Succinct Indexable Dictionaries with Applications to Encoding kk-ary Trees, Prefix Sums and Multisets

We consider the {\it indexable dictionary} problem, which consists of storing a set $S \subseteq \{0,...,m-1\}$ for some integer $m$, while supporting the operations of \Rank(x), which returns the number of elements in $S$ that are less than $x$ if $x \in S$, and -1 otherwise; and \Select(i) which returns the $i$-th smallest element in $S$. We give a data structure that supports both operations in O(1) time on the RAM model and requires ${\cal B}(n,m) + o(n) + O(\lg \lg m)$ bits to store a set of size $n$, where {\cal B}(n,m) = \ceil{\lg {m \choose n}} is the minimum number of bits required to store any $n$-element subset from a universe of size $m$. Previous dictionaries taking this space only supported (yes/no) membership queries in O(1) time. In the cell probe model we can remove the $O(\lg \lg m)$ additive term in the space bound, answering a question raised by Fich and Miltersen, and Pagh. We present extensions and applications of our indexable dictionary data structure, including: An information-theoretically optimal representation of a $k$-ary cardinal tree that supports standard operations in constant time, A representation of a multiset of size $n$ from $\{0,...,m-1\}$ in ${\cal B}(n,m+n) + o(n)$ bits that supports (appropriate generalizations of) \Rank and \Select operations in constant time, and A representation of a sequence of $n$ non-negative integers summing up to $m$ in ${\cal B}(n,m+n) + o(n)$ bits that supports prefix sum queries in constant time.Comment: Final version of SODA 2002 paper; supersedes Leicester Tech report 2002/1

PENGARUH PENERAPAN TEKNOLOGI INFORMASI DAN PENERAPAN PENCATATAN KEUANGAN BERBASIS SAK ETAP TERHADAP EFEKTIVITAS PENGENDALIAN BIAYA

Efektivitas pengendalian biaya di tingkat desa merupakan aspek krusial dalam menjaga keberlanjutan dan keseimbangan keuangan lokal. Desa memegang peranan penting dalam kemajuan perekonomian negara. Dalam Undang-Undang Republik Indonesia Nomor 6 Tahun 2014 tentang desa, desa dapat didefinisikan sebagai suatu kesatuan masyarakat hukum yang memiliki batas wilayah dan berwenang untuk mengatur masalah pemerintahan, kepentingan masyarakat berdasarkan prakarsa masyarakat, hal asal-usul dan/atau hak tradisional yang diakui dan dihormati dalam sistem pemerintahan Negara Republik Indonesia. Tujuan penelitian ini untuk mendorong perekonomian dan kesejahteraan masyarakat desa pemerintah perlu mendirikan lembaga mikro di wilayah desa yang dapat membantu dan menggerakkan pertumbuhan ekonomi masyarakat dengan memanfaatkan potensi yang dimiliki oleh desa yaitu Badan Usaha Milik Desa (BUMDes). Penelitian ini dilakukan di wilayah Kota Denpasar Provinsi Bali. Jumlah sampel dalam penelitian ini sebanyak 100. Pengumpulan data dilakukan melalui pengisian kuesioner yang sudah disebarkan oleh peneliti. Teknik analisis yang digunakan adalah analisis regresi linear berganda. Berdasarkan hasil penelitian ditemukan bahwa penerapan teknologi informasi berpengaruh positif dan signifikan terhadap efektivitas pengendalian biaya. Penerapan pencatatan keuangan berbasis SAK ETAP berpengaruh positif dan signifikan terhadap efektivitas pengendalian biaya

Intracellular cytokine staining and flow cytometry: Considerations for application in clinical trials of novel tuberculosis vaccines

