Type Checking Research Articles

Cardiovascular Safety in Type 2 Diabetes With Sulfonylureas as Second-Line Drugs: A Nation-Wide Population-Based Comparative Safety Study.

To assess the real-world cardiovascular (CV) safety for sulfonylureas (SU), in comparison with dipeptidylpeptidase-4 inhibitors (DPP4i) and thiazolidinediones (TZD), through development of robust methodology for causal inference in a whole nation study. A cohort study was performed including people with type 2 diabetes diagnosed in Scotland before 31 December 2017, who failed to reach HbA1c 48 mmol/mol despite metformin monotherapy and initiated second-line pharmacotherapy (SU/DPP4i/TZD) on or after 1 January 2010. The primary outcome was composite major adverse cardiovascular events (MACE), including hospitalization for myocardial infarction, ischemic stroke, heart failure, and CV death. Secondary outcomes were each individual end point and all-cause death. Multivariable Cox proportional hazards regression and an instrumental variable (IV) approach were used to control confounding in a similar way to the randomization process in a randomized control trial. Comparing SU to non-SU (DPP4i/TZD), the hazard ratio (HR) for MACE was 1.00 (95% CI: 0.91-1.09) from the multivariable Cox regression and 1.02 (0.91-1.13) and 1.03 (0.91-1.16) using two different IVs. For all-cause death, the HR from Cox regression and the two IV analyses was 1.03 (0.94-1.13), 1.04 (0.93-1.17), and 1.03 (0.90-1.17). Our findings contribute to the understanding that second-line SU for glucose lowering are unlikely to increase CV risk or all-cause mortality. Given their potent efficacy, microvascular benefits, cost effectiveness, and widespread use, this study supports that SU should remain a part of the global diabetes treatment portfolio.

Evaluation of the Wound Healing Potential of Hypericum triquetrifolium Turra: An Experimental Animal Study and Histopathological Examination

The wound healing potential of the aerial parts of Hypericum triquetrifolium Turra (Hypericaceae) was evaluated using an in vivo excision wound model in rats. Adult male Sprague Dawley rats were randomly assigned into seven groups; blank vehicles (olive oil and petroleum jelly), negative control, treatments [H. triquetrifolium ethanolic extract in petroleum jelly (5% and 10%) and H. triquetrifolium olive oil macerate (100 and 200 g/L)], and positive control (MEBO). Treatments were applied topically once daily until the wounds had completely healed. Wound areas and contraction rates were calculated, and full-thickness samples of the healed skin were collected for histopathological examination. H. triquetrifolium ointment (5%) showed the best wound healing activity with statistically significant differences when compared with the MEBO, petroleum jelly, and the negative control groups. Tissue sections were histopathologically examined in terms of re-epithelialization, granulation tissue development, collagen deposition, inflammatory cell infiltration, angiogenesis, and ulcer formation to support the in vivo excision wound model findings. H. triquetrifolium ointment (5%) showed the best histopathological scores in both re-epithelialization and ulcer formation. For quality control purposes, a high-performance liquid chromatography (HPLC) method was used to quantify key marker compounds in the extract, namely hypericin and rutin which showed a content of 0.64% and 4.46% (w/w), respectively. Based on the experimental results, H. triquetrifolium ointment (5%) exhibits remarkable wound healing properties at various stages of the wound healing process. Further investigations to prove its safety and efficacy in different types of wounds and to uncover its cellular mechanisms are warranted.

TRELAGLIPTIN'S REAL WORLD EFFICACY AMONG TYPE 2 DIABETES PATIENTS IN CAMBODIA (TRELA -REAL STUDY)

