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Background: Programmed death 1 (PD-1) binding to PD-L1 is a potent mechanism used by immunogenic tumors to evade the immune system and the immune checkpoint PD-1PD-L1 has emerged as a promising target in the search for new drugs to improve cancer treatment. The crystallographic structure of human PD-1 human PD-L1 shed light on the molecular characterization of this system and allowed computational studies to be carried out to characterize structural behaviors., Methods: This study demonstrated the importance of analyzing the flexibility of protein systems through molecular dynamics simulations (MDS) and its impacts on the interaction energy obtained through quantum biochemistry., Results: The computational results obtained provide a description of the flexibility and energetic profile of the PD-1PD-L1 contact surface using representative conformations from MDS. Variations of up to 50 % in the total interaction energy values were detected depending on the scrutinized conformation, which can be mainly attributed to the flexibility of the CC' loop, FG loop and ASP85-GLN91 of PD-1 and the MET58-LYS62 segment of PD-L1. Quantum biochemistry revealed the three hot spots in PD-L1: ARG113 L -ARG125 L  > ILE54 L -VAL76 L  > ALA18 L -ASP26 L ; and two energetic hot spots in PD-1: ALA125-ARG139 > VAL63-GLN88. Nonetheless, VAL63-GLN88 and GLY124-ARG139 exhibit significant variation in interaction energy between different conformations, while ARG113 L -ARG125 L is the only hot spot with high energetic fluctuation on the PD-L1 surface., Conclusion: This is the first application of MDS coupled to dimensionality reduction and density functional theory (DFT) demonstrating new structural and energetic features that might be useful in discovering/designing more potent PD-1PD-L1 inhibitors., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Autoimmune inflammatory diseases, such as rheumatoid arthritis (RA) and ulcerative colitis, are associated with an uncontrolled production of cytokines leading to the pronounced inflammatory response of these disorders. Their therapy is currently focused on the inhibition of cytokine receptors, such as the Janus kinase (JAK) protein family. Tofacitinib and peficitinib are JAK inhibitors that have been recently approved to treat rheumatoid arthritis. In this study, an in-depth analysis was carried out through quantum biochemistry to understand the interactions involved in the complexes formed by JAK1 and tofacitinib or peficitinib. Computational analyses provided new insights into the binding mechanisms between tofacitinib or peficitinib and JAK1. The essential amino acid residues that support the complex are also identified and reported. Additionally, we report new interactions, such as van der Waals; hydrogen bonds; and alkyl, pi-alkyl, and pi-sulfur forces, that stabilize the complexes. The computational results revealed that peficitinib presents a similar affinity to JAK1 compared to tofacitinib based on their interaction energies.

Aim: Synthetic antimicrobial peptides (SAMPs) present the potential to fight systemic fungal infections. Here, the PHO36 receptor from Candida albicans was analyzed by in silico tools as a possible target for three anticandidal SAMPs: Rc Alb-PepIII, PepGAT and PepKAA. Materials & methods: Molecular docking, dynamics and quantum biochemistry were employed to understand the individual contribution of amino acid residues in the interaction region. Results: The results revealed that SAMPs strongly interact with the PHO36 by multiple high-energy interactions. This is the first study to employ quantum biochemistry to describe the interactions between SAMPs and the PHO36 receptor. Conclusion: This work contributes to understanding and identifying new molecular targets with medical importance that could be used to discover new drugs against systemic fungal infections.

Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social communication and social interaction impairments accompanied by restrictive and repetitive behaviors or interests. Co-occurring conditions may greatly impact overall functioning and intervention needs, and contribute to individual variability and etiologic subtypes. Clinical care of individuals with ASD requires gathering a breadth of information across multiple domains. The neurodevelopmental parent report for outcome monitoring (ND-PROM) was developed to assess symptoms across core features of ASD as well as frequent concerns and comorbidities. The current study expands upon the initially reported psychometric properties of the ND-PROM and evaluates a proposed a clinically derived 12-factor structure of the ND-PROM., Methods and Procedures: The ND-PROM was completed for 246 children with ASD ands tested using confirmatory factor analysis (CFA) and measurement invariance based on sex., Outcomes and Results: A 12-factor correlated structure was found (expressive language, receptive language, nonverbal communication, social emotional understanding, social interaction, independent play, adaptive/toileting skills, restrictive and repetitive behaviors and interests, sensory processes, challenging behaviors, impulse/ADHD, and mental health), which did not vary by sex., Conclusions and Implications: The ND-PROM captures a range of distinct aspects of developmental and behavioral functioning in ASD that can be used to track independent functioning across domains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Baumer, Pawlowski, Amaral, Zhang, Sideridis and Levin.)

Aim: This study aimed to analyze the phylogenetic relationships between the ACE2 of humans and other animals and investigate the potential interaction between SARS-CoV-2 RBD and ACE2 of different species. Materials & methods: The phylogenetic construction and molecular interactions were assessed using computational models. Results & conclusion: Despite the evolutionary distance, 11 species had a perfect fit for the interaction between their ACE2 and SARS-CoV-2 RBD ( Chinchilla lanigera, Neovison vison , Rhinolophus sinicus, Emballonura alecto , Saccopteryx bilineata , Numida meleagris ). Among them, the avian N. meleagris was reported for the first time in this study as a probable SARS-CoV-2 host due to the strong molecular interactions. Therefore, predicting potential hosts for SARS-CoV-2 for understanding the epidemiological cycle and proposal of surveillance strategies., Competing Interests: The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed., (© 2023 Future Medicine Ltd.)

