Synaptic Transmission: An Information-Theoretic Perspective

Here we analyze synaptic transmission from an information-theoretic perspective. We derive closed-form expressions for the lower-bounds on the capacity of a simple model of a cortical synapse under two explicit coding paradigms. Under the ``signal estimation'' paradigm, we assume the signal to be encoded in the mean firing rate of a Poisson neuron. The performance of an optimal linear estimator of the signal then provides a lower bound on the capacity for signal estimation. Under the ``signal detection'' paradigm, the presence or absence of the signal has to be detected. Performance of the optimal spike detector allows us to compute a lower bound on the capacity for signal detection. We find that single synapses (for empirically measured parameter values) transmit information poorly but significant improvement can be achieved with a small amount of redundancy.Comment: 7 pages, 4 figures, NIPS97 proceedings: neuroscience. Originally submitted to the neuro-sys archive which was never publicly announced (was 9809002

Creating learning solutions for executive education programs

Executive education is both a growing and increasingly competitive industry. The traditional business school, once a dominant player in this space, now faces competition from sophisticated and focused consultants and for-profit training specialists offering a variety of face-to-face and on-line instructional vehicles. An abiding question has become ever more prevalent for business schools – are executive education clients getting meaningful, long-term value for their significant investments? Demonstrating value and building capabilities is different for a generic, open enrolment course than for a custom program. This paper proposes a solutions-based approach to the development and implementation of customized executive programs, arguing that the tailored customer focus and the operational rigor of a solutions perspective leads to sustainable and measurable client value both at the individual and corporate level. A case study involving a global high technology company is used to demonstrate the steps required to apply a solutions roadmap. The results show that a solutions approach – carefully and collaboratively undertaken in selected settings – can provide considerable benefits to both client and provider. Further research is proposed to validate and develop the learning points

Bilateral internal iliac artery ligation: the procedure of choice in life threatening postpartum haemorrhage

Background: The present study was to assess the indication and study the intraoperative and postoperative complications of bilateral internal iliac artery ligation. Aim of this study was to evaluate the effectiveness of internal iliac artery ligation in arresting postpartum haemorrhage.Methods: This is a retrospective study carried out between January 2015 to December 2018 at Shrimati Kashibai Navale Medical College and General Hospital, Pune. This study included 48 patients with life-threatening PPH. Bilateral internal iliac artery ligation was done by anterior approach in 7 patients and by posterior approach in 41 patients.Results: Intraoperative and postoperative complications were noted in all patients. Of the total patients, 10 required massive blood transfusion and 12 underwent obstetrical hysterectomies (n=12; 25%). Internal iliac vein injury was seen in 1 patient (n=1; 2.08%) and external vein thrombosis was noted in 3 patients (n=3; 6.25%). Maternal mortality was observed in 1 patient due to DIC on day 9 (n=1; 2.08%). The uterine salvage rate was 75%.Conclusions: Internal iliac artery ligation (IIAL) safe, rapid, effective, time tested method of controlling bleeding from genital tract

Complications of gynaecologic laparoscopy: an audit

Background: Minimal access surgery as a modality of treatment for various gynecologic conditions is rapidly gaining grounds in the recent years1. Approximately 30 years after its introduction; the use of laparoscopy in gynecology has evolved from diagnostic purposes into a more coordinated system for the repair or removal of diseased abdominal and pelvic organs. The rapid increase in the number of procedures being performed, the introduction of new equipment, and variability in the training of surgeons all contribute to the complication rate. The objective is to review complications associated with laparoscopic gynecological surgeries and identify associated risk factors.Methods: Hospital based descriptive observational study performed between January 2013 to December 2017 which included all gynecologic laparoscopies performed in present institute. Variables were recorded for patient characteristics, indication for surgery, length of hospital stay (in days), major and minor complications, conversions to laparotomy and postoperative complications. The laparoscopic procedures were divided into three subgroups: Diagnostic cases, tubal sterilization and Advanced operative laparoscopy.Results: Of all 3724 laparoscopies included, overall frequency of major was 1.96 %, and that of minor complications was 3.51%. Of 3724 laparoscopic procedures, 214 complications occurred (5.8% of all procedures) and one death occurred. The level of technical difficulty and existence of prior abdominal surgery were associated with a higher risk of major complications and conversions to laparotomy.Conclusions: Laparoscopic surgery has many advantages, but it is not without complications. Despite rapidly improving technical equipment’s and surgical skill; complication rates and preventable injuries demonstrate continuous pattern. Delayed recognition and intervention add to morbidity and mortality. Each laparoscopic surgeon should be aware of the potential complications, how they can be prevented and managed efficiently

Extracardiac 18F-florbetapir imaging in patients with systemic amyloidosis: more than hearts and minds