Background: Trelagliptin is the rst once-weekly oral therapy for type 2 diabetes in Cambodia. The afrmation of its efcacy and safety in Cambodian Type 2 Diabetes patients is to be established for extending the clinical benet of this unique oral anti-diabetic agent in this population Objective: To conrm the effect of Trelagliptin (TRELA), a selective once weekly dipeptidyl peptidase-4 (DPP-4) inhibitor, on glycemic control in the management of Type 2 Diabetes Mellitus (T2DM) in real-world practice settings in Cambodia Methods: An open-label, multicentric prospective, observational single-arm study was conducted across Phnom Penh and three other provinces in Cambodia which will include Siem Reap, Kampong Cham, and Battambang in outpatient settings. One hundred and fty patients with Type 2 Diabetes were enrolled after seeking informed consent. Trelagliptin 100 mg one tablet per week was administered to patients with type 2 diabetes who showed poor glycemic control (HbA1c ≥6.5% ) on diet/exercise therapy alone or diet/exercise therapy plus other oral antidiabetic agents or insulin. The study primary endpoint(s) included changes in glycated hemoglobin (HbA1c) from baseline at the end of three months, and at the end of six months of the study. The secondary endpoints included patient satisfaction and investigator assessment at the end of treatment (6 months) to once weekly treatment to Trelagliptin. Result: Treatment with Trelagliptin 100 mg/week led to a mean change in HbA1c 0.86% (from 8.76 ± 2.02 to 7.9 ± 1.60, p < 0.05, CI 95) at the end of 3 months. At the end of 6 months, the mean change in HbA1c was 1.26% (from 8.76 ± 2.02 to 7.5 ± 1.34), p<0.05, CI 95) (p-value signicant) Patient satisfaction and preference with once-weekly trelagliptin treatment was reported in 97.04 % (n=131) patients. As per the investigator's assessment, 77.04 % (n=104) of the patients reported a “good” response to Trelagliptin treatment at the end of the study over a period of 6 months. In 14.07 % (n=19) patients investigators reported that “excellent” response was achieved. Whereas 5.19% (n=7) and 3.7% (n=5) patients reported average and poor responses, respectively. Trelagliptin treatment once a week was demonstrated to be clinically efcacious as monotherapy and in combination with other anti-hyperglycemic agents. Trelagliptin treatment was found to be efcacious in treatment naïve and treatment-experienced patients. The clinical benets of Trelagliptin were consistent across age groups, body mass index (BMIs), and associated co-morbidities like hypertension. Trelagliptin was well tolerated and was safely used in addition to Metformin, Sulfonylureas, Thiazolidinediones, SGLT2-inhibitors & Insulin treatment. The glucose-lowering effect of Trelagliptin was comparable to other DPP4 inhibitors (gliptins), and other classes of oral anti-diabetic medications with the additional advantage of once-a-week dosing treatment regime. Conclusion: Treatment with once-a-week trelagliptin as initial monotherapy and in combination therapy with other anti-hyperglycemic agents for glucose control in Type 2 Diabetes was efcacious and well-tolerated. Trelagliptin 100 mg once a week treatment achieved treatment satisfaction in most patients and reported “good” investigator response in majority of type 2 diabetes patients. Trelagliptin 100 mg once-a-week treatment is a useful consideration in the management of type 2 diabetes patients

Could Tierless Languages Reduce IoT Development Grief?

Internet of Things (IoT) software is notoriously complex, conventionally comprising multiple tiers. Traditionally an IoT developer must use multiple programming languages and ensure that the components interoperate correctly. A novel alternative is to use a single tierless language with a compiler that generates the code for each component and ensures their correct interoperation. We report a systematic comparative evaluation of two tierless language technologies for IoT stacks: one for resource-rich sensor nodes (Clean with iTask) and one for resource-constrained sensor nodes (Clean with iTask and mTask). The evaluation is based on four implementations of a typical smart campus application: two tierless and two Python-based tiered. (1) We show that tierless languages have the potential to significantly reduce the development effort for IoT systems, requiring 70% less code than the tiered implementations. Careful analysis attributes this code reduction to reduced interoperation (e.g., two embedded domain-specific languages and one paradigm versus seven languages and two paradigms), automatically generated distributed communication, and powerful IoT programming abstractions. (2) We show that tierless languages have the potential to significantly improve the reliability of IoT systems, describing how Clean iTask/mTask maintains type safety, provides higher-order failure management, and simplifies maintainability. (3) We report the first comparison of a tierless IoT codebase for resource-rich sensor nodes with one for resource-constrained sensor nodes. The comparison shows that they have similar code size (within 7%), and functional structure. (4) We present the first comparison of two tierless IoT languages, one for resource-rich sensor nodes and the other for resource-constrained sensor nodes.

