Early mandated social distancing is a strong predictor of reduction in peak daily new COVID-19 cases.

OBJECTIVES: Mandated social distancing has been applied globally to reduce the spread of coronavirus disease 2019 (COVID-19). However, the beneficial effects of this community-based intervention have not been proven or quantified for the COVID-19 pandemic. STUDY DESIGN: This is a regional population-level observational study. METHODS: Using publicly available data, we examined the effect of timing of mandated social distancing on the rate of COVID-19 cases in 119 geographic regions, derived from 41 states within the United States and 78 other countries. The highest number of new COVID-19 cases per day recorded within a geographic unit was the primary outcome. The total number of COVID-19 cases in regions where case numbers had reached the tail end of the outbreak was an exploratory outcome. RESULTS: We found that the highest number of new COVID-19 cases per day per million persons was significantly associated with the total number of COVID-19 cases per million persons on the day before mandated social distancing (ß = 0.66, P < 0.0001). These findings suggest that if mandated social distancing is not initiated until the number of existing COVID-19 cases has doubled, the eventual peak would result in 58% more COVID-19 cases per day. Subgroup analysis on those regions where the highest number of new COVID-19 cases per day has peaked showed increase in ß values to 0.85 (P < 0.0001). The total number of cases during the outbreak in a region was strongly predicted by the total number of COVID-19 cases on the day before mandated social distancing (ß = 0.97, P < 0.0001). CONCLUSIONS: Initiating mandated social distancing when the numbers of COVID-19 cases are low within a region significantly reduces the number of new daily COVID-19 cases and perhaps also reduces the total number of cases in the region.

Next generation secondary electron detector with energy analysis capability for SEM.

We report the working of a novel detector design based on a Bessel Box (BB) electron energy analyser in a scanning electron microscope (SEM). We demonstrate the application of our detector for elemental identification through Auger electron detection in an SEM environment and its potential as a complementary technique to energy dispersive X-ray (EDX) spectroscopy. We also demonstrate energy-filtered secondary electron imaging of a copper-on-silicon sample using an electron pass energy of 12 eV. LAY DESCRIPTION: Advancements in the field of the Scanning Electron Microscopy have been one of the major nanotechnology enablers. A Scanning Electron Microscope (SEM) generates a magnified image of the sample by bombarding it with an electron beam and detecting the electrons that scatter off the surface along with the electrons that are generated in the sample. Conventional detectors such as the Everhart-Thornley detector (ET) or through-the-lens (TTL) detectors, either offer little to no energy analysis (ET) or limited energy filtering capability (e.g the low-pass energy filter in TTL). This information is crucial to interpret the image of the sample under study. What is needed is a smart and compact detector that can detect electrons and furnish energy inside the SEM chamber. Here, we report a novel secondary electron (SE) detector design with energy analysis capability for use in scanning electron microscopes. The detector is based on the design of a Bessel Box (BB) energy analyser. We have designed and experimentally tested it in an SEM environment. The band-pass filter action of the detector enables the BB to be operated at a selected energy and allows a narrow window of energies to be detected for generating energy-filtered images.

Fc-Silent Anti-CD154 Domain Antibody Effectively Prevents Nonhuman Primate Renal Allograft Rejection.

The advent of costimulation blockade provides the prospect for targeted therapy with improved graft survival in transplant patients. Perhaps the most effective costimulation blockade in experimental models is the use of reagents to block the CD40/CD154 pathway. Unfortunately, successful clinical translation of anti-CD154 therapy has not been achieved. In an attempt to develop an agent that is as effective as previous CD154 blocking antibodies but lacks the risk of thromboembolism, we evaluated the efficacy and safety of a novel anti-human CD154 domain antibody (dAb, BMS-986004). The anti-CD154 dAb effectively blocked CD40-CD154 interactions but lacked crystallizable fragment (Fc) binding activity and resultant platelet activation. In a nonhuman primate kidney transplant model, anti-CD154 dAb was safe and efficacious, significantly prolonging allograft survival without evidence of thromboembolism (Median survival time 103 days). The combination of anti-CD154 dAb and conventional immunosuppression synergized to effectively control allograft rejection (Median survival time 397 days). Furthermore, anti-CD154 dAb treatment increased the frequency of CD4+ CD25+ Foxp3+ regulatory T cells. This study demonstrates that the use of a novel anti-CD154 dAb that lacks Fc binding activity is safe without evidence of thromboembolism and is equally as potent as previous anti-CD154 agents at prolonging renal allograft survival in a nonhuman primate preclinical model.

Coagulase-negative staphylococci causing blood stream infection at an Indian tertiary care hospital: Prevalence, antimicrobial resistance and molecular characterisation.

