Background: Heat shock proteins (HSPs) are molecular chaperones known to bind and sequester client proteins under stress.Methods: To identify and better understand some of these proteins, we carried out a computational genome-wide survey of the bovine genome. For this, HSP sequences from each subfamily  were used to search the Pfam (Protein family) database, for identifying exact HSP domain sequences based on the hidden Markov model. ProtParam tool was used to compute potential physico-chemical parameters detectable from a protein sequence. Evolutionary trace (ET) method was used to extract evolutionarily functional residues of a homologous protein family.Results: We computationally identified 67 genes made up of 10, 43, 10 and 4 genes belonging to small HSP, HSP40, HSP70 and HSP90 families respectively. These genes were widely dispersed across the bovine genome, except in chromosomes 24, 26 and 27, which lack bovine HSP genes. We found an uncharacterized outer dense fiber (ODF1) gene in cattle with an intact alpha crystallin domain, like other small HSPs. Physico-chemical characteristic of aliphatic index was higher in HSP70 and HSP90 gene families, compared to small HSP and HSP40. Grand average hydropathy showed that small HSP (sHSP), HSP40, HSP70 and HSP90 genes had negative values except forDNAJC22, a member of HSP40 gene family. The uniqueness ofDNAJA3 andDNAJB13 among HSP40 members, based on multiple sequence alignment, evolutionary trace analysis and sequence identity dendrograms, suggests evolutionary distinct structural and functional features, with unique roles in substrate recognition and chaperone functions. The monophyletic pattern of the sequence identity dendrograms of cattle, human and mouse HSP sequences suggests functional similarities.Conclusions: Our computational results demonstrate the first-passin-silico identification of heat shock proteins and calls for further investigation to better understand their functional roles and mechanisms in Bovidae. Most newly synthesized proteins require the interplay of evolutionarily conserved protein co-factors known as molecular chaperones, activated in response to heat stress or other chemical stressors that impair cellular activity. Organisms respond to environmental stress through reprogramming leading to the production of heat shock proteins (HSPs) . EffectsEscherichia coli genednaJ , based on molecular mass . HSP40 fnednaJ . HSP70s nednaJ , althougnednaJ . The firp value = 0.001) of the non-redundant protein sequences inBos taurus using the BLOSUM62 matrix, with an expected threshold of 10, a word size of 6, a gap cost of 11 with an extension 1, and with a conditional compositional score matrix adjustment. We acquired the starting chromosomal locations of candidate HSP genes searching through TBLASTN  in the non-redundant protein sequences forBos taurus using the BLOSUM62 matrix, with an expected threshold of 10, a word size of 6, a gap cost of 11 with an extension 1, and with a conditional compositional score matrix adjustment and filtering the low complexity regions.BLAT searches of the UCSC database were used to confirm the chromosomal locations of the HSP sequences. Redundant sequences similarly located chromosomally were rejected. Candidate sequences fitting our criteria were analyzed in thePfam database and detected using theSMART program (version 6), as described  to search the Pfam (Protein family) database, for identifying exact HSP domain sequences based on the hidden Markov model (HMM) (ProtParam tool (Swiss Institute of Bioinformatics) to compute potential physico-chemical parameters detectable from a protein sequence , amino acid composition, estimated half-life, aliphatic index, grand average of hydropathicity (GRAVY)) etc., as described . Conserved regions in the alignment were shaded black and less conserved regions were shaded gray  files2WJ7 ,1HDJ (NMR solution structure of the HDJ-1-J-domain),1YUW  E213A/D214A mutants,3Q6N (hexameric structures of Human HSP90) obtained from PDB as trace-to-structure mapping for sHSP, HSP40, HSP70 and HSP90, respectively.To extract evolutionarily functional residues of a homologous protein family, we utilized the evolutionary trace (ET) method, as previously described. Multiple sequence alignment obtained from ClustalW for sHSP, HSP40 (type I and II), HSP70 and HSP90 were submitted to ET analysis Web server (ODF1) was identified in the genome-wide search due to the presence of an intact alpha-crystallin domain, as confirmed by Pfam and SMART tools. sHSPs were scattered across the chromosomes, with two genes (HSPB2 andCRYAB), found on chromosome 15 observed to be approximately 5 kb apart, possibly indicative of a tandem duplication.Our exhaustive search for HSP genes in the bovine genome using human and mouse sequences as queries resulted in the identification of 10 genes belonging to small HSPs , 43 geneDNAJA1,DNAJA2,DNAJA3 andDNAJA4) , and 27 HSP40 genes were assigned to HSP40 type III due to the presence of a single J domain. Although 22 out of 29 chromosomes contained the hsp40 gene family, with the highest number of HSP40 genes found on chromosome 12   possessesome 12 , no HSP4HSP90AA1,HSP90AB1,HSP90B1 andTRAP1 were mapped to chromosome 21, 23, 5 and 25, respectively , with majority of the HSP40 and HSP70 families very stable (II<40). Comparatively, values obtained for aliphatic index were high among sHSP, HSP40, HSP70 and HSP90 families, with higher values more pronounced in the HSP70 and HSP90 families. Similarly, results obtained from GRAVY showed sHSPs, HSP40, HSP70 and HSP90 proteins with negative values, except for DNAJC22 , which wAlignment results for sHSP gene family in cattle showed that the alpha crystallin domain is much more highly conserved than the N- and C-terminal regions. Multiple sequence alignment identified phenylalanine (F), proline (P), glycine (G), leucine (L), glycine (G) and L to be evolutionarily conserved . InteresTo examine the structural context of the invariant residues in sHSP gene family, the human alpha B crystallin (2WJ7) was used as our reference structure. sHSP sequences of human, mouse and cattle utilized for evolutionary trace analysis were partitioned into four groups. Multiple sequence alignment of the consensus sequences obtained from conserved residues in each group resulted in a trace, which identified three evolutionarily functional residues  and five residues which appeared to be class-specific . Amino aODF1 diverging first from other members of sHSPs, whileHSPB2,CRYAA,CRYAB andHSPB6 appeared to have recently diverged, withCRYAA andCRYAB branching from the same node , implying that cattle sHSP genes possess thermal stability, a feature consistent with its protective function in preventing cellular damage during heat stress  of homologous sequences offers a wealth of information by identifying conserved residues crucial to the function or structure of related proteins . EvolutiODF1 gene identified LxxxGxL as one of the conserved motifs shared among human, mouse and cattle sHSP sequences, while residues YxxxSxV are class-specific of theODF1 gene. In addition, downstream of the YxxxSxV motif was the presence of approximately 21 residues present only in theODF1 gene and this might suggest a structural and functional differences between theODF1 gene and other sHSPs in cattle. Interestingly, the sequence identity dendrogram also observed the separation of theODF1 gene prior to the divergence of other members of sHSP, thus further strengthening our previous hypothesis of a possible