Preliminary outcomes of DEB-TACE loaded with raltitrexed in the treatment of unresectable or recurrent hepatocellular carcinoma

PurposeRaltitrexed shows therapeutic effects and safety in many types of malignant tumors. However, reports of the clinical outcomes of raltitrexed-based transarterial chemoembolization (TACE) or drug-eluting beads TACE (DEB-TACE) in the treatment of hepatocellular carcinoma (HCC) are rare. We aim to report the preliminary outcomes of DEB-TACE loaded with raltitrexed in patients with unresectable or recurrent HCC.MethodsFrom June 2018 to March 2020, 29 patients with unresectable or recurrent HCC were recruited from our department and treated by DEB-TACE loaded with raltitrexed. Overall survival and progression-free survival were the primary end points. Tumor response was investigated by using the modified response evaluation criteria in solid tumors (mRECIST) criteria.ResultsA total of 49 sessions of DEB-TACE were performed, with a technique success rate of 100%. The overall response rate and disease control rate at 1, 3, and 6 months after DEB-TACE were 72.0% and 96.0%, 57.1% and 85.7%, 47.6% and 66.7% respectively. The median progression-free survival and overall survival was 25.7 and 33.9 months, respectively. The 6-, 24- and 36-month overall survival rates were 88.4%, 66.3% and 46.3%, respectively. Minor complications were observed in 17 patients (58.6%), with no treatment-related mortality or severe adverse events. The most common treatment-related complications were abdominal pain (41.4%) and elevated ALT/AST (27.6%).ConclusionDEB-TACE loaded with raltitrexed is suggested as a safe, feasible, efficacious palliative regimen in unresectable or recurrent HCC patients.

Therapeutic effect of gedatolisib, a pan-PI3K/mTOR inhibitor, on prostate cancer models with PI3K or PTEN mutational status.

149 Background: Metastatic castration-resistant prostate cancer (mCRPrC) is characterized by a loss of androgen receptor (AR) sensitivity and oncogenic activation of the PI3K, AKT, and mTOR (PAM) pathway. Loss of the PI3K regulator, PTEN, is frequent during prostate cancer (PrC) initiation, progression, and therapeutic resistance. Co-targeting PAM/AR pathways is a promising PrC treatment strategy but hampered by complex PAM-AR pathway crosstalk driving either reciprocal negative feedback inhibition or feedback relief. Most PAM inhibitors (PAM-i) selectively spare (or weakly inhibit) one or more key PAM pathway components, potentiating drug resistance depending on the PAM mutation status of patients. AKT-i demonstrated limited efficacy in PTEN-deficient PrC and even less efficacy in PTEN-wild type (wt) in recent clinical studies, suggesting that more comprehensive inhibition of the PI3K isoforms and mTOR may be required. We posited that gedatolisib, a well-tolerated and potent inhibitor of all Class I PI3K isoforms, mTORC1, and mTORC2, would be effective in both PTEN-wt and PTEN-deficient PrC. Methods: A panel of PrC cell lines with different PI3K or PTEN status ( wt: 22RV1, MDA-PCa-2b, DU145; null: LNCaP, PC3, C4-2) were assayed under different conditions for their sensitivity to gedatolisib and other PAM-I ( PI3K: alpelisib, copanlisib; AKT: capivasertib, ipatasertib; mTOR: everolimus; pan-PI3K/mTOR: samotolisib, gedatolisib). A combination of cell viability, growth rate, cytotoxicity and phospho-FACS analytical assays were used. Xenograft studies evaluating gedatolisib with a subset of these models were also performed in castrated mice. Results: We confirmed that AKT-i is more effective in PTEN-null than PTEN-wt PrC. In contrast, the two pan-PI3K/mTOR-i evaluated were effective independent of PI3K or PTEN status. Gedatolisib exhibited superior potency and efficacy compared to each of the other PAM-i for cell proliferation, death, or PAM pathway activation. In vivo, gedatolisib substantively inhibited tumor growth regardless of PTEN or PI3K status. Conclusions: We demonstrated that gedatolisib exerts superior activity regardless of PI3K or PTEN status in all PrC cell lines evaluated compared to the other PAM pathway inhibitors evaluated. Our results indicate potent and simultaneous blockade of all Class I PI3K isoforms, mTORC1, and mTORC2 could circumvent PTEN dependent resistance. Gedatolisib as a single agent and in combination with other therapies reported promising preliminary efficacy and safety in various solid tumor types. In light of the PrC findings reported here, development of gedatolisib may be warranted in PrC patients regardless of their PTEN or PI3K status.

