Application of automatic monitors for state water quality surveillance

August 1972.Includes bibliographic references (pages 136-143).Field use of automatic water quality monitors began during the mid 1950's. Experience gained since that time has revealed that the best application of automatic monitors is to supplement grab sampling surveillance systems. When employed on a real-time basis using telemetry and computer processing of collected data, automatic monitors are capable of satisfying the abatement objectives of state water quality management agencies. Presently, only five reliable sensors (DO, T, pH, Cond, and Turb) are available. With this limitation, automatic monitors are not presently able to provide 100 percent pollution event detection effectiveness. However, the present state-of-the-art on sensor detection ability indicates that a detection effectiveness of greater than 50 percent is possible using DO, T, pH, Cond, and Turb sensors. With this detection capability the abatement objectives of a state water quality management agency can be fulfilled by designing an automatic monitoring system which will optimize traceability (the accuracy and expediency with which a pollution event can be traced). The network of automatic monitoring stations which optimizes traceability is called the effective primary network. The design procedure developed in this study provides: (1) A quantitative basis for determining the location of effective primary stations and (2) A method of relating abatement effectiveness to the number of effective primary stations. The relationship between cost and number of effective primary stations is developed by computing the cost of automatic monitoring networks (1-30 stations in size) using average costs for purchase price, installation, and first year operation and maintenance expenditures. The cost effectiveness relationship is generated by comparing cost and abatement effectiveness while summing over the number of stations comprising the effective primary network. The cost effectiveness relationship reveals the benefits gained in abatement effectiveness per increment of cost for the acquisition of each effective primary station. A schedule for effective primary station acquisition is also indicated

Halting Planet Migration in the Evacuated Centers of Protoplanetary Disks

Precise Doppler searches for extrasolar planets find a surfeit of planets with orbital periods of 3-4 days, and no planets with orbital periods less than 3 days. The circumstellar distance, R_0, where small grains in a protoplanetary disk reach sublimation temperature (~1500 K) corresponds to a period of ~6 days. Interior to R_0, turbulent accretion due to magneto-rotational instability may evacuate the disk center. We suggest that planets with orbital periods of 3-4 days are so common because migrating planets halt once this evacuated region contains the sites of their exterior 2:1 Lindblad resonances.Comment: 9 pages, 1 figure, to appear in ApJ letter

Adhesion and Degranulation Promoting Adapter Protein (ADAP) Is a Central Hub for Phosphotyrosine-Mediated Interactions in T Cells

TCR stimulation leads to an increase in cellular adhesion among other outcomes. The adhesion and degranulation promoting adapter protein (ADAP) is known to be rapidly phosphorylated after T cell stimulation and relays the TCR signal to adhesion molecules of the integrin family. While three tyrosine phosphorylation sites have been characterized biochemically, the binding capabilities and associated functions of several other potential phosphotyrosine motifs remain unclear. Here, we utilize in vitro phosphorylation and mass spectrometry to map novel phosphotyrosine sites in the C-terminal part of human ADAP (486–783). Individual tyrosines were then mutated to phenylalanine and their relevance for cellular adhesion and migration was tested experimentally. Functionally important tyrosine residues include two sites within the folded hSH3 domains of ADAP and two at the C-terminus. Furthermore, using a peptide pulldown approach in combination with stable isotope labeling in cell culture (SILAC) we identified SLP-76, PLCγ, PIK3R1, Nck, CRK, Gads, and RasGAP as phospho-dependent binding partners of a central YDDV motif of ADAP. The phosphorylation-dependent interaction between ADAP and Nck was confirmed by yeast two-hybrid analysis, immunoprecipitation and binary pulldown experiments, indicating that ADAP directly links integrins to modulators of the cytoskeleton independent of SLP-76

Phase II Study of Paclitaxel, Carboplatin, and Cetuximab as First Line Treatment, for Patients with Advanced Non-small Cell Lung Cancer (NSCLC): Results of OPN-017

BackgroundCetuximab has demonstrated synergy with taxanes in preclinical models; as well as single agent activity. We assessed the activity of cetuximab with carboplatin and paclitaxel given on a 4-week schedule, in advanced, chemo-naive non-small cell lung cancer.Patients and MethodsThis phase II, single arm, multi-institution study featured standard dosage of cetuximab 400 mg/m2 day 1, then 250 mg/m2 with paclitaxel (100 mg/m2/wk, for 3 weeks), and carboplatin (area under curve = 6) day 1 of each 28 day cycle. After 4 to 6 cycles, in the absence of disease progression or excess toxicity, cetuximab was continued weekly. Primary end point was response rate.ResultsFifty-three patients (median age 63, 51% male) participated. Response rate was 57% (3 complete response and 27 partial response). At a median follow-up of 12.5 months, the estimated overall survival is 13.8 months (95% CI: 9.08–16.02) with an event-free survival rate of 5.53 months (95% CI: 4.77–7.99), 18.9% remain free from progression at 1 year. Improved survival was associated with female gender, absence of prior radiation, PS 0 and epidermal growth factor receptor expression. Toxicities included rash (28% grade 3), nail changes (3.7% grade 3), hypomagnesemia (7.5% grade 3 and 3.7% grade 4), and neutropenia (25% grade 3 and 13% grade 4) in addition to other typical side effects anticipated with paclitaxel/carboplatin. There were no grade 5 toxicities.ConclusionCombination of cetuximab/paclitaxel/carboplatin in non-small cell lung cancer was well tolerated and clinically active with manageable toxicities. This unique schedule, integrating weekly paclitaxel and cetuximab has not yet been tested in a randomized trial