existence of functional and structural differences between ODF1 and other members of the sHSP family. In a related study, several authors reported AxxxxGxL as the most conserved motif in the alpha crystallin domain  at R167  to DNAJ (HSP40)-bound substrates  would have clustered together because of the presence of the four canonical domains; however,DNAJA3 diverged earlier than expected when compared to other members which recently diverged. In addition,DNAJA3 did not cluster with any other HSP40 sequences and diverged from the tree after the divergence of theDNAJB14 andDNAJB12 clade. Although, the reason for this observation remains unknown at this moment but could be indicative of functional divergence ofDNAJA3. It therefore appears thatDNAJA3 performs its chaperoning function in a way and manner that is different compared to other HSP40 type 1 and 2 gene family, given the sudden shift of the pI of the DNAJA3 proteome toward basic values when compared to other HSP type I members. In any case, more research needs to be done to functionally verify these speculations.ET analysis involving HSP type I and II genes in humans, mice and cattle identified some evolutionarily conserved residues which are consistent with our observations during multiple sequence alignment. Although some class-specific residues were observed, all the invariant residues found in the J domain among orthologous sequences could be suggestive of their functional importance to regulate HSP70 ATPase activity or to ensure protein stabilityHSPA4 diverged first, followed byHSPA14, while the instability index was predicted to be unstable (II>40) for HSPA4 (45.24) and HSPA14 (44.95), presumably an indication of functional similarities between HSPA4 and HSPA14; that said, one cannot rule out the fact that one needs to conduct more experiments in order to gain mechanistic insights before valid inferences can be made.A total of 10 members of HSP70 were observed in cattle with the invariant residues mostly found in the nucleotide binding domain where HSP70 interacts with HSP40 J domains. Interestingly, isoelectric point (pI) for all the HSP70 protein sequences were all predicted to be acidic with very little variation between the isoelectric point values of HSP70 protein sequences. This could possibly suggest a functional similarity among the cattle HSP70, further confirmed by reports of conserved functional properties of HSP70 protein across species  possesses acidic properties. High values were also recorded in the aliphatic index, with the highest value occurring in TRAP1, indicative of high thermal stability when compared to the constitutive forms. Similarly, the stability of HSP90All GenBank accession numbers of the bovine sequences used in this study are detailed in in the silico approach to identify Hsps in the bovine genome. The authors identified 67 genes belonging to four Hsp families. The manuscript is well written and the observations do support the conclusions.In the manuscript entitled ‘Computational genome-wide identification of heat shock protein genes in the bovine genome’, the authors have usedThe purpose of the study should be more clear in the introduction.Have the authors checked the Heat Shock Factors similarities with human or mouse?The authors should discuss the functional co-relation of the identified Hsps. However, the authors should address the following concerns:I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. et al. present an important technically soundin silico data about the genes that code for sHsp, Hsp40, Hsp70 and Hsp90 fromBos Taurus. It can be accepted as it is after considering the following minor suggestions:Authors are requested to justify the reason for restricting their analysis to only sHsp, Hsp40, Hsp70 and Hsp90.It is unclear why the searches for Hsp90 were unable to identify genes for GRP94.Authors can keep all the identified genes in Tables 1 to 4 in the supplementary figure.Authors are requested to briefly provide comments on the physico-chemical values for the Hsps from bovine in comparison to humans and mouse.AjayiI have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard. et al. localize 67 different heat shock proteins in the genome ofBos taurus using human and mouse proteins and conserved motifs of each family. The proteins identified belong to the small HSP, HSP40, HSP70, and HSP90 groups. The ORF of each protein is analyzed to know its physicochemical properties and an evolutionary study is carried out. The different protein sequences are compared to get conclusions about the conservation and the main characteristics of each set of proteins.In this article AjayiB. taurus genome. The authors do not explain at any moment which database was used to obtain the genome. Most of the sequences are included in the NCBI protein database, so why did they decide to search directly in the genome before checking the database? On the other hand, they only analyzed the sequences of four families; why did they not include the hsp10, hsp60, and hps110 groups? About the results, it is striking that some proteins that show some of the motifs did not appear in the search. For example, gp96 is a protein with an Hsp90 motif so it is surprising that in a search with Hsp90, Pfam did not give any similarity. Some are similar with other proteins related with the HSP70 family (e.g. HSP12A) due to the presence of an HSP70 motif. The approach is adequate but I have some questions. The first one is the source of the About the results and discussion, they are mainly focused on the protein sequences and the differences and similarities of amino acids. I miss some discussion related to the gene structure (presence/absence of introns) and related to the transcriptional activity information (what is known from some of the genes described here). I understand that the number of genes is high and it is hard to discuss everything but, in some cases, this information can be helpful in relation to the putative function of the protein. For example, the authors seem to assume that sHSPs are related to stress but many of them have a role in processes like development. It should be taken in account when they are divided into different groups. As stated before, I miss some information related to the genes. It would be interesting to incorporate in the tables the position in the chromosomes since the authors have located each gene in the chromosome. In the sHSPs it would be interesting to know if they are close since it has been proposed that duplication is a putative mechanism of increasing the number of members of this family and, often, two related sHSPs are in head-to-head or head-to-tail positions. Also it will be helpful to include the existence of introns in the gene, as it could help to find homologs in other species. About the tree, why did the authors not include an example of an external group? Overall the article is technically sound and it is a first step to describe more deeply the heat shock protein set in this species. It is important that the authors remark that they are only analyzing four of the families, maybe the most important, but for example, they did not include the Hsp60 and Hsp10 families that are mitochondrial. On the other hand, the main weakness, in my opinion, is to discuss the results without taking into consideration any functional information  because it could help to associate putative physicochemical properties with an inducible role.I have read this submission. I believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above.