Temporal Verification with Answer-Effect Modification: Dependent Temporal Type-and-Effect System with Delimited Continuations

Type-and-effect systems are a widely used approach to program verification, verifying the result of a computation using types, and its behavior using effects. This paper extends an effect system for verifying temporal, value-dependent properties on event sequences yielded by programs, to the delimited control operators shift0/reset0. While these delimited control operators enable useful and powerful programming techniques, they hinder reasoning about the behavior of programs because of their ability to suspend, resume, discard, and duplicate delimited continuations. This problem is more serious in effect systems for temporal properties because these systems must be capable of identifying what event sequences are yielded by captured continuations. Our key observation for achieving effective reasoning in the presence of the delimited control operators is that their use modifies answer effects, which are temporal effects of the continuations. Based on this observation, we extend an effect system for temporal verification to accommodate answer-effect modification. Allowing answer-effect modification enables easily reasoning about traces that captured continuations yield. Another novel feature of our effect system is the support for dependently typed continuations, which allows us to reason about programs more precisely. We prove soundness of the effect system for finite event sequences via type safety and that for infinite event sequences using a logical relation.

Recursive Subtyping for All

Recursive types and bounded quantification are prominent features in many modern programming languages, such as Java, C#, Scala or TypeScript. Unfortunately, the interaction between recursive types, bounded quantification and subtyping has shown to be problematic in the past. Consequently, defining a simple foundational calculus that combines those features and has desirable properties, such as decidability , transitivity of subtyping, conservativity and a sound and complete algorithmic formulation has been a long time challenge. This paper presents an extension of kernel ‍ F ≤ , called F ≤ µ , with iso-recursive types. F ≤ is a well-known polymorphic calculus with bounded quantification. In F ≤ µ we add iso-recursive types, and correspondingly extend the subtyping relation with iso-recursive subtyping using the recently proposed nominal unfolding rules. We also add two smaller extensions to F ≤ . The first one is a generalization of the kernel ‍ F ≤ rule for bounded quantification that accepts equivalent rather than equal bounds. The second extension is the use of so-called structural folding/unfolding rules, inspired by the structural unfolding rule proposed by Abadi, Cardelli, and Viswanathan [1996]. The structural rules add expressive power to the more conventional folding/unfolding rules in the literature, and they enable additional applications. We present several results, including: type soundness; transitivity and decidability of subtyping; the conservativity of F ≤ µ over F ≤ ; and a sound and complete algorithmic formulation of F ≤ µ . Moreover, we study an extension of F ≤ µ , called F ≤≥ µ , which includes lower bounded quantification in addition to the conventional (upper) bounded quantification of F ≤ . All the results in this paper have been formalized in the Coq theorem prover.

Probabilistic Resource-Aware Session Types

Session types guarantee that message-passing processes adhere to predefined communication protocols. Prior work on session types has focused on deterministic languages but many message-passing systems, such as Markov chains and randomized distributed algorithms, are probabilistic. To implement and analyze such systems, this article develops the meta theory of probabilistic session types with an application focus on automatic expected resource analysis. Probabilistic session types describe probability distributions over messages and are a conservative extension of intuitionistic (binary) session types. To send on a probabilistic channel, processes have to utilize internal randomness from a probabilistic branching or external randomness from receiving on a probabilistic channel. The analysis for expected resource bounds is smoothly integrated with the type system and is a variant of automatic amortized resource analysis. Type inference relies on linear constraint solving to automatically derive symbolic bounds for various cost metrics. The technical contributions include the meta theory that is based on a novel nested multiverse semantics and a type-reconstruction algorithm that allows flexible mixing of different sources of randomness without burdening the programmer with complex type annotations. The type system has been implemented in the language NomosPro with linear-time type checking. Experiments demonstrate that NomosPro is applicable in different domains such as cost analysis of randomized distributed algorithms, analysis of Markov chains, probabilistic analysis of amortized data structures and digital contracts. NomosPro is also shown to be scalable by (i) implementing two broadcast and a bounded retransmission protocol where messages are dropped with a fixed probability, and (ii) verifying the limiting distribution of a Markov chain with 64 states and 420 transitions.

CN: Verifying Systems C Code with Separation-Logic Refinement Types

Despite significant progress in the verification of hypervisors, operating systems, and compilers, and in verification tooling, there exists a wide gap between the approaches used in verification projects and conventional development of systems software. We see two main challenges in bringing these closer together: verification handling the complexity of code and semantics of conventional systems software, and verification usability. We describe an experiment in verification tool design aimed at addressing some aspects of both: we design and implement CN, a separation-logic refinement type system for C systems software, aimed at predictable proof automation, based on a realistic semantics of ISO C. CN reduces refinement typing to decidable propositional logic reasoning, uses first-class resources to support pointer aliasing and pointer arithmetic, features resource inference for iterated separating conjunction, and uses a novel syntactic restriction of ghost variables in specifications to guarantee their successful inference. We implement CN and formalise key aspects of the type system, including a soundness proof of type checking. To demonstrate the usability of CN we use it to verify a substantial component of Google's pKVM hypervisor for Android.