Atrazine (ATR), one of the most used herbicides worldwide, causes persistent contamination of water and soil due to its high resistance to degradation. ATR is associated with low fertility and increased risk of prostate cancer in humans, as well as birth defects, low birth weight and premature delivery. Describing ATR binding to human serum albumin (HSA) is clinically relevant to future studies about pharmacokinetics, pharmacodynamics and toxicity of ATR, as albumin is the most abundant carrier protein in plasma and binds important small biological molecules. In this work we characterize, for the first time, the binding of ATR to HSA by using fluorescence spectroscopy and performing simulations using molecular docking, classical molecular dynamics and quantum biochemistry based on density functional theory (DFT). We determine the most likely binding sites of ATR to HSA, highlighting the fatty acid binding site FA8 (located between subdomains IA-IB-IIA and IIB-IIIA-IIIB) as the most important one, and evaluate each nearby amino acid residue contribution to the binding interactions explaining the fluorescence quenching due to ATR complexation with HSA. The stabilization of the ATR/FA8 complex was also aided by the interaction between the atrazine ring and SER454 (hydrogen bond) and LEU481(alkyl interaction)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Introduction: Candida krusei and Candida albicans are biofilm-forming drug-resistant yeasts that cause bloodstream infections that can lead to death. Materials & methods: nystatin and itraconazole were combined with two synthetic peptides, PepGAT and PepKAA, to evaluate the synergistic effect against Candida biofilms. Additionally, scanning electron and fluorescence microscopies were employed to understand the mechanism behind the synergistic activity. Results: Peptides enhanced the action of drugs to inhibit the biofilm formation of C. krusei and C. albicans and the degradation of mature biofilms of C. krusei . In combination with antifungal drugs, peptides' mechanism of action involved cell wall and membrane damage and overproduction of reactive oxygen species. Additionally, in combination, the peptides reduced the toxicity of drugs to red blood cells. Conclusion: These results reveal that the synthetic peptides enhanced the antibiofilm activity of drugs, in addition to reducing their toxicity. Thus, these peptides have strong potential as adjuvants and to decrease the toxicity of drugs.

Vaccines could be the solution to the current SARS-CoV-2 outbreak. However, some studies have shown that the immunological memory only lasts three months. Thus, it is imperative to develop pharmacological treatments to cope with COVID-19. Here, the in silico approach by molecular docking, dynamic simulations and quantum biochemistry revealed that ACE2-derived peptides strongly interact with the SARS-CoV-2 RBD domain of spike glycoprotein (S-RBD). ACE2-Dev-PepI, ACE2-Dev-PepII, ACE2-Dev-PepIII and ACE2-Dev-PepIV complexed with S-RBD provoked alterations in the 3D structure of S-RBD, leading to disruption of the correct interaction with the ACE2 receptor, a pivotal step for SARS-CoV-2 infection. This wrong interaction between S-RBD and ACE2 could inhibit the entry of SARS-CoV-2 in cells, and thus virus replication and the establishment of COVID-19 disease. Therefore, we suggest that ACE2-derived peptides can interfere with recognition of ACE2 in human cells by SARS-CoV-2 in vivo . Bioinformatic prediction showed that these peptides have no toxicity or allergenic potential. By using ACE2-derived peptides against SARS-CoV-2, this study points to opportunities for further in vivo research on these peptides, seeking to discover new drugs and entirely new perspectives to treat COVID-19.Communicated by Ramaswamy H. Sarma.

Late in 2019, SARS-CoV-2 (severe acute respiratory syndrome coronavirus-2) emerged, causing an unknown type of pneumonia today called coronaviruses disease 2019 (COVID-19). COVID-19 is still an ongoing global outbreak that has claimed and threatened many lives worldwide. Along with the fastest vaccine developed in history to fight SARS-CoV-2 came a critical problem, SARS-CoV-2. These new variants are a result of the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which is by far the most critical protein for SARS-CoV-2 to recognize cells and escape the immune system, in addition to playing a role in SARS-CoV-2 infection, pathogenicity, transmission, and evolution. In this review, we discuss mutation of S protein and how these mutations have led to new variants that are usually more transmissible and can thus mitigate the immunity produced by vaccination. Here, analysis of S protein sequences and structures from variants point out the mutations among them, how they emerge, and the behavior of S protein from each variant. This review brings details in an understandable way about how the variants of SARS-CoV-2 are a result of mutations in S protein, making them more transmissible and even more aggressive than their relatives., (Copyright © 2022 Elsevier B.V. All rights reserved.)

The outbreak caused by SARS-CoV-2 has taken many lives worldwide. Although vaccination has started, the development of drugs to either alleviate or abolish symptoms of COVID-19 is still necessary. Here, four synthetic peptides were assayed regarding their ability to protect Vero E6 cells from SARS-CoV-2 infection and their toxicity to human cells and zebrafish embryos. All peptides had some ability to protect cells from infection by SARS-CoV-2 with the D614G mutation. Molecular docking predicted the ability of all peptides to interact with and induce conformational alterations in the spike protein containing the D614G mutation. PepKAA was the most effective peptide, by having the highest docking score regarding the spike protein and reducing the SARS-CoV-2 plaque number by 50% (EC 50 ) at a concentration of 0.15 mg mL -1 . Additionally, all peptides had no toxicity to three lines of human cells as well as to zebrafish larvae and embryos. Thus, these peptides have potential activity against SARS-CoV-2, making them promising to develop new drugs to inhibit cell infection by SARS-CoV-2., Competing Interests: The authors declare no competing financial interest., (© 2022 The Authors. Published by American Chemical Society.)

C. albicans and C. parapsilosis are biofilm-forming yeasts responsible for bloodstream infections that can cause death. Synthetic antimicrobial peptides (SAMPs) are considered to be new weapons to combat these infections, alone or combined with drugs. Here, two SAMPs, called Mo -CBP 3 -PepI and Mo -CBP 3 -PepIII, were tested alone or combined with nystatin (NYS) and itraconazole (ITR) against C. albicans and C. parapsilosis biofilms. Furthermore, the mechanism of antibiofilm activity was evaluated by fluorescence and scanning electron microscopies. When combined with SAMPs, the results revealed a 2- to 4-fold improvement of NYS and ITR antibiofilm activity. Microscopic analyses showed cell membrane and wall damage and ROS overproduction, which caused leakage of internal content and cell death. Taken together, these results suggest the potential of Mo -CBP 3 -PepI and Mo -CBP 3 -PepIII as new drugs and adjuvants to increase the activity of conventional drugs for the treatment of clinical infections caused by C. albicans and C. parapsilosis .

