society of Peritoneal Surface Malignancies on standardizing the delivery of hyperthermic intraperitoneal chemotherapy (HIPEC) in colorectal cancer patients in the United States.

BACKGROUND: The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC. METHODS: A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests. RESULTS: Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin. CONCLUSIONS: This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Laparoscopic ventral rectopexy is effective for solitary rectal ulcer syndrome when associated with rectal prolapse.

AIM: Solitary rectal ulcer syndrome (SRUS) is uncommon and its management is controversial. The aim of this study was to evaluate the outcome of patients with SRUS who underwent laparoscopic ventral rectopexy (LVR). METHOD: A review was performed of a prospective database at the Oxford Pelvic Floor Centre to identify patients between 2004 and 2012 with a histological diagnosis of SRUS. All were initially treated conservatively and surgical treatment was indicated only for patients with significant symptoms after failed conservative management. The primary end-point was healing of the ulcer. Secondary end-points included changes in the Wexner Constipation Score and Faecal Incontinence Severity Index (FISI). RESULTS: Thirty-six patients with SRUS were identified (31 women), with a median age of 44 (15­81) years. The commonest symptoms were rectal bleeding (75%) and obstructed defaecation (64%). The underlying anatomical diagnosis was internal rectal prolapse (n = 20), external rectal prolapse (n = 14) or anismus (n = 2). Twenty-nine patients underwent LVR and one a stapled transanal rectal resection (STARR) procedure. Nine (30%) required a further operation, six required posterior STARR for persistent SRUS and two a per-anal stricturoplasty for a narrowing at the healed SRUS site. Healing of the SRU was seen in 27 (90%) of the 30 patients and was associated with significant improvements in Wexner and FISI scores at a 3-year follow-up. CONCLUSION: Almost all cases of SRUS in the present series were associated with rectal prolapse. LVR resulted in successful healing of the SRUS with good function in almost all patients, but a significant number will require further surgery such as STARR for persistent obstructed defaecation.

HIV-associated fatigue in the era of highly active antiretroviral therapy: novel biological mechanisms?

OBJECTIVE: The aim of the study was to determine the prevalence and risk factors for HIV-associated fatigue in the era of highly active antiretroviral therapy (HAART). METHODS: A cross-sectional survey of 100 stable HIV-infected out-patients was carried out. Severity of fatigue was measured using the Fatigue Impact Scale (FIS). Symptoms of orthostatic intolerance (dysautonomia) were evaluated using the Orthostatic Grading Scale (OGS). Data for HIV-infected patients were compared with those for 166 uninfected controls and 74 patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (encephalopathy) (ME). RESULTS: Ninety-one per cent of HIV-infected patients were on HAART and 78% had suppressed plasma HIV viral load (≤ 40 HIV-1 RNA copies/mL). Fifty-one per cent of HIV-infected patients reported excessive symptomatic fatigue (FIS ≥ 40), and 28% reported severe fatigue symptoms (FIS ≥ 80). The mean FIS score among HIV-infected patients was 50.8 [standard deviation (SD) 41.9] compared with 13.0 (SD 17.6) in uninfected control subjects, and 92.9 (SD 29.0) in CFS patients (P < 0.001 for comparison of HIV-infected patients and uninfected controls). Among HIV-infected patients, fatigue severity was not significantly associated with current or nadir CD4 lymphocyte count, HIV plasma viral load, or whether on HAART. Prior dideoxynucleoside analogue (d-drug) exposure (P = 0.016) and the presence of clinical lipodystrophy syndrome (P = 0.011) were associated with fatigue. Additionally, fatigue severity correlated strongly with symptomatic orthostatic intolerance (r = 0.65; P < 0.001). CONCLUSIONS: Fatigue is very common and often severe in HIV-infected out-patients, despite viral suppression and good immune function. In a subgroup of patients, prior d-drug exposure may contribute to fatigue, suggesting a metabolic basis. Dysautonomia may also drive fatigue associated with HIV infection, as in other chronic diseases, and CFS/ME, and should be further evaluated with the potential for a shared therapeutic approach.

Randomized clinical trial of glutamine-supplemented versus standard parenteral nutrition in infants with surgical gastrointestinal disease.