BackgroundPain and discomfort at the tourniquet and wound site are recognised complications of carpal tunnel surgery. Studies have shown that longer tourniquet times lead to increased pain, local and systematic complications. We hypothesise that minimising the intraoperative tourniquet time will reduce post-operative pain and complications.ObjectiveOur aim is to present the results of our novel operative technique for carpal tunnel decompression which minimises tourniquet time.MethodThe study represented a prospective case series in which 55 consecutive and unselected patients with positive nerve conduction study results were operated on by a single surgeon at a single hospital site over a period of 12 months. The patients filled in a questionnaire based on a visual analogue score (VAS) (1-10) for pain at (1) first presentation at the clinic, (2) recovery in theatre post-operatively and (3) on discharge from care at 12 weeks post-operatively. Questions included the perception of pain at the tourniquet site and at the wound site.Results A total of 55  patients participated in the study. The average tourniquet time was 5 minutes 50 seconds. 98% of patients had a VAS of 1 at both the wound and tourniquet site post-operatively. One patent had a score of 3 at the tourniquet site. Eleven patients had undergone contralateral carpal tunnel decompression surgery. Of the remaining 43 patients, all said they would have the other side operated on in the same way.Conclusion We have demonstrated a safe and efficient technique to reduce post-operative pain by minimising tourniquet inflation time. Our patient cohort experienced no significant complications and minimal pain post-operatively. Carpal tunnel decompression under local anaesthetic is an accepted method of treatment for carpal tunnel syndrome . Pain anOur aim is to present a safe and reproducible operative technique for carpal tunnel decompression under local anaesthetic which aims to minimise post-operative pain caused by the tourniquet. Our technique focuses on reducing the length of tourniquet time by the surgeon to help reduce the post-operative pain for patients.Fifty-five consecutive and unselected patients with positive nerve conduction study results were operated on by a single surgeon at a single site over a period of 12 months. The patients filled in a questionnaire based on a visual analogue score (VAS) (1-10) for pain at (1) first presentation at the clinic, (2) at recovery in theatre post-operatively and (3) on discharge from care at 12 weeks post-operatively. Questions included the perception of pain at the tourniquet site and at the wound site.Patient pathwayThe procedure is explained to all patients during the consent process in the clinic. All patients are admitted as a day case procedure.Once in the operating theatre complex, the tourniquet is applied to the upper arm but not inflated in the anaesthetic room Figure . Local aFifty-five patients were included in this study and their demographics are displayed in the table below Table . The aveCarpal tunnel release has been shown to be an excellent procedure in relieving pre-operative pain and has a high patient satisfaction . The maiThe main limitation of our study is that we have described a single surgeon technique, therefore, our results may not be replicable accounting for variation in surgeon experience and skill. Secondly, patient-related outcome measures were not assessed, as our main outcome measure was post-operative pain scoring.We have demonstrated a safe and efficient technique for carpal tunnel release under local anaesthesia and tourniquet. By focusing on carefully timing the inflation and deflation of tourniquet, we were able to minimise overall tourniquet time and reduce pain for the patient. Our patient cohort experienced no significant complications and 98% of our cohort had no pain post-operatively and at follow-up.


Despite intensive efforts to engage people living with HIV in the United States, less than half of the youth aged 13 to 24 years achieve viral suppression. There is a clear and continued need for innovative behavioral programs that support optimizing adherence among young persons with HIV.There are 3 phases of this project. Phase 1 involves conducting focus groups to obtain feedback from youth about an existing technology-based antiretroviral therapy (ART) adherence intervention. Phase 2 will be used to conduct beta testing with youth to refine and finalize the YouTHrive (YT) intervention. Phase 3 is a randomized controlled trial (RCT) to test the efficacy of the YT intervention among youth living with HIV (YLWH).look and feel and content of an existing adult-focused Web-based ART adherence intervention and (2) suggestions for adapting the intervention for YLWH similar to themselves. Phase 2 will involve updating the existing intervention to include features and functionality recommended by YLWH in phase 1; it will conclude with beta testing with 12 participants to gain feedback on the overall design and ensure proper functionality and ease of navigation. For phase 3, we will enroll 300 YLWH in 6 US cities  into a 2-arm prospective RCT. Participants will be randomized 1:1 to YT intervention or control group. The randomization sequence will be stratified by city and use random permuted blocks of sizes 2 and 4. Participants randomized to the control condition will view a weekly email newsletter on topics related to HIV, with the exception of ART adherence, for 5 months. Participants randomized to the YT intervention condition will be given access to the YT site for 5 months. Study assessments will occur at enrollment and 5, 8, and 11 months post enrollment. The primary outcome that will be assessed is sustained viral load (VL), defined as the proportion of participants in each study arm who have suppressed VL at both the 5- and 11-month assessment; the secondary outcome that will be assessed is suppressed VL at both the 5- and 11-month assessment between drug-using and nondrug-using participants assigned to the YT intervention arm.In phase 1, we will conduct 6 focus groups with approximately 8 youths (aged 15-19 years) and young adults (aged 20-24 years), each in 3 US cities to obtain (1) feedback from YLWH about the Participant recruitment began in May 2017 for phase 1 of the study. The data collection for aim 3 is anticipated to end in April 2020.The efficacy trial of the YT intervention will help to fill gaps in understanding the efficacy of mobile interventions to improve ART adherence among at-risk populations.ClinicalTrials.gov NCT03149757; https://clinicaltrials.gov/ct2/show/NCT03149757 (Archived by WebCite at http://www.webcitation.org/73pw57Cf1)DERR1-10.2196/11502 Youth aged between 13 and 24 years accounted for 22% of all new HIV infections in the United States in 2015. The majority of these infections (81%) occurred among gay and bisexual young men  and taking ART correctly with food [P<.05]) among the intervention group than the control group. Improvement in ART adherence outcomes was most pronounced for current  drug-using MSM among whom the TWM intervention arm reported significantly higher overall ART adherence (P=.02) and ART taken correctly with food (P=.01) than those in the control condition. Currently, TWM is being assessed in a large (n=400) efficacy trial of MSM residing in NYC [The New York . TWM is B) model ,28. A piB) model . MSM  of the YouTHrive (pronounced “Youth Thrive” or abbreviated as YT) Web-based intervention, which is being adapted from the TWM intervention. The primary goal of YT was to improve ART adherence and HIV treatment outcomes among viremic YLWH. YT uses a multicomponent package of peer-to-peer social support, tailored HIV and ART information, and self-monitoring to achieve this goal.The aims of the research include the following:The primary objective is to assess the efficacy of YouTHrive (YT) in a 2-arm RCT (n=300) to sustain suppressed viral load (VL) among YLWH, compared to an HIV information-only control condition.H1: A higher proportion of participants in the YT intervention arm than in the information-only control arm will have undetectable VL at both the 5- and 11-month follow-up time points.The secondary objective is to assess whether YT is more beneficial for substance-using than nonsubstance-using YLWH.H2: Among YLWH in the YT intervention arm, a higher proportion of substance-using YLWH will demonstrate VL suppression at both the 5- and 11-month follow-up time points compared to nonsubstance-using YLWH.The IMB