INTRODUCTION: Recent years have seen a rise of coagulase-negative staphylococci (CoNS) from common contaminants to agents of nosocomial blood stream infections (BSI's). Molecular typing and establishing a correlation with antibiotic resistance is essential particularly in countries like India where genotyping studies for drug-resistant CoNS are sparse. METHODS: A prospective study was done over 18 months, wherein 42,693 blood samples were received, and 59 patients with BSI due to CoNS were evaluated. The isolates recovered were identified by a biochemical test panel and matrix-assisted laser desorption ionization - time of flight mass spectrometry followed by antimicrobial susceptibility testing by Kirby-Baur disc diffusion method and E-test strips. Staphylococcal chromosomal cassette mec (SCCmec) element was characterised by multiplex polymerase chain reaction for all methicillin-resistant (MR) isolates. RESULTS: The majority of CoNS isolated were constituted by Staphylococcus haemolyticus (47.5%) followed by Staphylococcus epidermidis (33.9%), Staphylococcus hominis (11.86%), Staphylococcus cohnii (5.08%) and Staphylococcus warneri (1.69%). Among all isolates 57.6% were MR with statistically significant higher resistance versus methicillin sensitive-CoNS. This difference was significant for erythromycin (76% vs. 44%, P = 0.011), rifampicin (50% vs. 12%,P= 0.002) and amikacin (26.5% vs. 4%, P = 0.023), ciprofloxacin (64.7% vs. 20%, P = 0.001) and cotrimoxazole (55.9% vs. 20%, P = 0.006). SCCmec type I was predominant (61.8%, P = 0.028) and exhibited multidrug resistance (76.2%). Coexistence of SCCmec type I and III was seen in 8.82% MR isolates. CONCLUSION: CoNS exhibit high antimicrobial resistance thereby limiting treatment options. The presence of new variants of SCCmec type in hospital-acquired CoNS may predict the antibiotic resistance pattern. This is the first evaluation of the molecular epidemiology of CoNS causing BSI from India and can serve as a guide in the formulation of hospital infection control and treatment guidelines.

Physiologically based and population PK modeling in optimizing drug development: A predict-learn-confirm analysis.

Physiologically based pharmacokinetic (PBPK) modeling and classical population pharmacokinetic (PK) model-based simulations are increasingly used to answer various drug development questions. In this study, we propose a methodology to optimize the development of drugs, primarily cleared by the kidney, using model-based approaches to determine the need for a dedicated renal impairment (RI) study. First, the impact of RI on drug exposure is simulated via PBPK modeling and then confirmed using classical population PK modeling of phase 2/3 data. This methodology was successfully evaluated and applied to an investigational agent, orteronel (nonsteroidal, reversible, selective 17,20-lyase inhibitor). A phase 1 RI study confirmed the accuracy of model-based predictions. Hence, for drugs eliminated primarily via renal clearance, this modeling approach can enable inclusion of patients with RI in phase 3 trials at appropriate doses, which may be an alternative to a dedicated RI study, or suggest that only a reduced-size study in severe RI may be sufficient.

An anti-CD154 domain antibody prolongs graft survival and induces Foxp3(+) iTreg in the absence and presence of CTLA-4 Ig.

The use of monoclonal antibodies targeting the CD154 molecule remains one of the most effective means of promoting graft tolerance in animal models, but thromboembolic complications during early clinical trials have precluded their use in humans. Furthermore, the role of Fc-mediated deletion of CD154-expressing cells in the observed efficacy of these reagents remains controversial. Therefore, determining the requirements for anti-CD154-induced tolerance will instruct the development of safer but equally efficacious treatments. To investigate the mechanisms of action of anti-CD154 therapy, two alternative means of targeting the CD40-CD154 pathway were used: a nonagonistic anti-CD40 antibody and an Fc-silent anti-CD154 domain antibody. We compared these therapies to an Fc-intact anti-CD154 antibody in both a fully allogeneic model and a surrogate minor antigen model in which the fate of alloreactive cells could be tracked. Results indicated that anti-CD40 mAbs as well as Fc-silent anti-CD154 domain antibodies were equivalent to Fc-intact anti-CD154 mAbs in their ability to inhibit alloreactive T cell expansion, attenuate cytokine production of antigen-specific T cells and promote the conversion of Foxp3(+) iTreg. Importantly, iTreg conversion observed with Fc-silent anti-CD154 domain antibodies was preserved in the presence of CTLA4-Ig, suggesting that this therapy is a promising candidate for translation to clinical use.

Gene silencing of A-kinase anchor protein 4 inhibits cervical cancer growth in vitro and in vivo.