Prospective cohort study to identify prevalence, risk factors and outcomes of infection associated kidney disease in a regional hospital in Malawi

Objectives: Acute kidney injury (AKI) is a common and severe complication of community acquired infection, but data on impact in sub-Saharan Africa (SSA) are lacking. We determined prevalence, risk factors and outcomes of infection associated kidney disease in adults in Malawi. Design: A prospective cohort study of adults admitted to hospital with infection, from February 2021 to June 2021, collecting demographic, clinical, laboratory and ultrasonography data. Setting: Adults admitted to a regional hospital in Southern Region, Malawi. Primary and secondary outcome measures: The primary outcomes were prevalence of kidney disease and mortality by Cox proportional hazard model. AKI was defined according to Kidney Disease Improving Global Outcomes (KDIGO) guidelines. Secondary outcomes were risk factors for AKI identified by logistic regression and prevalence of chronic kidney disease at 3 months. Results: We recruited 101 patients presenting to hospital with infection. Median age was 38 years (IQR: 29–48 years), 88 had known HIV status of which 53 (60%) were living with HIV, and of these 42 (79%) were receiving antiretroviral therapy. AKI was present in 33/101 at baseline, of which 18/33 (55%) cases were severe (KDIGO stage 3). At 3 months, 28/94 (30%) participants had died, while 7/61 (11%) of survivors had chronic kidney disease. AKI was associated with older age (age: 60 years vs 40 years, OR: 3.88, 95% CI 1.82 to 16.64), and HIV positivity (OR: 4.08, 95% CI 1.28 to 15.67). Living with HIV was independently associated with death (HR: 3.97, 95% CI 1.07 to 14.69). Conclusions: Kidney disease is common among hospitalised adults with infection in Malawi, with significant kidney impairment identified at 3 months. Our study highlights the difficulty in diagnosing acute and chronic kidney disease, and the need for more accurate methods than creatinine based estimated glomerular filtration rate (eGFR) equations for populations in Africa. Patients with kidney impairment identified in hospital should be prioritised for follow-up

Mouse models for hereditary spastic paraplegia uncover a role of PI4K2A in autophagic lysosome reformation

Hereditary spastic paraplegia (HSP) denotes genetically heterogeneous disorders characterized by leg spasticity due to degeneration of corticospinal axons. SPG11 and SPG15 have a similar clinical course and together are the most prevalent autosomal recessive HSP entity. The respective proteins play a role for macroautophagy/autophagy and autophagic lysosome reformation (ALR). Here, we report that spg11 and zfyve26 KO mice developed motor impairments within the same course of time. This correlated with enhanced accumulation of autofluorescent material in neurons and progressive neuron loss. In agreement with defective ALR, tubulation events were diminished in starved KO mouse embryonic fibroblasts (MEFs) and lysosomes decreased in neurons of KO brain sections. Confirming that both proteins act in the same molecular pathway, the pathologies were not aggravated upon simultaneous disruption of both. We further show that PI4K2A (phosphatidylinositol 4-kinase type 2 alpha), which phosphorylates phosphatidylinositol to phosphatidylinositol-4-phosphate (PtdIns4P), accumulated in autofluorescent deposits isolated from KO but not WT brains. Elevated PI4K2A abundance was already found at autolysosomes of neurons of presymptomatic KO mice. Immunolabelings further suggested higher levels of PtdIns4P at LAMP1-positive structures in starved KO MEFs. An increased association with LAMP1-positive structures was also observed for clathrin and DNM2/dynamin 2, which are important effectors of ALR recruited by phospholipids. Because PI4K2A overexpression impaired ALR, while its knockdown increased tubulation, we conclude that PI4K2A modulates phosphoinositide levels at autolysosomes and thus the recruitment of downstream effectors of ALR. Therefore, PI4K2A may play an important role in the pathogenesis of SPG11 and SPG15. Abbreviations: ALR: autophagic lysosome reformation; AP-5: adaptor protein complex 5; BFP: blue fluorescent protein; dKO: double knockout; EBSS: Earle’s balanced salt solution; FBA: foot base angle; GFP: green fluorescent protein; HSP: hereditary spastic paraplegia; KO: knockout; LAMP1: lysosomal-associated membrane protein 1; MAP1LC3B/LC3: microtubule-associated protein 1 light chain 3 beta; MEF: mouse embryonic fibroblast; SQSTM1/p62: sequestosome 1; PI4K2A: phosphatidylinositol 4-kinase type 2 alpha; PtdIns3P: phosphatidylinositol-3-phosphate; PtdIns4P: phosphatidylinositol-4-phosphate; RFP: red fluorescent protein; SPG: spastic paraplegia gene; TGN: trans-Golgi network; WT: wild typ

Ultrasound appearance of the kidney among radiology department attendees of a tertiary centre in Malawi.