model proposes that health behavior and behavior change results from being well and accurately informed, having the personal and social motivation to engage in the behavior, and having the appropriate behavioral skills and self-efficacy to use them ,30. The The institutional review board (IRB) at the University of North Carolina Raleigh Durham, NC, is the IRB of record for all participating institutions and subject recruitment venues (SRVs) participating in the study. It will review all procedures outlined in this protocol. Procedures for phase 1 of the study (outlined below) have been approved (UNC IRB 16-3136). A waiver of parental consent was obtained for participants who are aged 15 to 17 years. The study is registered as a clinical trial .We will evaluate the YT intervention in a randomized controlled efficacy trial see . There alook and feel and content of the original TWM intervention and (2) suggestions for adapting the intervention for YLWH similar to themselves. Focus groups will be transcribed verbatim, and a content analysis will be assisted by the analytic core (AC). Feedback from the focus groups will be used to inform phase 2.We will conduct 6 focus groups with approximately 8 youth (aged 15-19 years) and young adults (aged 20-24 years), each at 3 SRVs  to obtain (1) feedback from YLWH about the look and feel of YT), functionality , and navigability  to finalize all features and components of the intervention for phase 3.We will work with our technology partner, Radiant Creative Group (RCG), to adapt the TWM intervention to include features and functionality that are identified in the first phase of our research. Beta testing with 12 participants will be conducted to get feedback on intervention design  will be recruited by staff from 6 SRVs located in Atlanta, Chicago, Houston, New York (the Bronx borough), Philadelphia, Tampa, and (see Recruitment Strategy below). Persons who are interested in the study will be screened for eligibility using an online screening survey. YLWH who meet all inclusion criteria (detailed below) will complete an enrollment visit, which may be on the same day as screening or on a different day.At the enrollment visit, participants will complete an in-office baseline computer-assisted survey instrument (CASI) and will be randomized at survey outset to either intervention or control. YLWH will then complete in-person overview and training on condition-specific site use. Youth assigned to the YT intervention will be shown example webpages of the intervention, will be given basic training on how to navigate the intervention, and will be given the opportunity to ask questions they have about the website. Control condition assigned participants will be shown example control arm webpages. Intervention and control conditions are detailed below.The active intervention and control period will last 5 months. We will employ up to 5 YLHW to be active in the YT site at first until there are 10 participants randomized to the YT intervention arm. This is to ensure that youth entering the intervention arm early have others with whom they can interact and not requiring participants to wait until other participants are enrolled. During the 5-month intervention period, YT intervention arm participants will have continuous access to the YT site, whereas youth in the control condition will receive an email newsletter with HIV-related information once per week.Follow-up assessments will be conducted at 5-month , 8-month (follow-up 2 in an online-only CASI), and 11-month  time points. Follow-up visits 1 and 3 will include an in-office administered CASI, a blood draw to test for detectable VL, and a urine screen for drug use, whereas follow-up 2 is an online CASI only.At the 5-month visit, up to 20 participants randomized to the YT intervention arm will participate in a remote video-based interview conducted by study staff. The purpose of this interview is to elicit feedback on their experiences using the YT site, any technical difficulties encountered, and how the site could be further improved. Participants will be selected for interviews using purposive sampling based on level of engagement with the site . All interviews will be audio recorded for transcription and analysis. Study staff will track activity levels and select participants for the interview.We plan to enroll 360 HIV-positive adolescents and young adults in this study. Up to 48 participants will be recruited for focus group discussions  for phase 1, 12 participants will be recruited to conduct beta testing of the YT intervention in phase 2, and 300 participants (n=150 YT and n=150 control) will be recruited to participate in the YT RCT in phase 3. Participants who are pregnant at the time of screening or who become pregnant during the study period will not be excluded from the study.Inclusion criteria for each phase of the study are described below:The focus group inclusion criteria are as follows: (1) self-reporting 15 to 24 years of age at screening; (2) HIV positive; (3) currently taking ART medication; (4) self-reporting missed medication doses in the past month or detectable VL or no VL in past 12 months; (5) engaged in care at the Chicago, Houston, or New York City SRV; (6) owns a cell phone; and (7) proficient in English as determined by study staff (as the intervention will be built in English). Focus groups will be stratified by age  to ensure that the perspectives of both youth and young adults are explored.Beta testing inclusion criteria are as follows: (1) 15 to 24 years of age at the enrollment visit; (2) HIV-positive status ; (3) HIV clinical care in Atlanta, Chicago, Houston, New York City, Philadelphia, or Tampa area; (4) currently prescribed ART ; (5) medical chart–verified detectable VL  within 52 weeks of enrollment date and an ART prescription for at least 90 days before this VL test date; (6) English-speaking; (7) internet and short message service (SMS) messaging access for the beta testing period (approximately 2 weeks); (8) available to meet with site project staff in person for the first research appointment; and (9) available to meet with University of Minnesota project staff for a remote  feedback interview.RCT inclusion criteria are as follows: (1) aged 15 to 24 years at the enrollment visit; (2) HIV-positive status; (3) residing in Chicago, Houston, NYC, Philadelphia, Atlanta, or Tampa area and respond that they will be available to meet with SRV staff for visits at baseline, and 5-month and 11-month follow-up assessments; (4) evidence of a current ART prescription; (5) English-speaking; (6) anticipated continuous internet access and SMS messaging for the intervention period (approximately 5 months); and (7) has or is willing to create an e-mail address to use during the study period; (8) not a member of an iTech Youth Advisory Board (YAB); and (9) meets one of the following medical-chart verified or self-reported criteria: (a) one or more detectable VL test result  in the past 12-months while on ART for at least 3 months, (b) having failed to show up for or missed 1 or more scheduled HIV care appointment in the past 12 months, (c) last HIV care visit was more than 6 months ago, or (d) self-reporting less than 90% ART adherence in the past 4 weeks. Persons enrolled in another ART adherence intervention research study at the time of screening will be excluded from participation.Participants for all phases of this study may be approached and recruited in 1 of 2 ways: (1) in the SRV HIV clinic or (2) in the community. Recruitment procedures may vary slightly depending on the SRV and study phase.Youth who are patients at the SRV will have his or her medical chart reviewed to assess for potential eligibility  and, if an appropriate candidate, will be approached for recruitment. Potential participants will be informed of the nature of the study, the information to be collected, and the evaluations and assessments that are involved. Those who express interest in the study will be required to be screened using a computer-based screener on a desktop computer or tablet (located at the SRV) to determine if they meet all inclusion criteria . If eligibility criteria are met, the youth will be invited to enroll in the study immediately or at a later date if they are not available then.Community outreach may bring in youth who are patients at other local HIV clinics or who are out of HIV care and would benefit from the SRV clinical care program. New patients can be considered for this project if they meet eligibility