Earlier, we reported an association of A-kinase anchor protein 4 (AKAP4) expression in cervical cancer patient specimens, indicating its implications as an immunotherapeutic target. In this study, we investigated the possible role of AKAP4 in cervical carcinogenesis. AKAP4 messenger RNA and protein expression was assessed in four cervical cancer cell line models, C-33A, CaSki, HeLa and SiHa. Gene silencing approach was employed to investigate the potential role of AKAP4 in cellular growth, proliferation, colony-forming ability, migration and invasion in aggressive squamous cell carcinoma cells (SiHa). Further, the effect of downregulation of AKAP4 on tumor growth was examined in the cervical cancer xenograft model in nude mice. Our data clearly indicated that AKAP4 was expressed in all cervical cancer cells at the gene and protein level. We also observed distinct cytoplasmic and surface localization by indirect immunofluorescence and flow cytometry, respectively. Ablation of AKAP4 protein caused significant inhibition in cellular proliferation, colony-forming ability, migration and invasion ability of SiHa cells. Further, gene silencing of AKAP4 also resulted in reduced tumor growth in nude mice in vivo. Collectively, AKAP4 surface localization and its significant association with malignant properties of cervical cancer cells imply its clinical utility as an immunotherapeutic target.

Investigation of the extraction complexes of palladium(II) with novel thiodiglycolamide and dithiodiglycolamide ligands by EXAFS and computational methods.

The structure of the extraction complexes of palladium(II) with novel ligands, namely, N,N,N',N'-tetra-(2-ethylhexyl) thiodiglycolamide (T(2EH)TDGA) and N,N,N',N'-tetra-(2-ethylhexyl) dithiodiglycolamide (DTDGA), have been determined by extended X-ray absorption fine structure spectroscopy (EXAFS). The interpretation of the EXAFS data is well supported by theoretical calculations of the complex geometry based on density functional theory (DFT). T(2EH)TDGA, having one thioetheric 'S' atom, forms a square planar complex with the Pd(II) ion, exhibiting 2: 1stoichiometry with one sulphur atom and one carbonyl oxygen atom from each T(2EH)TDGA molecule interacting with Pd(II) at distances of 2.24 and 2.04 Å, respectively. On the other hand, DTDGA, having two 'S' atoms in addition to two carbonyl groups, forms a square planar complex with Pd(II), exhibiting 1: 1stoichiometry, wherein both the sulphur atoms and the carbonyl oxygen of DTDGA interact with Pd(II) at distances of 2.29 and 2.05 Å, respectively. The slight distortion from the perfect square planar geometry could be attributed to the steric hindrance imposed by the bulky alkyl group of the amidic moieties. DFT calculations for the Pd-ligand complexes show that the Pd(II)-DTDGA complex with 1: 1stoichiometry is energetically more stable than the Pd(II)-T(2EH)TDGA complex with 1: 2stoichiometry. Among the two possible Pd(II)-T(2EH)TDGA complex geometries, the cis configuration appears more favorable. The methodology of fitting the EXAFS data has been validated by fitting the EXAFS data of a Pd(II)-aquo complex which showed square planar geometry with two axial water molecules constituting the secondary hydration sphere.

Role of simvastatin in prevention of vasospasm and improving functional outcome after aneurysmal sub-arachnoid hemorrhage: a prospective, randomized, double-blind, placebo-controlled pilot trial.

BACKGROUND: Vasospasm plays a major role in the morbidity and mortality after aneurysmal subarachnoid hemorrhage (aSAH). The preliminary studies suggest that statins protect against cerebral vasospasm. OBJECTIVE: The aim of the study was to determine the role of simvastatin in preventing clinical vasospasm and improving functional outcome in patients with aSAH. METHODS: All patients with aSAH admitted within 96 h of ictus were randomized to receive either Simvastatin or placebo - 80 mg/day for 14 days. Thirty eight patients were recruited in the study- 19 received Simvastatin and 19 placebo. All the patients underwent surgical clipping of the aneurysm. The primary outcome of the study was the development of clinical cerebral vasospasm. The secondary outcomes included Glasgow Outcome Score (GOS), Modified Rankin Scale (MRS) and Barthel Index Score (MBI) at follow-up at 1, 3 and 6 months. RESULTS: 16% of the patients in the simvastatin group had high Middle Cerebral Artery velocities (> 160 cm/sec) on transcranial Doppler on one or more than one day during the study duration as compared to 26% of the patients in the placebo group (p = 0.70). Neurological deterioration occurred in 26% and 42% of the patients in simvastatin group versus placebo group, respectively (p = 0.31). There was an improvement in the functional outcome in the simvastatin group at 1, 3 or 6 months in the follow-up; however, this difference was not statistically significant. CONCLUSIONS: There was benefit of simvastatin in terms of reduction in clinical vasospasm, mortality or improved functional outcome, however, this was not statistically significant.