BACKGROUND: Addition of glutamine to parenteral nutrition in surgical infants remains controversial. The aim of this trial was to determine whether glutamine supplementation of parenteral nutrition in infants requiring surgery would reduce the time to full enteral feeding and/or decrease the incidence of sepsis and septicaemia. METHODS: A prospective double-blind multicentre randomized clinical trial was performed in surgical infants less than 3 months old who required parenteral nutrition. Patients were allocated to treatment or control groups by means of minimization. Infants received either 0·6 g per kg per day alanyl-glutamine (treatment group) or isonitrogenous isocaloric parenteral nutrition (control group) until full enteral feeding was achieved. Primary outcomes were time to full enteral feeding and incidence of sepsis. Cox regression analysis was used to compare time to full enteral feeding, and to calculate risk of sepsis/septicaemia. RESULTS: A total of 174 patients were randomized, of whom 164 completed the trial and were analysed (82 in each group). There was no difference in time to full enteral feeding or time to first enteral feeding between groups, and supplementation with glutamine had no effect on the overall incidence of sepsis or septicaemia. However, during total parenteral nutrition (before the first enteral feed), glutamine administration was associated with a significantly decreased risk of developing sepsis (hazard ratio 0·33, 95 per cent confidence interval 0·15 to 0·72; P = 0·005). CONCLUSION: Glutamine supplementation during parenteral nutrition did not reduce the incidence of sepsis in surgical infants with gastrointestinal disease. REGISTRATION NUMBER: ISRCTN83168963 (http://www.controlled-trials.com).

Current practice in preoperative therapy and surgical management of locally advanced rectal cancer: a bi-national survey.

AIM: The Australasian colorectal surgeon's current approach to preoperative rectal cancer management was compared with international guidelines. METHOD: Members of the Colorectal Surgical Society of Australia and New Zealand were surveyed in 2010, on the use of MRI and the management of locally advanced rectal cancer. Surgeons had to decide the appropriate management in five scenarios that were developed from national guidelines. RESULTS: Of 174 invitations sent, 108 (62.1%) replies were received. Most surgeons (98.1%) had access to MRI. Ninety-three (86.1%) would use MRI routinely for staging. The majority selected a tumour-specific mesorectal resection for upper rectal cancer (58.2%) and a total mesorectal excision for distal cancer (100%). Almost all restorative operations included a covering ileostomy. One third of surgeons recommended that patients with a favourable cT3 mid-rectal tumour (N0, clear circumferential resection margins) should not have preoperative therapy and should proceed directly to surgery. When high-risk features, such as threatened resection margins or cN1 stage, were present, 5% and 15% of surgeons, respectively, would continue to treat by standard resection without preoperative therapy. CONCLUSION: Evidence-based international guidelines for the management of rectal cancer have changed little in the last 10 years. Despite this, there is a clear gap between these and clinical practice. The main variance relates to the role of radiotherapy in locally advanced rectal cancer. Despite considerable evidence that radiotherapy reduces local recurrence for all stages of rectal cancer, current practice in Australasia is for its selective use.

Offering HIV testing in an acute medical admissions unit in Newcastle upon Tyne.

The objective of this study was to offer HIV testing to all patients attending the acute medical admissions unit (AMU) in Newcastle upon Tyne to assess feasibility, acceptability and point prevalence in accordance with the 2008 UK National HIV testing guidelines. A prospective audit was performed offering HIV testing to all patients with the capacity to give verbal consent who attended the AMU. In total, 3,753 eligible patients were admitted during the audit period and 586 (15.6%) were considered for testing. Of those approached, 108 (18.4%) were clinically ineligible to test and 478 were offered a test. In the 396 patients who consented (82.8%), there were two new HIV diagnoses (point prevalence 0.5%). Offering HIV testing in an AMU setting is feasible and acceptable to patients. The high uptake rate but low proportion of admissions tested suggests a lack of confidence of medical staff in offering a test. Misconceptions regarding HIV testing remain and greater education is required for healthcare workers.

High-Transmission-Efficiency and Side-Viewing Micro OIDRS Probe for Fast and Minimally-Invasive Tumor Margin Detection.

The determination of a cancer free margin I organs is a difficult and time consuming process, with an unmet need for rapid determination of tumor margin at surgery. In this paper, we report the design, fabrication and testing of a novel miniaturized optical sensor probe with "side-viewing" capability. Its unprecedented small size, unique "side-viewing" capability and high optical transmission efficiency enable the agile maneuvering and efficient data collection even in the narrow cavities inside the human body. The sensor probe consists of four micromachined substrates with optical fibers for oblique light incidence and collection of spatially resolved diffuse reflectance from the contacted tissues. The optical sensor probe has been used to conduct the oblique incidence diffuse reflectance spectroscopy (OIDRS) on a human pancreatic specimen. Based on the measurement results, the margin of the malignant tumor has been successfully determined optically, which matches well with the histological results.