criteria. Outreach to community-recruited youth can include contacting potential participants via telephone or electronically , attendance at community venues where youth not in HIV care spend time or through targeted ads on widely used social media channels . Youth who are approached for recruitment in person or contacted remotely  will be asked to complete the online screener and, if preliminarily eligible, scheduled for an enrollment visit. The receipt of clinic services will not depend on expressing interest or enrolling in the YT study .Once participants are enrolled and complete the baseline assessment, they will be randomized 1:1 to YT intervention or control group, based on a randomization sequence developed by the AC statistician and programmed into SurveyGizmo. Study staff will not be blinded to which arm youth are randomized; however, because both conditions are active , we have confidence that youth will not be aware of whether they are assigned to the intervention or control condition. The randomization sequence will be stratified by city  and use We will consistently work with Youth Advisory Boards (YABs) at each SRV to elicit feedback from YLWH regarding our language, design, and gaming choices that would be most interesting and relevant to youth. YABs, at most SRVs, meet monthly to review study materials and provide feedback to study teams during phase 2 and as needed in phase 3.cleared for posting. Rather, the moderator reviews posted material and acts accordingly. This is to retain the immediacy of posting, which users of social media largely expect. Similar to the TWM intervention for adult MSM [In the RCT, intervention participants will have access to the full YT website for 5 months. The YT intervention will be developed as a safe space for sharing information and helping youth feel empowered and supported to make healthy choices around living with HIV. To be available to answer questions and enforce community standards , the YT website is moderated by trained research staff. Moderating includes reading through posted comments on the wall each day and identifying posts that are concerning . The study protocol and procedures manual for moderating details the exact steps taken for each potential situation. Note that posts are not delayed or held until dult MSM , there aThe YT homepage will consist of an interface for participants to asynchronously interact with one another through message posting. Unlike widely used social networking platforms such as Facebook, participants will view all posts on 1 shared feed . Other users may comment on a post as well as use reaction buttons . Message posting is the primary social support component of the intervention, as it allows participants to directly and voluntarily interact with one another in a similar manner as a face-to-face peer support group see .Grab Bag tips that include content about general well-being while living with HIV . All participants in the intervention arm will receive every Thrive Tip in the first half of the 5-month intervention period. Tips that reflect a participant’s unique adherence information, motivation, and adherence self-efficacy barriers, as assessed from the baseline survey responses, will be identified with an icon  to encourage greater engagement with tips tailored to youth’s specific adherence barriers. At the halfway point, youth in the YT condition will retake the IMB-related adherence information and motivation scales and the Adherence Self-Efficacy Scale (ASES) to update their adherence barriers profile, and all of the Thrive Tips will be shown a second time for the last half of the intervention period.Adherence and HIV content see  will be Content for the Thrive Tips is curated and created by the study team with input from the YABs. Aim 1 focus groups will be used to guide revisions of Thrive Tips from the TWM intervention to include youth-oriented language, images, and videos as well as content that is inclusive to all genders and sexual identities . As participants are in the intervention for longer periods, they accumulate more saved Thrive Tips. They can search and revisit all accumulated Thrive Tips through a keyword search.My Check-in feature on the YT interface. Youth will have the ability to retrospectively input their adherence and mood for up to 72 hours. Underneath, a calendar will be displayed that reflects their personal adherence behaviors through color coding  with overlaid emojis that indicate their mood for the day to promote greater insight of the connection between participants’ adherence behaviors and mood states  of ART each day as well as indicate their daily mood by selecting the representative emoji, through the ates see .Youth will view an interface called “My Journey” that leads them through steps to set and self-monitor 1 or more goals. Goals will include, but will not be limited to, those about living with HIV and ART adherence. For example, a youth may identify that she or he would like to improve school performance. Participants could choose the goal of determining which time is best to take their HIV medications if the medications interfere with their thinking or could choose the goal of asking for help with their homework from a classmate, teacher, tutor, or parent/guardian. In addition, youth will be given the option of writing in their own goal. Once a goal is set, youth will indicate when they would like to achieve that goal . The goal will then appear as an active goal in which youth will self-monitor how much progress they have made toward that goal with a 7-point scale from “thinking about starting” to “journey complete.” Youth will be asked if they would like to share on the community wall that they have completed a journey. Participants may start and complete as many journeys as they wish during the study period.“Extra, extra! Read all about it! Log in here to see today’s tip.”), goal setting and monitoring , adherence and mood monitoring , advancing point levels , and trending topics on the community wall .All participants will receive a weekly SMS text message that prompts and encourages them to visit the YT site. SMS text messages will be designed to engage youth with the different aspects of the site, including Thrive Tips  during the intervention period, which unlocks new features of the site  when a new level is achieved. Points are earned through posting to the YT feed , responding to other users’ comments, setting new goals, clicking on a Thrive Tip, and other actions that may be taken in YT. Youth will be able to view the number of points and their current level as part of their profile.newsletter. This weekly newsletter will be provided to participants as an email with a link they can click on to open the newsletter on their mobile internet browser. The newsletters will contain information on topics related to living with HIV  and devoted to improving general well-being  but not specifically about ART adherence. Informational content will be chosen from a list of topics reported to be of most interest and relevance by participants in phase 1 focus groups and YLWH serving on YAB.The control condition consists of 21 brief informational text and graphic-based webpages that will be released weekly (1 webpage per week for approximately 5 months), similar to a Study outcome measures and the timing of their administration are provided in Sustained undetectable VL is the primary outcome, defined as having an undetectable VL at both the 5- and 11-month time points. VL was chosen as the primary outcome as it is one of the most objective and reliable indicators of ART adherence . VL dataCommon demographic factors will be collected, including date of birth, race or ethnicity, zip code, sex assigned at birth, sexual identity, outness of sexual identity to others , education, employment status, health insurance, family income, housing stability, and history in the criminal justice system.We will use the 3-item Adherence Scale developed by Wilson et al , which aTo assess theoretically derived ART adherence strengths and barriers, the information and motivations scales from the IMB ART Adherence Questionnaire (IMB-AAQ)  will be Finally, we will ask youth to indicate the kinds of adherence support they received from their clinic, provider, friends, or family during the intervention period. Adherence support may include electronic dose monitoring devices, dose reminder texts, alarms, phone calls, pillboxes, reminders, and help from family and friends and support groups.The