Systematic evaluation of the efficacy and safety of botulinum toxin type A in the treatment of spastic cerebral palsy

Systematic evaluation of the efficacy and safety of botulinum toxin type A in the treatment of spastic cerebral palsy

Evaluation the Safety and Quality of Ready-to-Eat Sandwiches: Short Communication

Increase in the consumption of ready-to-eat foods such as sandwiches, raises concerns about its microbial safety and quality. The aim of the study was to evaluate the microbial safety and quality of different type of sandwiches. In total 60 of chicken shawarma (15), normal chicken (15), eggs (15) and meat (15) sandwiches were purchased from different cafes and evaluated microbiologically for total bacterial and Enterobacteriaceae counts and incidence of Salmonella sp. The results showed that the total bacterial counts were 5.48±1.01, 5.53±1.11, 5.58±0.97 and 6.72±0.77 log10 CFU g−1 in the chicken shawarma, normal chicken, eggs and meat sandwiches respectively, whereas, the counts of Enterobacteriaceae in chicken shawarma, normal chicken, eggs and meat sandwiches were 3.56±1.02, 1.63±1.30, 2.48±1.76 and 3.64±1.81 log10 CFU g−1 respectively. Salmonella sp. was suspected in 10% of the sandwiches. In conclusion, all most sandwich types were found at satisfactory level except meat sandwiches which were found at marginal level. Microbial contamination and hygiene handling status indicated that almost all sandwich types were at marginal level except normal chicken sandwiches which were found at satisfactory level. Strictly implementation of food safety laws and further studies were recommended to clarify the safety and quality of the sandwiches.

: Asynchronous global types in co-logic programming

Global types are at the core of communication-based programming. They allow a high-level specification of protocols involving many participants and enforce good safety and liveness properties, such as deadlock freedom, and the absence of locked participants and orphan messages. The present software provides an implementation in co-logic programming of a novel formalism of global types for sessions with asynchronous communications, where we use coinduction to properly handle the coinductive syntax of global types and processes. It also offers a simple query language to write sessions and global types, providing primitives for type checking. • Implementation of a global type system for asynchronous multiparty sessions. • Query language to easily write declarations and queries. • Interesting and challenging case study for co-logic programming.

Type Checking Data Structures More Complex than Trees

Type Checking Data Structures More Complex than Trees

Bodily Sensation Type Safety Education of SANKI ENGINEERING CO.,LTD.

Bodily Sensation Type Safety Education of SANKI ENGINEERING CO.,LTD.

Sustained Efficacy, Safety and High Adherence Rate of Onabotulinum Toxin Type A in Chronic Migraine Patients: A Multicentric Prospective Real-Life Study.

Guidelines regarding long-term use with onabotulinumtoxinA (onaBT-A) in chronic migraine (CM) prophylaxis are lacking. This multicentric prospective real-life study aimed to assess the efficacy and safety of a long-term treatment. A total of 195 chronic migraine patients were treated with onaBT-A, every 3 months for 5 cycles (Phase 1). In the Phase 2 of the study, depending on response rate, patients were divided into "responders" (R), "partially responders" (PR) and "non-responders" (NR). Then, we proposed to R and PR patients to continue with an additional 12 months of treatment (additional 4 sessions). Response to treatment and adverse events were collected for the entire duration of the study. Of the 195 patients included (females 82.1%, mean age 47.4 ± 12.4), at the end of Phase 1 there were 52.3% of R patients, 17.9% of PR patients, 15.4% of NR patients and 14.4% drop-outs. During Phase 2 of treatment, R patients presented a maintenance of the improvement achieved during the first year of treatment, as well as PR patients. Except for three serious adverse events not related to treatment, all other adverse events were mild or moderate in severity and resolved without sequelae. In the literature, adherence to oral migraine-preventive medications among patients with CM was found to be less than 25%. The results of this prospective real-life multicenter study show efficacy, safety and adherence to a long-term treatment with onaBT-A.