Background: Diagnostic and therapeutic decisions in nephrology in low-resource settings are frequently based on ultrasound assessment of kidney size. An understanding of reference values is critical, particularly given the rise of non-communicable disease and the expanding availability of point-of-care ultrasound. However, there is a paucity of normative data from African populations. We determined estimates of kidney ultrasound measures, including kidney size based on age, sex, and HIV status, among apparently healthy outpatient attendees of Queen Elizabeth Central hospital radiology department, Blantyre, Malawi. Methods: We performed a cross-sectional cohort study of 320 adults attending the radiology department between October 2021 and January 2022. Bilateral kidney ultrasound was performed on all participants using a portable Mindray DP-50 machine and a 5MHz convex probe. The sample was stratified by age, sex, and HIV status. Predictive linear modelling was used to construct reference ranges for kidney size estimating the central 95 percentiles of 252 healthy adults. Exclusion criteria for the healthy sample were known kidney disease, hypertension, diabetes, BMI > 35, heavy alcohol intake, smoking and ultrasonographic abnormalities. Results: There were 162/320 (51%) male participants. The median age was 47 (interquartile range [IQR] 34-59). Among people living with HIV 134/138 (97%) were receiving antiretroviral therapy. Men had larger average kidney sizes: mean 9.68 cm (SD 0.80 cm), compared to 9.46 cm (SD 0.87 cm) in women ( = 0.01). Average kidney sizes in people living with HIV were not significantly different from those who were HIV-negative, 9.73 cm (SD 0.93 cm) versus 9.58 cm (SD 0.93 cm) ( = 0.63). Conclusions: This is the first report of the apparently healthy kidney size in Malawi. Predicted kidney size ranges may be used for reference in the clinical assessment of kidney disease in Malawi

Photoprocesses in protoplanetary disks

Circumstellar disks are exposed to intense ultraviolet radiation from the young star. In the inner disks, the UV radiation can be enhanced by more than seven orders of magnitude compared with the average interstellar field, resulting in a physical and chemical structure that resembles that of a dense photon-dominated region (PDR). This intense UV field affects the chemistry, the vertical structure of the disk, and the gas temperature, especially in the surface layers of the disk. The parameters which make disks different from traditional PDRs are discussed, including the shape of the UV radiation field, grain growth, the absence of PAHs, the gas/dust ratio and the presence of inner holes. New photorates for selected species, including simple ions, are presented. Also, a summary of available cross sections at Lyman alpha 1216 A is made. Rates are computed for radiation fields with color temperatures ranging from 4000 to 30,000 K, and can be applied to a wide variety of astrophysical regions including exo-planetary atmospheres. The importance of photoprocesses is illustrated for a number of representative disk models, including disk models with grain growth and settling.Comment: A website with the final published version and all photodissociation cross sections and rates can be found at http://www.strw.leidenuniv.nl/~ewine/phot

The application of adjuvant autologous antravesical macrophage cell therapy vs. BCG in non-muscle invasive bladder cancer: a multicenter, randomized trial

<p>Abstract</p> <p>Introduction</p> <p>While adjuvant immunotherapy with Bacille Calmette Guérin (BCG) is effective in non-muscle-invasive bladder cancer (BC), adverse events (AEs) are considerable. Monocyte-derived activated killer cells (MAK) are discussed as essential in antitumoural immunoresponse, but their application may imply risks. The present trial compared autologous intravesical macrophage cell therapy (BEXIDEM^®) to BCG in patients after transurethral resection (TURB) of BC.</p> <p>Materials and methods</p> <p>This open-label trial included 137 eligible patients with TaG1-3, T1G1-2 plurifocal or unifocal tumours and ≥ 2 occurrences within 24 months and was conducted from June 2004 to March 2007. Median follow-up for patients without recurrence was 12 months. Patients were randomized to BCG or mononuclear cells collected by apheresis after ex vivo cell processing and activation (BEXIDEM). Either arm treatment consisted of 6 weekly instillations and 2 cycles of 3 weekly instillations at months 3 and 6. Toxicity profile (primary endpoint) and prophylactic effects (secondary endpoint) were assessed.</p> <p>Results</p> <p>Patient characteristics were evenly distributed. Of 73 treated with BCG and 64 with BEXIDEM, 85% vs. 45% experienced AEs and 26% vs. 14% serious AEs (SAE), respectively (p < 0.001). Recurrence occurred significantly less frequent with BCG than with BEXIDEM (12% vs. 38%; p < 0.001).</p> <p>Discussion</p> <p>This initial report of autologous intravesical macrophage cell therapy in BC demonstrates BEXIDEM treatment to be safe. Recurrence rates were significantly lower with BCG however. As the efficacy of BEXIDEM remains uncertain, further data, e.g. marker lesions studies, are warranted.</p> <p>Trial registration</p> <p>The trial has been registered in the ISRCTN registry <url>http://isrctn.org</url> under the registration number ISRCTN35881130.</p