The recent outbreak caused by SARS-CoV-2 continues to threat and take many lives all over the world. The lack of an efficient pharmacological treatments are serious problems to be faced by scientists and medical staffs worldwide. In this work, an in silico approach based on the combination of molecular docking, dynamics simulations, and quantum biochemistry revealed that the synthetic peptides RcAlb -PepI, PepGAT, and PepKAA, strongly interact with the main protease (Mpro) a pivotal protein for SARS-CoV-2 replication. Although not binding to the proteolytic site of SARS-CoV-2 Mpro, RcAlb -PepI, PepGAT, and PepKAA interact with other protein domain and allosterically altered the protease topology. Indeed, such peptide-SARS-CoV-2 Mpro complexes provoked dramatic alterations in the three-dimensional structure of Mpro leading to area and volume shrinkage of the proteolytic site, which could affect the protease activity and thus the virus replication. Based on these findings, it is suggested that RcAlb -PepI, PepGAT, and PepKAA could interfere with SARS-CoV-2 Mpro role in vivo . Also, unlike other antiviral drugs, these peptides have no toxicity to human cells. This pioneering in silico investigation opens up opportunity for further in vivo research on these peptides, towards discovering new drugs and entirely new perspectives to treat COVID-19.Communicated by Ramaswamy H. Sarma.

Gastric cancer is one of the most common and deadly types of cancer in the world, and poor prognosis with treatment failure is widely reported in the literature. In this context, kinases have been considered a relevant choice for targeted therapy in gastric cancer. Here, we explore the antiproliferative and antimigratory effects of the AURKA inhibitor and the prognostic and therapeutic value as a biomarker of gastric cancer. A total of 145 kinase inhibitors were screened to evaluate the cytotoxic or cytostatic effects in the gastric cancer cell line. Using the Alamar Blue assay, flow cytometry, quantitative polymerase chain reaction, and observation of caspase 3/7 activity and cell migration, we investigated the antiproliferative, proapoptotic, and antimigratory effects of the AURKA inhibitor. Moreover, AURKA overexpression was evaluated in the gastric cell lines and the gastric tumor tissue. Out of the 145 inhibitors, two presented the highest antiproliferative effect. Both molecules can induce apoptosis by the caspases 3/7 pathway in addition to inhibiting cancer cell migration, mainly the AURKA inhibitor. Moreover, molecular docking analysis revealed that GW779439X interacts in the active site of the AURKA enzyme with similar energy as a well-described inhibitor. Our study identified AURKA overexpression in the gastric cancer cell line and gastric tumor tissue, revealing that its overexpression in patients with cancer is correlated with low survival. Therefore, it is feasible to suggest AURKA as a potential marker of gastric cancer, besides providing robust information for diagnosis and estimated survival of patients. AURKA can be considered a new molecular target used in the prognosis and therapy of gastric cancer., (© 2021 Wiley Periodicals LLC.)

Aims: The Candida genus is composed of opportunistic pathogens that threaten public health. Given the increase in resistance to current drugs, it is necessary to develop new drugs to treat infections by these pathogens. Antimicrobial peptides are promising alternative molecules with low cost, broad action spectrum and low resistance induction. This study aimed to clarify the action mechanisms of synthetic peptides against Candida albicans., Main Methods: The mode of action of the anticandidal peptides Mo-CBP 3 -PepIII were analyzed through molecular dynamics and quantum biochemistry methods against Exo-β-1,3-glucanase (EXG), vital to cell wall metabolism. Furthermore, scanning electron (SEM) and fluorescence (FM) microscopies were employed to corroborate the in silico data., Key Findings: Mo-CBP 3 -PepIII strongly interacted with EXG (-122.2 kcal mol -1 ) at the active site, higher than the commercial inhibitor pepstatin. Also, molecular dynamics revealed the insertion of Mo-CBP 3 -PepIII into the yeast membrane. SEM analyses revealed that Mo-CBP 3 -PepIII induced cracks and scars of the cell wall and FM analyses confirmed the pore formation on the Candida membrane., Significance: Mo-CBP 3 -PepIII has strong potential as a new drug with a broad spectrum of action, given its different mode of action compared to conventional drugs., (Copyright © 2021. Published by Elsevier Inc.)

Fungal contamination is among the main reasons for food spoilage, affecting food safety and the economy. Among fungi, Penicillium digitatum is a major agent of this problem. Here, the in vitro activity of eight synthetic antimicrobial peptides was assessed against P. digitatum, and their action mechanisms were evaluated. All peptides were able to inhibit fungal growth. Furthermore, atomic force and fluorescence microscopies revealed that all peptides targeted the fungal membrane leading to pore formation, loss of internal content, and death. The induction of high levels of reactive oxygen species (ROS) was also a mechanism employed by some peptides. Interestingly, only three peptides (PepGAT, PepKAA, and Mo-CBP 3 -PepI) effectively control P. digitatum colonization in orange fruits, at a concentration (50 µg mL -1 ) 20-fold lower than the commercial food preservative (sodium propionate). Altogether, PepGAT, PepKAA, and Mo-CBP 3 -PepI showed high biotechnological potential as new food preservatives to control food infection by P. digitatum., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Recently, the dramatic emergence of antimicrobial resistance has received attention from World Health Organization. Synthetic antimicrobial peptides (SAMPs) are considered new weapons to fight against infections caused by multi-drug resistant pathogens. Here, the authors provide an overview of the current research on SAMPs. The focus is SAMPs, how to design them, which features must be considered during design, and comparison with natural peptides. This review also includes a discussion about the natural AMPs, mechanisms of action and applications as new drugs or even as adjuvants molecules to enhance commercial drugs activity. The advances in chemical synthesis have reduced the cost to produce synthetic peptides open ways to achieve new antimicrobial agents. Therefore, synthetic peptides are new promising molecules to safeguard human and animal health., (Copyright © 2021 Elsevier Inc. All rights reserved.)