PURPOSE: 18F-Florbetapir has been reported to show cardiac uptake in patients with systemic light-chain amyloidosis (AL). This study systematically assessed uptake of 18F-florbetapir in patients with proven systemic amyloidosis at sites outside the heart. METHODS: Seventeen patients with proven cardiac amyloidosis underwent 18F-florbetapir PET/CT imaging, 15 with AL and 2 with transthyretin amyloidosis (ATTR). Three patients had repeat scans. All patients had protocolized assessment at the UK National Amyloidosis Centre including imaging with 123I-serum amyloid P component (SAP). 18F-Florbetapir images were assessed for areas of increased tracer accumulation and time-uptake curves in terms of standardized uptake values (SUVmean) were produced. RESULTS: All 17 patients showed 18F-florbetapir uptake at one or more extracardiac sites. Uptake was seen in the spleen in 6 patients (35%; 6 of 9, 67%, with splenic involvement on 123I-SAP scintigraphy), in the fat in 11 (65%), in the tongue in 8 (47%), in the parotids in 8 (47%), in the masticatory muscles in 7 (41%), in the lungs in 3 (18%), and in the kidney in 2 (12%) on the late half-body images. The 18F-florbetapir spleen retention index (SRI) was calculated. SRI >0.045 had 100% sensitivity/sensitivity (in relation to 123I-SAP splenic uptake, the current standard) in detecting splenic amyloid on dynamic imaging and a sensitivity of 66.7% and a specificity of 100% on the late half-body images. Intense lung uptake was seen in three patients, one of whom had lung interstitial infiltration suggestive of amyloid deposition on previous high-resolution CT. Repeat imaging showed a stable appearance in all three patients suggesting no early impact of treatment response. CONCLUSION: 18F-Florbetapir PET/CT is a promising tool for the detection of extracardiac sites of amyloid deposition. The combination of uptake in the heart and uptake in the spleen on 18F-florbetapir PET/CT, a hallmark of AL, suggests that this tracer holds promise as a screening tool for AL

Autologous stem cell transplantation vs bortezomib based chemotheraphy for the first‐line treatment of systemic light chain amyloidosis in the UK

OBJECTIVES: The benefit of autologous stem cell transplantation (ASCT) in the treatment of light chain (AL) amyloidosis requires re-evaluation in the modern era. This retrospective case-matched study compares ASCT to bortezomib for the treatment of patients with AL amyloidosis. METHODS: Newly diagnosed patients with AL amyloidosis treated with ASCT or bortezomib between 2001-2018 were identified. Patients were excluded if the time from diagnosis to treatment exceeded 12 months. Patients were matched on a 1:1 basis, using a propensity matched scoring approach. RESULTS: A total of 136 propensity-score matched patients were included (ASCT n= 68, bortezomib n=68). There was no significant difference in overall survival at two years (p=0.908, HR: 0.95, CI:0.41-2.20). For ASCT vs. bortezomib: overall haematological response rate at six months was 90.6% vs. 92.5%; organ response at 12 months: cardiac (70.0% vs. 54%, p>0.999), renal (74% vs.24%, p=0.463)) liver (21% vs. 22%, p=0.048); median progression free survival (50 vs. 42 months p=0.058, HR:0.61, CI:0.37-1.02) and time to next treatment (68 vs. 45 months, p=0.145, HR:0.61, CI:0.31-1.19). More patients required treatment in the bortezomib group compared to ASCT group at 24 months (41 vs. 23, Chi squared p=0.004) and 48 months (57 vs 41, Chi squared p= 0.004). CONCLUSIONS: This small retrospective study suggests that there is no clear survival advantage of ASCT over bortezomib therapy. A prospective randomised controlled trial evaluating ASCT in AL amyloidosis is critically needed

Consequences of converting graded to action potentials upon neural information coding and energy efficiency

Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na+ and K+ channels, with generator potential and graded potential models lacking voltage-gated Na+ channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na+ channels necessary for action potential generation increase intrinsic noise and (2) introduce non-linearities, and (3) the finite duration of the action potential creates a ‘footprint’ in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation

Candidate Sequence Variants and Fetal Hemoglobin in Children with Sickle Cell Disease Treated with Hydroxyurea

Fetal hemoglobin level is a heritable complex trait that strongly correlates with the clinical severity of sickle cell disease. Only few genetic loci have been identified as robustly associated with fetal hemoglobin in patients with sickle cell disease, primarily adults. The sole approved pharmacologic therapy for this disease is hydroxyurea, with effects largely attributable to induction of fetal hemoglobin. In a multi-site observational analysis of children with sickle cell disease, candidate single nucleotide polymorphisms associated with baseline fetal hemoglobin levels in adult sickle cell disease were examined in children at baseline and induced by hydroxyurea therapy. For baseline levels, single marker analysis demonstrated significant association with BCL11A and the beta and epsilon globin loci (HBB and HBE, respectively), with an additive attributable variance from these loci of 23%. Among a subset of children on hydroxyurea, baseline fetal hemoglobin levels explained 33% of the variance in induced levels. The variant in HBE accounted for an additional 13% of the variance in induced levels, while variants in the HBB and BCL11A loci did not contribute beyond baseline levels. These findings clarify the overlap between baseline and hydroxyurea-induced fetal hemoglobin levels in pediatric disease. Studies assessing influences of specific sequence variants in these and other genetic loci in larger populations and in unusual hydroxyurea responders are needed to further understand the maintenance and therapeutic induction of fetal hemoglobin in pediatric sickle cell disease