Efficacy and safety of native type II collagen in modulating knee osteoarthritis symptoms: a randomised, double-blind, placebo-controlled trial

PurposeKnee osteoarthritis (OA) is the most common form of clinical arthritis in middle-aged and older individuals. Undenatured or native type II (TII) collagen derived from the chicken sternum has a good therapeutic effect on relieving severe pain of OA. Hence, the present study aimed to investigate the efficacy and safety of TII collagen (Native CT-II®) in individuals with knee OA.MethodsWe conducted a 12-week randomised, double-blind, placebo-controlled, parallel-group study on 101 participants aged 40–65 years with knee OA. The participants were randomised to receive either TII collagen, glucosamine hydrochloride + chondroitin sulfate (G + C) or a placebo. The primary outcome was an improvement in the joint health of the participants assessed using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) compared to G + C and placebo.ResultsCompared with the placebo group (n = 27), the TII collagen group (n = 29) and G + C group (n = 29) significantly improved the overall joint health measured by the change in WOMAC total score (week 12: TII collagen = -32.47 ± 19.51 and G + C = -33.74 ± 24.64 vs. placebo = -13.84 ± 17.61; p < 0.05) and relieved knee joint pain (week 12: TII collagen = -5.69 ± 3.66 and G + C = -6.03 ± 4.72 vs. placebo = -2.71 ± 3.95; p < 0.05). The statistically significant effect was observed as early as 4 weeks after the investigational product administration. Additionally, the TII collagen was more effective in improving the quality of life than the G + C.ConclusionTII collagen not only has a significantly better effect and high safety profile for OA but also improves the quality of life of patients.Level of EvidenceLevel 1 – Randomized Controlled Trial.Trial registrationClinicalTrials.gov Identifier: NCT04470336; First submitted date: July 08, 2020; First posted date: July 14, 2020.

A Type Discipline for Message Passing Parallel Programs

We presentParTypes, a type discipline for parallel programs. The model we have in mind comprises a fixed number of processes running in parallel and communicating via collective operations or point-to-point synchronous message exchanges. A type describes a protocol to be followed by each processes in a given program. We present the type theory, a core imperative programming language and its operational semantics, and prove that type checking is decidable (up to decidability of semantic entailment) and that well-typed programs do not deadlock and always terminate. The article is accompanied by a large number of examples drawn from the literature on parallel programming.

Comparative efficacy and safety of monoamine oxidase type B inhibitors plus channel blockers and monoamine oxidase type B inhibitors as adjuvant therapy to levodopa in the treatment of Parkinson's disease: a network meta-analysis of randomized controlled trials.

The monoamine oxidase type B inhibitors plus channel blockers (MAO-BIs plus) are a new class of antiparkinsonian drug with additional mechanisms of action for their property as ion channel blockers. The present study aimed to compare the efficacy and safety of MAO-BIs plus and conventional MAO-BIs, as well as their corresponding doses, as adjuvant therapy to levodopa in the treatment of Parkinson's disease (PD). Randomized controlled trials enrolling PD patients treated with selegiline, rasagiline, safinamide or zonisamide as adjuvant therapy to levodopa were identified. Bayesian network meta-analysis was conducted. Thirty-one randomized controlled trials comprising 7142 PD patients were included. Compared with levodopa monotherapy, the combination therapy of MAO-BIs and levodopa was significantly more effective, with a mean difference of 2.74 (1.26-4.18) on the Unified Parkinson's Disease Rating Scale (UPDRS) III score change for selegiline, 2.67 (1.45-3.87) for safinamide, 2.2 (0.98-3.64) for zonisamide and 2.04 (1.24-2.87) for rasagiline. No significant difference was detected amongst MAO-BIs. The surface under the cumulative ranking results showed that safinamide 100 mg and rasagiline 1mg ranked first in improving UPDRS III and UPDRS II, respectively. Zonisamide 100 mg ranked first in reducing OFF time. For safety outcomes, rasagiline was associated with a higher incidence of adverse events than placebo and safinamide. MAO-BIs plus had a higher probability of being safer agents compared to conventional MAO-BIs. Monoamine oxidase type B inhibitors plus, conventional MAO-BIs and the corresponding doses are similar in efficacy in PD treatment. MAO-BIs plus might be safer than conventional MAO-BIs. Head-to-head comparisons are needed for further investigation.

Evaluation of the safety, immunogenicity, and faecal shedding of novel oral polio vaccine type 2 in healthy newborn infants in Bangladesh: a randomised, controlled, phase 2 clinical trial

Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants. In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0-3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on ClinicalTrials.gov, NCT04693286. Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 [67%]) or placebo (n=110 [33%]). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies. nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies. Bill & Melinda Gates Foundation.