The interaction of the steviol and its glycosides (SG), steviolbioside, and rebaudioside A, with bovine serum albumin (BSA) was studied by absorption and fluorescence spectroscopy techniques alongside molecular docking. The stevia derivatives quenched the fluorescence of BSA by a dynamic quenching mechanism, indicating the interaction between the stevia derivatives and BSA. The binding constant (K b ) of steviol was 100-1000-fold higher than those of SG. The stevia derivative/BSA binding reaction was spontaneous and involved the formation of hydrogen bonds and van der Waals interactions between steviol and steviolbioside with BSA, and water reorganization around the rebaudioside A/BSA complex. Molecular docking pointed out the FA1 and FA9 binding sites of BSA as the probable binding sites of steviol and SG, respectively. In conclusion, steviol enhanced hydrophobicity and small size compared to SG may favor its binding to BSA. As steviol and its glycosides share binding sites on BSA with free fatty acids and drugs, they may be competitively displaced from plasma albumin under various physiological states or disease conditions. These findings are clinically relevant and provide an insight into the pharmacokinetics and pharmacodynamics of the stevia glycosides., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Three coronaviruses (CoVs) have threatened the world population by causing outbreaks in the last two decades. In late 2019, the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) emerged and caused the coronaviruses to disease 2019 (COVID-19), leading to the ongoing global outbreak. The other pandemic coronaviruses, SARS-CoV and Middle East respiratory syndrome CoV (MERS-CoV), share a considerable level of similarities at genomic and protein levels. However, the differences between them lead to distinct behaviors. These differences result from the accumulation of mutations in the sequence and structure of spike (S) glycoprotein, which plays an essential role in coronavirus infection, pathogenicity, transmission, and evolution. In this review, we brought together many studies narrating a sequence of events and highlighting the differences among S proteins from SARS-CoV, MERS-CoV, and SARS-CoV-2. It was performed here, analysis of S protein sequences and structures from the three pandemic coronaviruses pointing out the mutations among them and what they come through. Additionally, we investigated the receptor-binding domain (RBD) from all S proteins explaining the mutation and biological importance of all of them. Finally, we discuss the mutation in the S protein from several new isolates of SARS-CoV-2, reporting their difference and importance. This review brings into detail how the variations in S protein that make SARS-CoV-2 more aggressive than its relatives coronaviruses and other differences between coronaviruses., Competing Interests: Declaration of competing interest All authors declare no conflicts of interest., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The global outbreak of COVID-19 (Coronavirus Disease 2019) caused by SARS-CoV-2 (Severe Acute Respiratory Syndrome caused by Coronavirus 2) began in December 2019. Its closest relative, SARS-CoV-1, has a slightly mutated Spike (S) protein, which interacts with ACE2 receptor in human cells to start the infection. So far, there are no vaccines or drugs to treat COVID-19. So, research groups worldwide are seeking new molecules targeting the S protein to prevent infection by SARS-CoV-2 and COVID-19 establishment. We performed molecular docking analysis of eight synthetic peptides against SARS-CoV-2 S protein. All interacted with the protein, but Mo-CBP 3 -PepII and PepKAA had the highest affinity with it. By binding to the S protein, both peptides led to conformational alterations in the protein, resulting in incorrect interaction with ACE2. Therefore, given the importance of the S protein-ACE2 interaction for SARS-CoV-2 infection, synthetic peptides could block SARS-CoV-2 infection. Moreover, unlike other antiviral drugs, peptides have no toxicity to human cells. Thus, these peptides are potential molecules to be tested against SARS-CoV-2 and to develop new drugs to treat COVID-19., Competing Interests: Declaration of competing interest All authors declare no conflict of interest., (Copyright © 2020 Elsevier B.V. All rights reserved.)

Cancer is a group of diseases involving disordered growth of abnormal cells with the potential to invade and spread to other parts of the body. Today, immunotherapy is the most efficient treatment, with fewer side effects. Notably, the employment of monoclonal antibodies to inhibit checkpoint proteins, such as CTLA-4, has caused much excitement among cancer immunotherapy researchers. Thus, in-depth analysis through quantum biochemistry and molecular dynamics simulations was performed to understand the complex formed by ipilimumab and its target CTLA-4. Our computational results provide a better understanding of the binding mechanisms and new insights about the CTLA-4: ipilimumab interaction, identifying essential amino acid residues to support the complex. Additionally, we report new interactions such as aromatic-aromatic, aromatic-sulfur, and cation-pi interactions to stabilize the CTLA-4:ipilimumab complex. Finally, quantum biochemistry analyses reveal the most important amino acid residues involved in the CTLA-4:ipilimumab interface, which were used to design synthetic peptides to inhibit CTLA-4. The computational results presented here provide a better understanding of the CTLA-4:ipilimumab binding mechanisms, and can support the development of alternative antibody-based drugs with high relevance in cancer immunotherapy., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Impact pile driving creates intense, impulsive sound that radiates into the surrounding environment. Piles driven vertically into the seabed generate an azimuthally symmetric underwater sound field whereas piles driven on an angle will generate an azimuthally dependent sound field. Measurements were made during pile driving of raked piles to secure jacket foundation structures to the seabed in waters off the northeastern coast of the U.S. at ranges between 500 m and 15 km. These measurements were analyzed to investigate variations in rise time, decay time, pulse duration, kurtosis, and sound received levels as a function of range and azimuth. Variations in the radiated sound field along opposing azimuths resulted in differences in measured sound exposure levels of up to 10 dB and greater due to the pile rake as the sound propagated in range. The raked pile configuration was modeled using an equivalent axisymmetric FEM model to describe the azimuthally dependent measured sound fields. Comparable sound level differences in the model results confirmed that the azimuthal discrepancy observed in the measured data was due to the inclination of the pile being driven relative to the receiver.