following items will be abstracted from the medical chart of participants: (1) date of HIV diagnosis, (2) current and recent HIV medications, (3) past 12 month HIV care visits, (4) missed HIV care appointments in the past 12 months, and (5) future HIV care appointments from the date of abstraction.Substance use will be assessed in several ways. First, youth will complete a urine screen at baseline, immediate postintervention, and 6-month postintervention time points to assess for the following illicit substances: cocaine, methamphetamines, marijuana, opiates, and phencyclidine, using a generic 5-panel screening test . The estimated detection periods for the test used are 2 to 4 days for cocaine and opiates, 5 to 30 days for marijuana, 1 to 3 days for ecstasy, and 3 to 5 days for methamphetamine. Second, participants will complete an adapted version of the National Institute on Drug Abuse (NIDA)-Modified Alcohol, Smoking, and Substance Involvement Screening Test (ASSIST). The ASSIST is a 9-item questionnaire developed by the World Health Organization and addiction researchers to screen for all levels of problem or risky substance abuse . The ASSDepression and anxiety symptoms will be assessed using the 8-item Patient Health Questionnaire (PHQ-8 ) and theEmotional regulation will be assessed using the Emotional Regulation Questionnaire, which is designed to assess individual differences in the habitual use of 2 emotional regulation strategies: cognitive reappraisal and expressive suppression . ParticiHIV stigma will be assessed using the stigma scale developed by Earnshaw et al . DesigneTo assess relationship status, youth will be asked to define their primary relationship status  and for those reporting being in partnership, whether they have sex outside the primary relationship as well. Sexual behavior is assessed by asking whether they have ever and in the past 3 months engaged in vaginal, anal, or oral sex. If they reported having sex in the past 3 months, youth will be asked how frequently  they use a condom during insertive and receptive anal sex and vaginal sex.The Patient-Reported Outcomes Measurement System (PROMIS) short-form versions of the Social Relationships Scales will be used to measure perceived social isolation and social support . PROMIS,Technology use questions and items assessing participants’ attitudes toward technology were taken from items developed by the Pew Research Center’s Internet, Science, and Tech initiative. Youth in YT will be asked to report device ownership; how they access the internet; which smartphone operating system they use and how they pay for service; how many hours a day they spend on the internet; how often they use mobile apps; frequency of internet use for social, sex-seeking, work, and health-seeking activities; the frequency with which they use social networking service ; and whether and how they may have faced discrimination while looking for partners on online venues. In addition, the 8-item eHealth Literacy Scale will be used to assess participants’ perceptions of their skills for using information technology  for health .Youth in both study arms will be asked to rate the ease of use of their respective activities (either the YT intervention or the active control condition) using the System Usability Scale (SUS) . The SUSfavorites, (6) number of SMS engagement messages clicked on to take the user to the site, (7) number of days ART adherence reported, (8) number of mood responses reported, (9) number of goals set, (10) number of times progress toward goals is reported, (11) total number of active intervention days, (12) number of times the participant updated their outward-facing profile features, and (13) total points earned.Intervention use data will be collected during the active trial period to assess user engagement with the intervention. Standard use data include (1) participant identification (ID) number, (2) study arm, (3) log-in date and time, (4) type of device used, and (5) total duration of the session. Intervention use data will include the following variables reflecting peer-to-peer interaction: (1) date of post, (2) original post content, (3) participant ID of original post, (4) content of replies to the original post, and (5) participant ID of each reply. Additional user engagement variables collected are (1) frequency of wall posts by participant ID, (2) number of comments by participant ID, (3) number of Thrive Tips viewed, (4) number of tailored Thrive Tips viewed, (5) number of Thrive Tips marked as Audio recordings from each focus group will be transcribed and checked for accuracy by a member of the AC. Next, all transcriptions will be reviewed by at least three members of the study team. Participants’ overall feedback and their suggestions for changes to the overall look and feel, content, and specific features will be compiled in a document and reviewed by investigators. Recommendations for changes to the user interface will be prioritized and presented to RCG to guide the development of the beta version of YT.Interviews with YLWH during beta testing will be audio recorded and reviewed by study team members. Feedback from youth will be recorded in a spreadsheet by intervention component, with suggestions for improving the overall design and content recorded separately. A beta testing report will be compiled by Dr Horvath and reviewed by the investigator team and RCG. The report will include a list of common navigation problems by intervention component, suggestions for improvement in design and content by intervention component, and recommended design and content improvements for the overall site. The study team and RCG will review the beta testing report to prioritize modifications that need to be made, given the importance of the change to the user experience as well as what changes are possible, given time and budget constraints. They will then agree on final modifications to YT.Stata version 15 (StataCorp) and SAS version 9.4 (SAS Institute) were used for power calculations and will be used for all analyses. The primary study outcome is HIV viral suppression at both 5 and 11 months of follow-up, measured as undetectable VL based on the standard level of detectability. The primary statistical test of intervention efficacy for YT will be the comparison between intervention and control arms of the proportion of participants with undetectable VLs at both the 5-month and 11-month follow-up time points using a differences in proportions test and confidence intervals. If there is evidence of baseline imbalance between intervention arms for important predictors of viral suppression, we will fit logistic regression models that adjust for those covariates.As a secondary aim, we will investigate whether there is greater benefit from the YT intervention for substance-using participants compared with nonsubstance-using participants. We will use the same modeling approach described above to address this aim. First, we will examine the association between the intervention and viral detection separately among those who did and did not self-report current (since the last visit) substance use . Second, to formally test whether there is an interaction between intervention arm and substance use, the models described above will be refit including an interaction term between substance use and interaction arm. Interactions will be evaluated on the additive scale. We will carefully examine the distribution of potential confounders of the substance use and VL association and adjust for them as necessary. As mentioned previously, we will adjust for covariates where appropriate.The models described use logistic regression to model the outcomes. We will use estimates from these models to report prevalence differences and ratios. However, alternative (log-linear and Poisson) models may be explored to allow easy interpretation of parameters in the presence of common outcomes. In the event of loss-to-follow-up among study participants, we will perform sensitivity analyses of an alternative outcome. We will define an additional outcome where a failure is defined as either detectable VL or loss-to-follow-up. The analyses described above will be repeated with this alternative outcome. All of the models mentioned above can be modified to accommodate missing values in the outcome or covariates over time without dropping participants. Although attempts will be made to limit missing data, in the event that this occurs, we will carefully examine patterns of missingness. Multiple