Intracellular cytokine staining combined with flow cytometry is one of a number of assays designed to assess T-cell immune responses. It has the specific advantage of enabling the simultaneous assessment of multiple phenotypic, differentiation and functional parameters pertaining to responding T-cells, most notably, the expression of multiple effector cytokines. These attributes make the technique particularly suitable for the assessment of T-cell immune responses induced by novel tuberculosis vaccines in clinical trials. However, depending upon the particular nature of a given vaccine and trial setting, there are approaches that may be taken at different stages of the assay that are more suitable than other alternatives. In this paper, the Tuberculosis Vaccine Initiative (TBVI) TB Biomarker Working group reports on efforts to assess the conditions that will determine when particular assay approaches should be employed. We have found that choices relating to the use of fresh whole blood or peripheral blood mononuclear cells (PBMC) and frozen PBMC; use of serum-containing or serum-free medium; length of stimulation period and use of co-stimulatory antibodies can all affect the sensitivity of intracellular cytokine assays. In the case of sample material, frozen PBMC, despite some loss of sensitivity, may be more advantageous for batch analysis. We also recommend that for multi-site studies, common antibody panels, gating strategies and analysis approaches should be employed for better comparability

Gene expression and cytokine profile correlate with mycobacterial growth in a human BCG challenge model

Background:  Bacillus Calmette-Guerin (BCG) vaccine is the most widely administered vaccine in the world, yet its mechanism of action remains unclear. We hypothesize that certain immune pathways are associated with reduced mycobacterial growth following BCG challenge in human volunteers. Methods:  We used samples from a mycobacterial challenge in which previously BCG-vaccinated or BCG-naive adults in the United Kingdom were challenged intradermally with a standard dose of BCG. Any remaining BCG was quantified in a skin biopsy specimen obtained 2 weeks after challenge and used as a measure of BCG growth and functional antimycobacterial immunity. We measured the immune response over the 2-week challenge, using DNA microarrays and flow cytometry, and correlated this with mycobacterial growth. Results:  The magnitude of the immune response to BCG is greater in previously vaccinated volunteers, and this correlates with reduced mycobacterial growth but increased scarring at the vaccination site. In particular, the interferon γ and interleukin 17 pathways are strongly induced in previously vaccinated volunteers and correlate with reduced mycobacterial growth in this population. Conclusion:  This study identifies pathways associated with control of mycobacterial growth in vivo in human volunteers and supports the use of BCG challenge as a tool for evaluating vaccine efficacy and identifying mechanisms of antimycobacterial immunity

Risk of diabetes mellitus among users of immune checkpoint inhibitors: A population‐based cohort study

Background Immune checkpoint inhibitors (ICIs) are increasingly established cancer therapeutics, but they are associated with new-onset diabetes mellitus (DM). Such risks have not been adequately quantified, and between-class and -sex differences remain unexplored. Methods This was a prospective cohort study of cancer patients receiving any ICI in Hong Kong between 2013 and 2021. Patients with known DM were excluded. Due to few patients using other ICIs, only programmed cell death 1 inhibitors (PD-1i) and programmed death ligand 1 inhibitors (PD-L1i) were compared, alongside between-sex comparison. When comparing PD-1i against PD-L1i, patients with the use of other ICIs or both PD-1i and PD-L1 were further excluded. Inverse probability treatment weighting (IPTW) was used to minimize between-group covariate imbalances. Results Altogether, 3375 patients were analyzed (65.2% males, median age 62.2 [interquartile range 53.8–69.5] years old). Over a median follow-up of 1.0 [0.4–2.4] years, new-onset DM occurred in 457 patients (13.5%), with a 3-year risk of 14.5% [95% confidence interval 13.3%, 15.8%]. IPTW achieve acceptable covariate balance between sexes, and between PD-1i (N = 622) and PD-L1i (N = 2426) users. Males had significantly higher risk of new-onset DM (hazard ratio 1.35 [1.09, 1.67], p = 0.006), while PD-1i and PD-L1i users did not have significantly different risks (hazard ratio vs PD-L1i 0.81 [0.59, 1.11], p = 0.182). These were consistent in those with at least 1 year of follow-up, and on competing risk regression. Conclusion Users of ICI may have a substantial risk of new-onset DM, which may be higher in males but did not differ between PD-1i and PD-L1i

Randomised, double-blind, controlled phase 1 trial of the candidate tuberculosis vaccine ChAdOx1-85A delivered by aerosol versus intramuscular route.