Facilitated transport of Pd(II) through a supported liquid membrane (SLM) containing N,N,N',N'-tetra-(2-ethylhexyl) thiodiglycolamide T(2EH)TDGA: a novel carrier.

A novel carrier, N,N,N',N'-tetra-(2-ethylhexyl) thiodiglycolamide, T(2EH)TDGA has been studied for transport of Pd(II) from nitric acid medium across a supported liquid membrane (SLM). Pd(II) was found to be almost quantitatively transported (≈ 99.9%) within 2h from 3.0M HNO(3) medium using 0.05 M T(2EH)TDGA in n-dodecane as carrier and 0.01 M thiourea in 0.2M HNO(3) as strippant. Pd(II) transport was also studied against various parameters like feed acidity, carrier concentration, membrane pore size, etc. Palladium transport was found to be diffusion controlled and the diffusion co-efficient value was found to be 3.56 × 10(-5)cm(2)/s. Selectivity of T(2EH)TDGA for palladium over other fission products was found to be quite high, with the separation factors for Pd, with respect to different fission products being >10(3). With respect to leaching out of carrier from the membrane support, the membrane was found to be stable for six consecutive cycles. Thus, T(2EH)TDGA can be used as an efficient carrier of Pd(II) from nitric acid medium.

Monitored gradual occlusion of the internal carotid artery followed by ligation for giant internal carotid artery aneurysms.

OBJECTIVE: To demonstrate a technique of gradual monitored occlusion of the internal carotid artery (ICA) followed by ligation for giant aneurysms as an option for balloon test occlusion followed by permanent ligation of ICA. MATERIALS AND METHODS: Authors retrospectively analyzed 27 patients with giant and complex ICA aneurysms who underwent carotid artery ligation between January 2001 and December 2010. Clinical presentation included headache, vision loss and diplopia. There were 19 patients with cavernous aneurysm, 5 supraclinoid, 1 ophthalmic, 1 petrous segment and 1 cervical segment aneurysm located extracranially. All demonstrated good cross-circulation. Selverstone clamp was used for gradual occlusion of the ICA over 72 h under closed observation in the intensive care unit. RESULTS: Six patients developed hemiparesis in the postoperative period. Improvement occurred in one patient over two to three weeks while the remaining five patients had residual hemiparesis. One patient developed malignant MCA infarct for which decompressive craniectomy had to be done. There was no mortality in the present series. CONCLUSIONS: Gradual monitored occlusion and ICA ligation may be a simple, safe alternative procedure to clipping in surgically inaccessible and complex aneurysms, especially for surgeons with limited experience. Cross circulation study is an absolute requisite for carotid ligation.

Extractive spectrophotometric determination of palladium with N,N,N',N'-tetra(2-ethylhexyl)-thiodiglycolamide T(2EH)TDGA.

A precise, sensitive and selective method for the spectrophotometric determination of palladium (II) using N,N,N',N'-tetra(2-ethylhexyl) thiodiglycolamide T(2EH)TDGA as an extractant is described. Palladium (II) forms yellow colored complex with T(2EH)TDGA which exhibits an absorption maximum at ∼ 300 nm. The colored complex obeys Beer's law in the concentration range 1.0-15.0 µg ml(-1) of palladium with a molar absorptivity of 1.29 × 10(5)M(-1)cm(-1). The effects of various experimental parameters have been studied to establish the optimum conditions for the extraction and determination of palladium. The precision of the method has been evaluated and the relative standard deviation has been found to be less than 0.5%. The method has been successfully applied to the determination of palladium in simulated high level liquid waste (SHLW) solution.

Targeted therapy for high-grade glioma with the TGF-ß2 inhibitor trabedersen: results of a randomized and controlled phase IIb study.