Impairments in social interaction and communicating with others are core features of autism spectrum disorder (ASD), but the specific processes underlying such social competence impairments are not well understood. An important key for increasing our understanding of ASD-specific social deficits may lie with the social motor synchronization that takes place when we implicitly coordinate our bodies with others. Here, we tested whether dynamical measures of synchronization differentiate children with ASD from controls and further explored the relationships between synchronization ability and motor control problems. We found (a) that children with ASD exhibited different and less stable patterns of social synchronization ability than controls; (b) children with ASD performed motor movements that were slower and more variable in both spacing and timing; and (c) some social synchronization that involved motor timing was related to motor ability but less rhythmic synchronization was not. These findings raise the possibility that objective dynamical measures of synchronization ability and motor skill could provide new insights into understanding the social deficits in ASD that could ultimately aid clinical diagnosis and prognosis. Autism Res 2017, 10: 1687-1699. © 2017 International Society for Autism Research, Wiley Periodicals, Inc., (© 2017 International Society for Autism Research, Wiley Periodicals, Inc.)

Impairments in social interaction and communication are critical features of ASD but the underlying processes are poorly understood. An under-explored area is the social motor synchronization that happens when we coordinate our bodies with others. Here, we explored the relationships between dynamical measures of social motor synchronization and assessments of ASD traits. We found (a) spontaneous social motor synchronization was associated with responding to joint attention, cooperation, and theory of mind while intentional social motor synchronization was associated with initiating joint attention and theory of mind; and (b) social motor synchronization was associated with ASD severity but not fully explained by motor problems. Findings suggest that objective measures of social motor synchronization may provide insights into understanding ASD traits.

Objective: To survey educational outcomes after an interdisciplinary, neuropsychologically based team assessment for learning disorders., Method: Parents of 137 children who underwent a comprehensive interdisciplinary neuropsychologically based assessment for learning problems completed an online survey one to four years later. Questions pertained broadly to school outcomes: positive or negative school responses, changes in special education services, and parental perceptions about the helpfulness of those services. These outcomes were examined in relation to demographic characteristics and parent satisfaction with the evaluation. We also obtained recent performance on state-based academic testing for descriptive purposes., Results: Parents reported that schools generally responded positively (78%), and 70% reported that their children had access to more or different special education services after the evaluation. Parents nearly uniformly (98%) viewed these services as helpful. Positive changes in education services were related to income (lower income received more services, p < .05) and parent satisfaction with the evaluation (p < .05). The intensity of special education services was strongly related to performance on state-based testing (p < .0001-p < .01)., Conclusions: School response is a relatively objective and meaningful metric of educational outcome after neuropsychologically based evaluation for children with learning problems.

Cervical cancer, the second most common cancer affecting women in Northern Brazil, is strongly associated with human papillomavirus (HPV) infection. Diseases affecting the immune state of a patient, including autoimmune diseases like systemic lupus erythematosus (SLE), can lead to persistent HPV infection and cancer. We evaluated cervical HPV prevalence and the associated risk factors in 70 women with SLE in the city of Belém, located in Brazilian Amazon. HPV DNA was detected by PCR using primers MY9 and MY11. HPV subtypes were determined by real-time PCR, using specific probes. Overall, prevalence of cervical HPV in women with SLE was 22.8%. HPV prevalence was significantly higher in younger women (aged 18-25 years; 75%, p< 0.0001), in women who had not given birth (50%, p = 0.01), and in women with no prior pregnancy (57%, p = 0.003). Five women (7.1%) had Pap smears with a cytopathological outcome suggestive of HPV; four of these women were HPV-positive. No women with both, SLE and HPV, had a normal Pap smear. Of the women diagnosed with SLE in the last 1-5 years, 75% was HPV-positive (p = 0.04). The two most prevalent HPV subtypes were HPV 58 (37.5%) and HPV 31 (31.3%). These results are important for understanding HPV infection in women with SLE and are valuable tools for developing cervical cancer prevention strategies and health management policies.

Latex fractions from Calotropis procera, Cryptostegia grandiflora, Plumeria rubra, and Himatanthus drasticus were assayed in order to prospect for new plant peptidases with milk-clotting activities, for use as rennet alternatives. Only C. procera and C. grandiflora latex fractions exhibited proteolytic and milk-clotting activities, which were not affected by high concentrations of NaCl and CaCl 2 . However, pre-incubation of both samples at 75°C for 10min eliminated completely their activities. Both proteolytic fractions were able to hydrolyze k-casein and to produce peptides of 16kDa, a similar SDS-PAGE profile to commercial chymosin. RP-HPLC and mass spectrometry analyses of the k-casein peptides showed that the peptidases from C. procera or C. grandiflora hydrolyzed k-casein similar to commercial chymosin. The cheeses made with both latex peptidases exhibited yields, dry masses, and soluble proteins similar to cheeses prepared with commercial chymosin. In conclusion, C. procera and C. grandiflora latex peptidases with the ability to coagulate milk can be used as alternatives to commercial animal chymosin in the cheese manufacturing process., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Differences were examined between three groups of adults with Down syndrome in their behavioral presentation, social life/activities, health, and support needs. We compared those with comorbid dementia, with comorbid psychopathology, and with no comorbid conditions. Adults with comorbid dementia were more likely to be older, have lower functional abilities, have worse health and more health conditions, and need more support in self-care. Adults with comorbid psychopathology were more likely to exhibit more behavior problems and to be living at home with their families. Adults with no comorbidities were most likely to be involved in community employment. Differences in behavioral presentation can help facilitate clinical diagnoses in aging in Down syndrome, and implications for differential diagnosis and service supports are discussed.