A BCG booster vaccination administered via the respiratory mucosa may establish protective immune responses at the primary site of Mycobacterium tuberculosis infection. The primary objective of this trial was to compare the safety and immunogenicity of inhaled versus intramuscular administered ChAdOx1-85A. We conducted a single-centre, randomised, double-blind, controlled phase 1 study (Swiss National Clinical Trials Portal number SNCTP000002920). After a dose-escalation vaccination in nine BCG-vaccinated healthy adults, a dose of 1 × 10 <sup>10</sup> vp of ChAdOx1-85A was administered to twenty BCG-vaccinated adults that were randomly allocated (1:1) into two groups: aerosol ChAdOx1-85A with intramuscular saline placebo or intramuscular ChAdOx1-85A with aerosol saline placebo, using block randomisation. A control group of ten BCG-naïve adults received aerosol ChAdOx1-85A at the same dose. Primary outcomes were solicited and unsolicited adverse events (AEs) up to day 16 post-vaccination and Serious AEs (SAEs) up to 24 weeks; secondary outcomes were cell-mediated and humoral immune responses in blood and bronchoalveolar lavage (BAL) samples. Both vaccination routes were well tolerated with no SAEs. Intramuscular ChAdOx1-85A was associated with more local AEs (mostly pain at the injection site) than aerosol ChAdOx1-85A. Systemic AEs occurred in all groups, mainly fatigue and headaches, without differences between groups. Respiratory AEs were not different between BCG-vaccinated groups. Aerosol ChAdOx1-85A vaccination induced Ag85A BAL and systemic cellular immune responses with compartmentalisation of the immune responses: aerosol ChAdOx1-85A induced stronger BAL cellular responses, particularly IFNγ/IL17+CD4+ T cells; intramuscular ChAdOx1-85A induced stronger systemic cellular and humoral responses. Inhaled ChAdOx1-85A was well-tolerated and induced lung mucosal and systemic Ag85A-specific T-cell responses. These data support further evaluation of aerosol ChAdOx1-85A and other viral vectors as a BCG-booster vaccination strategy

Inflammatory and myeloid-associated gene expression before and one day after infant vaccination with MVA85A correlates with induction of a T cell response.

BACKGROUND: Tuberculosis (TB) remains a global health problem, with vaccination likely to be a necessary part of a successful control strategy. Results of the first Phase 2b efficacy trial of a candidate vaccine, MVA85A, evaluated in BCG-vaccinated infants were published last year. Although no improvement in efficacy above BCG alone was seen, cryopreserved samples from this trial provide an opportunity to study the immune response to vaccination in this population. METHODS: We investigated blood samples taken before vaccination (baseline) and one and 28 days post-vaccination with MVA85A or placebo (Candin). The IFN-γ ELISpot assay was performed at baseline and on day 28 to quantify the adaptive response to Ag85A peptides. Gene expression analysis was performed at all three timepoints to identify early gene signatures predictive of the magnitude of the subsequent adaptive T cell response using the significance analysis of microarrays (SAM) statistical package and gene set enrichment analysis. RESULTS: One day post-MVA85A, there is an induction of inflammatory pathways compared to placebo samples. Modules associated with myeloid cells and inflammation pre- and one day post-MVA85A correlate with a higher IFN-γ ELISpot response post-vaccination. By contrast, previous work done in UK adults shows early inflammation in this population is not associated with a strong T cell response but that induction of regulatory pathways inversely correlates with the magnitude of the T cell response. This may be indicative of important mechanistic differences in how T cell responses develop in these two populations following vaccination with MVA85A. CONCLUSION: The results suggest the capacity of MVA85A to induce a strong innate response is key to the initiation of an adaptive immune response in South African infants but induction of regulatory pathways may be more important in UK adults. Understanding differences in immune response to vaccination between populations is likely to be an important aspect of developing successful vaccines and vaccination strategies. TRIAL REGISTRATION: ClinicalTrials.gov number NCT00953927