Administration of BPX-501 Cells Following Αβ T and B-Cell-Depleted HLA Haploidentical HSCT (haplo-HSCT) in Children with Acute Leukemias (AL)

Background Allogeneic HSCT is a well-established treatment for children with AL. For pts lacking a compatible matched related or unrelated donor, HLA-haplo-HSCT represents an alternative. Promising results were reported with selective depletion of αβ T and B cells (Locatelli, Blood 2017). PX-501 is an allogeneic product consisting of T cells modified to express the inducible caspase-9 (iC9) safety switch and truncated CD19 to allow monitoring and expansion of BPX-501 following transplant. BPX-501 provides broad virus and tumor-specific immunity; the safety switch provides the unique ability to promptly and durably resolve graft-versus-host disease (GvHD) symptoms following the administration of rimiducid. Aims Evaluate the safety and efficacy of BPX-501 in pediatric pts with AL by determining whether BPX-501 infusion can increase efficacy outcomes through an enhanced graft-versus-leukemic (GvL) effect, while maintaining a low risk of GvHD. Methods A subset of pts had high-risk ALs. BPX-501 was planned to be infused on day14±4 after the allograft with no post-transplant GvHD prophylaxis allowed. Pts who developed steroid-resistant GvHD could receive ≥1 dose of rimiducid. Results As of June 30, 2018, 100 pts with AL (described in Table 1) were efficacy evaluable. Median time for neutrophil and platelet engraftment was 16 and 12 days, respectively. Four pts (4.1%) experienced primary graft failure. Of 96 evaluable pts, 5 (3.1%) developed Grade III-IV aGvHD. Of 82 evaluable pts, 12 developed cGvHD (18.1%), with 3 moderate-severe. Rimiducid was administered to 10 pts. Best overall clinical response (CR/PR) post-rimiducid was 80% (8 pts). Among responding patients, 7 (87.5%) had a CR. Six (6.6%) pts died after transplantation. Efficacy outcomes in AL subsets are in Table 2. CD3+ and CD3+CD4+ T cells above 500 cells/ml were achieved by 180 and 270 days, respectively. IgA and IgM levels achieved normal values by 180 days. Conclusion BPX-501 following αβ-T and B-cell depleted haplo-HSCT represents a highly effective transplantation strategy for pediatric pts with AL. Rimiducid was an effective treatment for pts with steroid-resistant GvHD

99mTc-DPD scintigraphy in immunoglobulin light chain (AL) cardiac amyloidosis

AIMS: Technetium-99m-labelled 3,3-diphosphono-1,2-propanodicarboxylic acid (99mTc-DPD scintigraphy) is recognized as highly accurate for the non-invasive diagnosis of transthyretin (ATTR) cardiac amyloidosis (CA). A proportion of patients with immunoglobulin light chain (AL) CA have also been reported to show cardiac 99mTc-DPD uptake. Herein, we assessed the frequency and degree of cardiac 99mTc-DPD uptake and its clinical significance among patients with AL CA. METHODS AND RESULTS: Between 2010 and 2017, 292 consecutive patients with AL CA underwent 99mTc-DPD scintigraphy and were included in this study: 114 (39%) had cardiac 99mTc-DPD uptake: grade 1 in 75%, grade 2 in 17%, and grade 3 in 8% of cases. Patients with cardiac 99mTc-DPD uptake had poorer cardiac systolic function and higher N-terminal pro-brain natriuretic peptide. No differences were noted in cardiac magnetic resonance parameters between patients with and without cardiac 99mTc-DPD uptake (N = 19 and 42, respectively). Patients with cardiac 99mTc-DPD uptake showed a trend to worse survival than those with no uptake (log-rank P = 0.056). Among 22 patients who underwent serial 99mTc-DPD scintigraphy, 5 (23%) showed reduction in the grade of cardiac uptake. CONCLUSIONS: In this large cohort of patients with AL CA, 99mTc-DPD scintigraphy ∼40% of cases showed cardiac uptake, including grade 2-3 in 10% of all patients (25% of those with cardiac 99mTc-DPD uptake). Cardiac 99mTc-DPD uptake was associated with poorer cardiac function and outcomes. These data highlight the critical importance of ruling out AL amyloidosis in all patients with cardiac 99mTc-DPD uptake to ensure such patients are not assumed to have ATTR CA