The purpose of this study was to develop automatic classifiers to simplify the clinical use and increase the accuracy of the forced oscillation technique (FOT) in the categorisation of airway obstruction level in patients with chronic obstructive pulmonary disease (COPD). The data consisted of FOT parameters obtained from 168 volunteers (42 healthy and 126 COPD subjects with four different levels of obstruction). The first part of this study showed that FOT parameters do not provide adequate accuracy in identifying COPD subjects in the first levels of obstruction, as well as in discriminating between close levels of obstruction. In the second part of this study, different supervised machine learning (ML) techniques were investigated, including k-nearest neighbour (KNN), random forest (RF) and support vector machines with linear (SVML) and radial basis function kernels (SVMR). These algorithms were applied only in situations where high categorisation accuracy [area under the Receiver Operating Characteristic curve (AUC)≥0.9] was not achieved with the FOT parameter alone. It was observed that KNN and RF classifiers improved categorisation accuracy. Notably, in four of the six cases studied, an AUC≥0.9 was achieved. Even in situations where an AUC≥0.9 was not achieved, there was a significant improvement in categorisation performance (AUC≥0.83). In conclusion, machine learning classifiers can help in the categorisation of COPD airway obstruction. They can assist clinicians in tracking disease progression, evaluating the risk of future disease exacerbations and guiding therapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Context: Cardiac surgery patients undergoing coronary artery bypass grafting with cardiopulmonary bypass., Objective: Evaluate the effect of adding intrathecal sufentanil to general anesthesia on hemodynamics., Design: Prospective, randomized, not blinded study, after approval by local ethics in Research Committee., Setting: Monocentric study performed at Dante Pazzanese Institute of Cardiology, Sao Paulo, Brazil., Patients: 40 consenting patients undergoing elective coronary artery bypass, both genders., Exclusion Criteria: Chronic kidney disease; emergency procedures; reoperations; contraindication to spinal block; left ventricular ejection fraction less than 40%; body mass index above 32kg/m(2) and use of nitroglycerin., Interventions: Patients were randomly assigned to receive intrathecal sufentanil 1μg/kg or not. Anesthesia induced and maintained with sevoflurane and continuous infusion of remifentanil., Main Outcome Measures: Hemodynamic variables, blood levels of cardiac troponin I, B-type natriuretic peptide, interleukin-6 and tumor necrosis factor alfa during and after surgery., Results: Patients in sufentanil group required less inotropic support with dopamine when compared to control group (9.5% vs 58%, p=0.001) and less increases in remifentanil doses (62% vs 100%, p=0.004). Hemodynamic data at eight different time points and biochemical data showed no differences between groups., Conclusions: Patients receiving intrathecal sufentanil have more hemodynamical stability, as suggested by the reduced inotropic support and fewer adjustments in intravenous opioid doses., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Objective: Evaluate the ability of clonidine to reduce pulmonary arterial pressure in patients with pulmonary hypertension undergoing heart surgery, either by reducing the pressure values from the direct measurement of pulmonary arterial pressure or by reducing or eliminating the need for intraoperative dobutamine and nitroprusside., Method: Randomized, double-blind, placebo-controlled, comparative study conducted in 30 patients with pulmonary arterial hypertension type 2 undergoing cardiac surgery. Mean pulmonary arterial pressure and dosage of dobutamine and sodium nitroprusside were assessed four times: before intravenous administration of clonidine (2 μg/kg) or placebo (T0), 30 min after tested treatment and before cardiopulmonary bypass (T1), immediately after CPB (T2), 10 min after protamine injection (T3)., Results: There were no significant differences regarding mean pulmonary arterial pressure at any time of evaluation. There was no significant difference between groups regarding other variables, such as mean systemic arterial pressure, heart rate, total dose of dobutamine, total dose of sodium nitroprusside, and need for fentanyl., Conclusion: Data analysis from patients included in this study allows us to conclude that intravenous clonidine (2 μg/kg) was not able to reduce the mean pulmonary arterial pressure in patients with pulmonary hypertension in group 2 (pulmonary venous hypertension), undergoing heart surgery, or reduce or eliminate the need for intraoperative administration of dobutamine and sodium nitroprusside., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

The purpose of this study was to develop an automatic classifier to increase the accuracy of the forced oscillation technique (FOT) for diagnosing early respiratory abnormalities in smoking patients. The data consisted of FOT parameters obtained from 56 volunteers, 28 healthy and 28 smokers with low tobacco consumption. Many supervised learning techniques were investigated, including logistic linear classifiers, k nearest neighbor (KNN), neural networks and support vector machines (SVM). To evaluate performance, the ROC curve of the most accurate parameter was established as baseline. To determine the best input features and classifier parameters, we used genetic algorithms and a 10-fold cross-validation using the average area under the ROC curve (AUC). In the first experiment, the original FOT parameters were used as input. We observed a significant improvement in accuracy (KNN=0.89 and SVM=0.87) compared with the baseline (0.77). The second experiment performed a feature selection on the original FOT parameters. This selection did not cause any significant improvement in accuracy, but it was useful in identifying more adequate FOT parameters. In the third experiment, we performed a feature selection on the cross products of the FOT parameters. This selection resulted in a further increase in AUC (KNN=SVM=0.91), which allows for high diagnostic accuracy. In conclusion, machine learning classifiers can help identify early smoking-induced respiratory alterations. The use of FOT cross products and the search for the best features and classifier parameters can markedly improve the performance of machine learning classifiers., (Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.)