Controlled One-Pot Synthesis of Polystyrene-block-Polycaprolactone Copolymers by Simultaneous RAFT and ROP

A convenient one-pot method for the controlled synthesis of polystyrene- block -polycaprolactone (PS- b -PCL) copolymers by simultaneous reversible addition?fragmentation chain transfer (RAFT) and ring-opening polymerization (ROP) processes is reported. The strategy involves the use of 2-(benzylsulfanylthiocarbonylsulfanyl)ethanol (1) for the dual roles of chain transfer agent (CTA) in the RAFT polymerization of styrene and co-initiator in the ROP of ε -caprolactone. One-pot poly merizations using the electrochemically stable ROP catalyst diphenyl phosphate (DPP) yield well-defi ned PS- b -PCL in a relatively short reaction time (≈4 h; Mn = 9600−43 600 g mol−1 ; Mw/Mn = 1.21−1.57). Because the hydroxyl group is strategically located on the Z substituent of the CTA, segments of these diblock copolymers are connected through a trithiocarbonate group, thus offering an easy way for subsequent growth of a third segment between PS and PCL. In contrast, an oxidatively unstable Sn(Oct) 2 ROP catalyst reacts with (1) leading to multimodal distributions of polymer chains with variable composition.Fil: de Freitas, Augusto G. O.. Universidade Federal de Santa Maria; BrasilFil: Trindade, Suelen G.. Universidade Federal de Santa Maria; BrasilFil: Muraro, Paulo I. R.. Universidade Federal de Santa Maria; BrasilFil: Schmidt, Vanessa. Universidade Federal de Santa Maria; BrasilFil: Satti, Angel Jose. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Planta Piloto de Ingeniería Química (i); ArgentinaFil: Villar, Marcelo Armando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Planta Piloto de Ingeniería Química (i); ArgentinaFil: Ciolino, Andrés Eduardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Bahía Blanca. Planta Piloto de Ingeniería Química (i); ArgentinaFil: Giacomelli, Cristiano. Universidade Federal de Santa Maria; Brasi

A phase I study evaluating the safety and immunogenicity of MVA85A, a candidate TB vaccine, in HIV-infected adults

PMCID: PMC3221299Objectives Control of the tuberculosis (TB) epidemic is a global health priority and one that is likely to be achieved only through vaccination. The critical overlap with the HIV epidemic requires any effective TB vaccine regimen to be safe in individuals who are infected with HIV. The objectives of this clinical trial were to evaluate the safety and immunogenicity of a leading candidate TB vaccine, MVA85A, in healthy, HIV-infected adults. Design This was an open-label Phase I trial, performed in 20 healthy HIV-infected, antiretroviral-naïve subjects. Two different doses of MVA85A were each evaluated as a single immunisation in 10 subjects, with 24 weeks of follow-up. The safety of MVA85A was assessed by clinical and laboratory markers, including regular CD4 counts and HIV RNA load measurements. Vaccine immunogenicity was assessed by ex vivo interferon γ (IFN-γ) ELISpot assays and flow-cytometric analysis. Results MVA85A was safe in subjects with HIV infection, with an adverse-event profile comparable with historical data from previous trials in HIV-uninfected subjects. There were no clinically significant vaccine-related changes in CD4 count or HIV RNA load in any subjects, and no evidence from qPCR analyses to indicate that MVA85A vaccination leads to widespread preferential infection of vaccine-induced CD4 T cell populations. Both doses of MVA85A induced an antigen-specific IFN-γ response that was durable for 24 weeks, although of a lesser magnitude compared with historical data from HIV-uninfected subjects. The functional quality of the vaccine-induced T cell response in HIV-infected subjects was remarkably comparable with that observed in healthy HIV-uninfected controls, but less durable. Conclusion MVA85A is safe and immunogenic in healthy adults infected with HIV. Further safety and efficacy evaluation of this candidate vaccine in TB- and HIV-endemic areas is merited.Wellcome Trust (grant no WT076943MA), TBVAC (an EU 6th Framework programme grant) and The National Institute of Health Research Oxford Biomedical Research Centr