This randomized, open-label, active-controlled, dose-finding phase IIb study evaluated the efficacy and safety of trabedersen (AP 12009) administered intratumorally by convection-enhanced delivery compared with standard chemotherapy in patients with recurrent/refractory high-grade glioma. One hundred and forty-five patients with central reference histopathology of recurrent/refractory glioblastoma multiforme (GBM) or anaplastic astrocytoma (AA) were randomly assigned to receive trabedersen at doses of 10 or 80 µM or standard chemotherapy (temozolomide or procarbazine/lomustine/vincristine). Primary endpoint was 6-month tumor control rate, and secondary endpoints included response at further timepoints, survival, and safety. Six-month tumor control rates were not significantly different in the entire study population (AA and GBM). Prespecified AA subgroup analysis showed a significant benefit regarding the 14-month tumor control rate for 10 µM trabedersen vs chemotherapy (p= .0032). The 2-year survival rate had a trend for superiority for 10 µM trabedersen vs chemotherapy (p = .10). Median survival for 10 µM trabedersen was 39.1 months compared with 35.2 months for 80 µM trabedersen and 21.7 months for chemotherapy (not significant). In GBM patients, response and survival results were comparable among the 3 arms. Exploratory analysis on GBM patients aged ≤55 years with Karnofsky performance status >80% at baseline indicated a 3-fold survival at 2 and 3 years for 10 µM trabedersen vs chemotherapy. The frequency of patients with related or possibly drug-related adverse events was higher with standard chemotherapy (64%) than with 80 µM trabedersen (43%) and 10 µM trabedersen (27%). Superior efficacy and safety for 10 µM trabedersen over 80 µM trabedersen and chemotherapy and positive risk-benefit assessment suggest it as the optimal dose for further clinical development in high-grade glioma.

Use of intravenous immune globulin in the ICU: a retrospective review of prescribing practices and patient outcomes.

RATIONALE: Intravenous immune globulin (IVIG) is a pooled human blood product. Much of IVIG use in Canada is prescribed for 'unlabelled' or 'off-label' indications. Due to costs, risk of use and limited supply, knowledge about the use of IVIG is important. We collected data regarding the usage of IVIG and outcomes of patients receiving IVIG in the intensive care units (ICUs) of two community and three academic hospitals. METHODS: We reviewed the charts of adult patients who received IVIG in the five ICUs over a 5-year period. Data collection included demographics, severity of illness, indication for and dose of IVIG, mortality and adverse effects. On the basis of a classification developed by Canadian Blood Services, the indications for IVIG were then classified as 'appropriate' or 'inappropriate'. RESULTS: One hundred and forty-five patients received IVIG in the ICU. In all, 19% of IVIG prescriptions were for 'appropriate' indications and 7% were 'inappropriate'. The remaining 74% were prescribed for indications with some evidence to support their use. Three indications accounted for 50% of all IVIG prescribed: Guillain-Barre syndrome (GBS), necrotising fasciitis (NF) and toxic epidermal necrolysis (TEN). Both the community and academic centres prescribed IVIG for similar indications. Adverse effects associated with IVIG administration included deep vein thrombosis/pulmonary embolism, fever and renal failure, although direct causation related to IVIG could not be established. The overall mortality rate was 55%. CONCLUSIONS: IVIG is used relatively infrequently in the critical care setting. The most common indications were GBS, TEN and NF. Mortality was high. There was no difference between community and academic ICUs.

Early administration of thrombolysis can prevent myocardial necrosis: time is myocardium.

A case is presented in which a 66-year-old man received thrombolysis for an acute ST elevation myocardial infarction (STEMI) within 6 minutes of developing chest pain. An ECG performed 10 minutes after thrombolysis showed complete resolution of the ST segment elevation and showed no other abnormality. An echocardiogram showed normal left ventricular function and there was no detectable myocardial necrosis, as evidenced by two negative troponin assays. The case clearly reinforces the benefits of the rapid delivery of thrombolysis when appropriate for patients with STEMI. Clinicians need to be aware of the benefits of early thrombolysis as laid out in the national service framework. Evidence for the early administration of thrombolysis, data from the Myocardial Infarction National Audit Project and the future with regard to improving thrombolysis times are discussed.

Endoscopic third ventriculostomy: 5 years' experience at the All India Institute of Medical Sciences.

Endoscopic third ventriculostomy (ETV) is one of the efficacious surgical options available for obstructive hydrocephalus, and is preferable to a ventriculoperitoneal shunt in those eligible. We retrospectively studied 115 cases, who underwent ETV at our institute over the last 5 years. Thirty-eight patients were infants. Major indications for ETV were aqueductal stenosis (n = 60/115, 52.2%), Dandy-Walker malformation (15/115, 13%), associated arachnoid cyst (n = 13/115, 11.3%) and post-meningitic hydrocephalus (n = 12/115, 10.4%). Average duration of the follow-up was 10.6 months. Ninety-nine patients (86.1%) showed clinical improvement after surgery. Clinical improvement was seen in 27 out of 38 infants (71%) followed up. ETV is a highly effective tool in all age groups of patients for the management of hydrocephalus. Clinical features should be considered as indications of the success or failure of ventriculostomy in infants who have low-pressure hydrocephalus.