Background: The use of ultrasound (US) in regional anaesthesia enables a reduction in the local anaesthetic volume. The present study aimed to determine the minimum effective volume (MEV(90)) of 0.5% bupivacaine with epinephrine for interscalene brachial plexus block (ISBPB)., Methods: The volume of the anaesthetic was determined using a step-up/step-down method and was based on the outcome of the preceding block. A positive or negative block resulted in a 1 ml reduction or increase in volume, respectively. The success of the block was defined as the presence of motor block in three muscle groups and the absence of thermal and pain sensations in three dermatomes within 30 min of the injection. Diaphragmatic paralysis and analgesia were assessed at 30 min, 4, and 6 h., Results: The MEV(90) for US-guided brachial plexus block under the conditions of the present study was 0.95 ml [R(2): 0.97, 95% confidence interval (CI): 0.6-1.22 ml]. The estimated maximum volume that did not cause diaphragmatic block was 4.29 ml (R(2): 0.84, 95% CI: 3.56-4.98 ml). Effective postoperative analgesia was achieved with 2.34 ml (R(2): 0.87, 95% CI: 0.48-11.47 ml)., Conclusions: The MEV(90) of 0.5% bupivacaine with epinephrine (1:200 000) for US-guided ISBPB was 0.95 ml. Adequate postoperative analgesia and a reduced incidence of diaphragmatic block can be obtained using from 2.34 to 4.29 ml. ClinicalTrials.gov. Registry NCT01244932.

Background and Objectives: Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in São Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009., Methods: Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009., Results: Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In five episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isoflurane; 3, sevoflurane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the five MH episodes were tachycardia (5), increased expired carbon dioxide (4), hyperthermia (3), acidemia (1), rhabdomyolysis (1), and myoglobinuria (1). One patient received dantrolene. All five patients with MH episodes were follow-up in the intensive care unit and recovered without sequelae. Susceptibility to MH was later confirmed in two patients by in vitro muscle contracture test., Conclusions: The number of calls per year in the Brazilian hotline service for MH is still low. The characteristics of MH episode were similar to those reported in other countries. The knowledge of MH in Brazil needs to be increased., (Copyright © 2013 Sociedade Brasileira de Anestesiologia. Published by Elsevier Editora Ltda. All rights reserved.)

Background and Objectives: Malignant hyperthermia (MH) is a pharmacogenetic disease that causes abnormal hypermetabolic reaction to halogenated anesthetics and/or depolarizing muscle relaxants. In Brazil, there is a hotline telephone service for MH since 1991, available 24 hours a day in São Paulo. This article analyzes the activity of the Brazilian hotline service for MH in 2009., Methods: Prospective analysis of all phone calls made to the Brazilian hotline service for MH from January to December 2009., Results: Twenty-two phone calls were received: 21 from the South/Southeast region of Brazil and one from the North region. Fifteen calls were requests for general information about MH. Seven were about suspected MH acute episodes, two of which were not considered as MH. In five episodes compatible with MH, all patients received halogenated volatile anesthetics (2, isoflurane; 3, sevoflurane) and one also used succinylcholine; there were four men and one woman, with a mean age of 18 years (2-27). The problems described in the five MH episodes were tachycardia (5), increased expired carbon dioxide (4), hyperthermia (3), acidemia (1), rhabdomyolysis (1), and myoglobinuria (1). One patient received dantrolene. All five patients with MH episodes were follow-up in the intensive care unit and recovered without sequelae. Susceptibility to MH was later confirmed in two patients by in vitro muscle contracture test., Conclusions: The number of calls per year in the Brazilian hotline service for MH is still low. The characteristics of MH episode were similar to those reported in other countries. The knowledge of MH in Brazil needs to be increased., (Copyright © 2013 Elsevier Editora Ltda. All rights reserved.)

The purpose of this study is to develop a clinical decision support system based on machine learning (ML) algorithms to help the diagnostic of chronic obstructive pulmonary disease (COPD) using forced oscillation (FO) measurements. To this end, the performances of classification algorithms based on Linear Bayes Normal Classifier, K nearest neighbor (KNN), decision trees, artificial neural networks (ANN) and support vector machines (SVM) were compared in order to the search for the best classifier. Four feature selection methods were also used in order to identify a reduced set of the most relevant parameters. The available dataset consists of 7 possible input features (FO parameters) of 150 measurements made in 50 volunteers (COPD, n = 25; healthy, n = 25). The performance of the classifiers and reduced data sets were evaluated by the determination of sensitivity (Se), specificity (Sp) and area under the ROC curve (AUC). Among the studied classifiers, KNN, SVM and ANN classifiers were the most adequate, reaching values that allow a very accurate clinical diagnosis (Se > 87%, Sp > 94%, and AUC > 0.95). The use of the analysis of correlation as a ranking index of the FOT parameters, allowed us to simplify the analysis of the FOT parameters, while still maintaining a high degree of accuracy. In conclusion, the results of this study indicate that the proposed classifiers may contribute to easy the diagnostic of COPD by using forced oscillation measurements., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

Background: Gastric bypass is the bariatric surgery most frequently performed in the world. It is responsible for sustainable weight loss, resolution of comorbidities, and improvement of quality of life. However, weight loss is not homogeneous, at times being insufficient in some patients. Our objective was to assess which factors were important in influencing this differentiated weight loss over a period of 4 years after surgery., Methods: In this retrospective study, we assessed several physical, socioeconomic, behavioral, surgical, and demographic factors in morbidly obese patients submitted to Roux-en-Y gastric bypass that might influence excess weight loss over a period of 4 years after surgery. The same factors were assessed in order to characterize insufficient excess weight loss (<50% EWL)., Results: Review of the medical records of 149 patients showed that type-2 diabetes mellitus and dyslipidemia were the most important factors related to a lower EWL up to the third year. Preoperative weight loss, lower schooling, and lack of adherence to nutritional guidelines were important after 2 and 3 years. The presence of depression and lack of adherence to nutritional guidelines were the factors related to EWL of less than 50%., Conclusions: Special attention and clarification should be provided to patients with diabetes mellitus type 2 and dyslipidemia and to patients with depression and lower schooling, since these patients tend to lose less excess weight after surgery. Multiprofessional care should also be provided so that the patients will follow nutritional guidelines more rigorously after surgery.

Background and Objectives: The new cardiopulmonary resuscitation (CPR) guidelines emphasize the importance of high-quality chest compressions and modify some routines. The objective of this report was to review the main changes in resuscitation practiced by anesthesiologists., Contents: The emphasis on high-quality chest compressions with adequate rate and depth allowing full recoil of the chest and with minimal interruptions is highlighted in this update. One should not take more than ten seconds checking the pulse before starting CPR. The universal relationship of 30:2 is maintained, modifying its order, initiating with chest compressions, followed by airways and breathing (C-A-B instead of A-B-C). The procedure "look, listen, and feel whether the patient is breathing" was removed from the algorithm, and the use of cricoid pressure during ventilations is not recommended any more. The rate of chest compressions was changed for at least one hundred per minute instead of approximately one hundred per minute, and its depth in adults was changed to 5 cm instead of the prior recommendation of 4 to 5 cm. The single shock is maintained, and it should be of 120 to 200 J when it is biphasic; and 360 J when it is monophasic. In advanced cardiac life support, the use of capnography and capnometry to confirm intubation and monitoring the quality of CPR is a formal recommendation. Atropine is no longer recommended for routine use in the treatment of pulseless electrical activity or asystole., Conclusions: Updating the phases of the new CPR guidelines is important, and continuous learning is recommended. This will improve the quality of resuscitation and survival of patients in cardiac arrest., (Copyright © 2011 Elsevier Editora Ltda. All rights reserved.)

Background and Objectives: Reducing the mass of local anesthetic minimizes the effects of hypotension after spinal anesthesia for cesarean section and the incidence of maternal adverse events preserving fetal well-being, but it may result in insufficient anesthesia. Hypotension associated with greater masses of subarachnoid anesthesia can be controlled by prophylactic continuous infusion of phenylephrine. The effects of prophylactic continuous infusion of phenylephrine on pressure control on maternal and fetus results in cesarean sections with different doses of hyperbaric bupivacaine in spinal anesthesia., Methods: A non-randomized prospective study of 60 gravidas at term scheduled for elective cesarean sections was undertaken. Patients were allocated into two groups depending on hyperbaric bupivacaine dose administered for spinal anesthesia, 12 or 8 mg, along with 5 μg of sufentanil and 100 μg of morphine. Patients were hydrated with 10 mL.kg(-1) of Ringer's lactate before the anesthesia. Shortly after, continuous infusion of 100 μg.min(-1) of phenylephrine was initiated to maintain blood pressure at baseline levels. The following parameters were evaluated: level of anesthetic blockade, consumption of vasopressors, incidence of maternal events, and conditions of the newborn., Results: Maternal data was similar in both groups regarding the level of anesthetic blockade, phenylephrine consumption along time, incidence of hypotension, hypertension, bradycardia, nausea, vomiting, dyspnea, pain, and tremors. Conceptual data showed similarities between both groups regarding blood gases and umbilical vein lactate levels. The pH of all newborns was > 7.2., Conclusions: On maintaining the blood pressure with prophylactic continuous infusion of phenylephrine the incidence of maternal adverse events and conditions of birth do not differ whether spinal anesthesia is performed with 12 mg or 8 mg of hyperbaric bupivacaine., (Copyright © 2011 Elsevier Editora Ltda. All rights reserved.)

Objective: Homocysteine and sepsis are both associated with inflammation and endothelial activation. Therefore this study was aimed to evaluate if the plasma homocystein level is related with the septic patient clinical severity., Methods: Severe sepsis or septic shock patients, with less than 48 hours from organ dysfunction start, were admitted to this prospective observational study. Homocysteine levels were determined by the time of study admission and then on the Days 3, 7 and 14. The homocysteine association with the Sequential Organ Failure Assessment (SOFA) score was evaluated using the Sperman test, and its association with mortality using the Mann-Whitney test. A p<0.05 value was considered statistically significant., Results: Twenty one patients were enrolled, and 60 blood samples were collected to measure total homocysteine [median 6.92 (5.27 - 9.74 μmol/L)]. The Sperman correlation test showed no association between homocysteine and SOFA ( r=0.15 and p=0.26). Also no correlation was found for the homocysteine level by the study admission time and the difference between the Day 3 SOFA score versus by study admission (deltaSOFA) (r=0.04 and p=0.87). Homocysteine variation between the Day 3 and the study admission (deltaHmc) and SOFA score variation in the same period were not correlated (r=-0.11 and p=0.66). Homocysteine by the study admission was not correlated with death in intensive care unit rate (p= 0.46) or in-hospital death rate (p = 0.13). This was also true for deltaHmc (p=0.12 and p=0.99, respectively)., Conclusion: Baseline homocysteine levels and its variations within the first dysfunction days were not related with septic patients' worsened organ function parameters or mortality.

Background and Objectives: The interscalene is one of the most common approaches used in brachial plexus block. However, the association of this approach with the ipsilateral blockade of the phrenic nerve has been demonstrated. The resulting diaphragmatic dysfunction causes changes in lung mechanics, which can be potentially deleterious in patients with limited respiratory reserve. The objective of the present study was to evaluate the repercussion of interscalene brachial plexus block on pulmonary function by measuring forced vital capacity (FVC)., Methods: This is a double-blind study with 30 patients, physical status ASA I or II, randomly separated into two groups of 15 patients each; 0.5% ropivacaine (Ropi Group) or 0.5% bupivacaine with epinephrine (Bupi Group) was administered. A peripheral nerve stimulator was used, and 30 mL of the local anesthetic were administered. Four spirometries were done in each patient: before the blockade, 30 minutes, four hours, and six hours after the blockade. Patients were not sedated., Results: One patient in the Ropi Group and three patients in the Bupi Group were excluded from the study due to failure of the blockade. The Ropi Group showed maximal FVC reduction at 30 minutes (25.1%), with a tendency for recovery from this point on. With bupivacaine, the reduction in FVC was less important at the different study moments; an additional reduction was observed between 30 (15.8%) and four hours (17.3%), but it was not statistically significant. A tendency for recovery was observed from four hours on. In both groups, the FVC six hours after the blockade was still below baseline levels., Conclusions: Interscalene block reduces FVC in most cases. Changes were more pronounced in the Ropivacaine group.