imputation will be implemented, as needed, to deal with missing covariate data.Finally, we will examine models that include covariates that quantify the degree of site usage and which components were used. The additional outcome of self-reported ART adherence will be examined. The outcome will be defined as the percentage of ART taken in the past 30 days. Differences in this proportion by study arm will be evaluated using the same approach as described above. To explore the effects of the YT intervention on the intermediate theory-based processes of change, we will use the IMB-AAQ informational and motivational scales, adherence self-efficacy, and social support measures at each time point. These scales will be included as outcome variables in linear regression models to test the main effect of intervention arm.The method for compensation will be determined separately by each site and approved by each SRV’s IRB. Participants at all sites will be compensated with the following cash or cash equivalent. Focus group participants will be compensated US $30 and refreshments during visits. Beta test participants will be paid US $25 at the first visit and US $25 at the second visit. RCT participants will be compensated US $50 at the enrollment visit and the 5-month and 11-month follow-up visits. Participants will be compensated US $20 for completing the 8-month remote online survey. Participants who complete the exit interview at the 5-month follow-up visit will be compensated an additional US $50. If a participant is unable to go into the clinic to complete a follow-up study visit, the Web-based CASI survey could be completed on his or her own. SRV study staff will be notified when a participant has completed a CASI survey on his or her own, and the compensation will be provided to the subject. Compensation can be mailed to participants, if allowed at the site.This study is powered to detect a meaningful effect for the main aim that there will be a difference between the proportion of virally suppressed participants in the intervention and control arm. The sample will consist of people who are and are not virally suppressed at baseline. We assume that 30% of participants will not be virally suppressed at baseline. Among this 30% who are not virally suppressed, we assume 30% of them will be virally suppressed at all follow-up times in the control arm and 47% will be virally suppressed at all follow-up times in the intervention arm (for a difference of .17). Among the 70% who are virally suppressed at follow-up, we assume 80% will be virally suppressed at all follow-up times in the control arm and 95% will be virally suppressed in the intervention arm (for a difference of 0.15). The average risk of the viral suppression in the control arm is therefore 65% and the average risk in the intervention arm is 80.6% (a risk difference of .16 or a risk ratio of 1.24). Assuming a type 1 error rate of 5% and a 1:1 allocation of participants to the treatment and control arm, we have 80% power to detect this difference of .16 or risk ratio of 1.2 if we enroll 256 participants (128 per arm). We assume there will be 15% loss to follow-up and will attempt to enroll 300 participants to account for this.Participant recruitment began in May 2017 for phase 1 of the study. The data collection for phase 2 is expected to be completed in June 2018 and for phase 3 in October 2020. Final results are anticipated for April 2021.There are a number of challenges to the YT clinical trial. First, it will require a multipronged effort to meet our recruitment goals, especially for younger YLWH. To address this, the research team will work with recruitment venues to reach out to as many of their current clinic population who meet eligibility requirements as possible. In addition, we will implement community and social media recruitment strategies to identify potential participants who may either be out of HIV care or are not current patients at recruitment clinics. Second, we do not provide smartphones or other Web-enabled devices to study participants but rather require that participants own or have access to a Web-enabled device. This may restrict participation by lower socioeconomic status youth and young adults on the one hand but will increase the potential for scale-up on the other hand. Moreover, providing devices to study participants is cost prohibitive and, therefore, not feasible within this protocol. That said, given that nearly all (95%) of teens have access to a smartphone , we beliWith these limitations in mind, YLWH face numerous intrapersonal, social, structural, and cultural challenges, many of which impact their engagement in HIV care and, ultimately, interfere with their ability to adhere to ART. Given that the HIV epidemic in the United States has shifted toward younger ages of infection  and the There is a growing use of technology as a medium to reach youth with HIV with adherence interventions -60; howe


Epidemiologic data have shown an increasing incidence and declining mortality rate in sepsis. However, confounding effects due to differences in disease classification might have contributed to these trends.To assess if a declining mortality over time could be supported by data derived from high-quality prospective studies, we performed a meta-analysis using data from randomised controlled trials (RCTs) on sepsis. The primary aim was to assess whether the mortality in sepsis trials has changed over time. The secondary aim was to investigate how many of the included trials could show efficacy of the studied intervention regarding 28-day mortality.We searched PubMed for RCTs enrolling patients with severe sepsis and septic shock, published between 2002 and 2016. The included trials were assessed for quality and sorted by date of first inclusion. A meta-analysis was performed to synthesise data from the individual sepsis trials.p = 0.04) to give a total decline of 9.24%. In subgroup analyses with adjustments for APACHE II, SAPS II and SOFA scores, the observed time trend was not significant . Only four of the included trials showed any efficacy with regard to mortality.Of 418 eligible articles, 44 RCTs on sepsis were included in the analysis, enrolling 13,315 patients in the usual care arm between 1991 and 2013. In this time period, mortality decreased by 0.42% annually  contains supplementary material, which is available to authorized users. Sepsis is a potentially life-threatening condition which is estimated to affect over 30 million people worldwide each year . Recent In order to study trends of mortality in patients with severe sepsis with reduced risk of classification bias, Stevenson et al. assessed the trends of sepsis mortality based on data from randomised controlled trials (RCTs) . They foAccordingly, we hypothesised that a trend in the mortality of patients enrolled in the usual care arm of interventional high-quality sepsis studies published between 2002 and 2016 should be concordant with the previously reported trends from RCT data where quality assessments of the included studies had not been performed.The primary aim of this study was to investigate whether the reported 28-day mortality of patients with severe sepsis and septic shock, included as controls in randomised controlled trials, has declined over time. The secondary aim was to assess how many of the included trials could show any beneficial effect of the studied intervention with regard to 28-day mortality.According to international guidelines, there is currently no approved sepsis-specific drug or intervention . In addihttps://www.crd.york.ac.uk/PROSPERO/) and given number CRD42018091100. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement and the Meta-Analysis of Observational Studies in Epidemiology (MOOSE) Statement were referred to for methodological guidance [The study was registered in the International Prospective Register of Systematic Reviews  model: P, patients aged 16 years or older presenting with severe sepsis or septic shock; I, all treatments of severe sepsis and septic shock regardless of length of treatment and hospital setting; C, usual care; and O, mortality at 28 ± 2 days.Two independent investigators (RL and SC) reviewed abstracts in order to select potentially eligible studies according to pre-defined inclusion criteria. All selected studies were subsequently evaluated for quality assessment using the Jadad score .Studies were excluded if they (i) enrolled fewer than 50 patients in the control arm, since small trials may be more likely to have biased estimates, (ii) did not report mortality by day 28 (± 2), (iii) were considered to be of poor quality (Jadad score < 3), (iv) used data from other RCTs or (v) were written in a language other than English. To minimise the risk of the results being influenced by the difference in disease classification, only trials using the first and second international consensus definition of sepsis were included .The data extraction required for meta-analysis included the following information: (1) mortality at 28 ± 2 days, (2) number of patients enrolled in the usual care group, (3) number of patients in the intervention group, (4) whether or not the studied intervention had any beneficial effect on mortality, (5) age of the patients, (6) severity of condition at inclusion , (7) country, (8) author, (9) year of publication and (10) enrolment period.i is the mortality in the year i and β1 (slope) is the estimated temporal effect size per year on the pooled mortality. The same model was used to evaluate trends in age and disease severity. To reveal the effects of potential confounding factors, we also performed sensitivity analyses that included the average age of the patients as a dichotomous variable (< 65 vs. ≥ 65 years) in the meta-regression model.To analyse temporal trends in severe sepsis and septic shock mortality, we performed a meta-regression analysis of the included trials pooled by year of first patient inclusion . The temI2 was calculated to evaluate the statistical heterogeneity across the studies [I2 > 30% considered as at least moderate heterogeneity. The pooled relative risk (RR) with corresponding 95% confidence interval (CI) was presented based on the random effects model. To investigate differences between the efficacy of different types of intervention, the trials were divided into eight subgroups and, accordingly, the RR were pooled within each subgroup.The Higgins  studies , with I2p values were calculated. Statistical significance was defined as a 95% CI excluding 0 or a RR excluding 1 and two-sided p < 0.05, except where otherwise specified.The statistical analyses were performed in version 15.1 of Stata . All statistical tests were two-sided. Overall combined RRs with 95% CIs and This was a systematic review of previously published data from trials which had all been ethically approved before commencement, so no additional ethical approval was considered necessary.Of the 418 publications reviewed, 44 were included in the final analysis  between 1991 and 2013 . APACHE II, SAPS II and SOFA scores on study inclusion were reported in 28, 14 and 24 studies, respectively  . When adjusting the meta-regression analysis of the mortality over time for the three severity scores, the trend was no longer significant  revealed that mortality was 8% higher in studies including patients with a mean age ≥ 65 years. Meta-regression of the mortality trend with adjustment for dichotomous age (< 65 vs. ≥ 65 years) still demonstrated a significant decline of 0.57% annually .The overall relative risk of mortality in the 44 included trials was 1.00 (95% CI 0.94 to 1.05). Four of the 44 trials showed the efficacy of the studied intervention with regard to 28-day mortality Fig. . These fIn this study, we performed a meta-regression analysis of data derived from RCTs published between 2002 and 2016 (inclusion start date from 1991 to 2013) after a systematic literature search of studies including severe sepsis and septic shock. Our primary aim was to study the mortality trend of patients enrolled in the control arm. We found an annual decrease of 0.42% in the 28-day mortality among all patients enrolled as controls. Interestingly, the mortality trend was still a significantly decreasing one after adjustments for age and was found to be more pronounced in studies enrolling patients with a mean age ≥ 65 years. Severity scores were not adjusted for in our primary meta-regression analysis as different severity scores were used between the studies. However, when performing subgroup analyses with adjustments for APACHE II, SAPS II and SOFA scores on study inclusion, the mortality trend was no longer significantly decreasing over time. Consequently, the observed sepsis mortality decline in the control arm of RCTs could in part be explained by the inclusion of patients with a lower predicated mortality over time.In the similar study from 2014 by Stevenson et al., also using data from sepsis patients included as controls of RCTs, a declining mortality trend by 3.0% annually was demonstrated . The resAnother important issue that should be discussed in relation to the study by Stevenson et al. is their final conclusion stating that a declining sepsis mortality over time in the control arm from RCTs supports the use of administrative data to monitor trends in sepsis mortality. In our opinion, this may be questioned as several studies comparing clinical data with administrative claims data have shown that the decreases in sepsis mortality over time shown by administrative data are overestimated –13.The so-called Will Rogers phenomenon explains reduced disease-related mortality as a result of increased disease awareness and a higher proportion of less severely ill patients . Indeed,As a secondary aim of this study, we assessed the intervention effect on 28-day mortality. Overall, we found no efficacy regarding 28-day mortality. Four of the 44 included trials showed a beneficial effect of the studied intervention on mortality –25. HoweAs already established, sepsis is largely a heterogeneous syndrome. This diversity extends both to administrative aspects, leading to risks of classification errors, and to the pathobiology constituting the disease, creating a great variance in the presentation of the ailment based on properties of the pathogen and the host alike. The heterogeneity of patients included in RCTs investigating interventions for sepsis is probably an important reason for a large number of trials that have failed to prove efficacy. Although many post hoc analyses of large RCTs have been performed to control for this, including stratification to identify subgroups of patients who may benefit from the interventions that failed to prove efficacy, individualised treatments have not been implemented in clinical care . PrecisiIn order to address the difficulties caused by the heterogeneity of the disease, in 2016, the Society of Critical Care Medicine and the European Society of Intensive Care Medicine presented the third international consensus definition for sepsis and septic shock . This aiIn recent decades, even though only a few specific interventions have shown some effect on mortality, progress has been made and embraced in the shaping of international guidelines. Several studies have raised a warning flag regarding excessive fluid therapy , 52, oneOur study has several strengths. First, as this meta-analysis included over 13,000 patients enrolled in the control group in 44 trials from 55 countries and 6 continents, the reported results do not seem to be confined to a single part of the world. Moreover, all studies considered for inclusion were assessed for quality and excluded if they did not meet the pre-defined quality criteria. Lastly, as we used 28-day mortality ± 2 days as an inclusion criterion, the risk of missing important papers on the matter was reduced.This study also has several important limitations. First, we only used one database to conduct our search and so may have left some studies out of our analysis. Second, the exclusion of trials published in languages other than English may have limited the findings of this meta-analysis to Western countries. Third, our choice to exclude trials assessed to be of poor quality may have further limited the number and diversity of the included trials. However, the limited number of trials excluded based on the quality assessment suggests that this is unlikely to have had any major impact on our results. Fourth, there might be differences related to the heterogeneity of the included sepsis trials as we included studies with severe sepsis and septic shock defined by either Sepsis-1 or Sepsis-2 criteria and from different parts of the world. Indeed, the degree and type of organ failure in sepsis are shown to be associated with the in-hospital mortality . UnfortuFinally, studies on trends in mortality from the usual care arm of sepsis trials may shed light on the history of sepsis research and partly mirror the trends in sepsis mortality, but are not suited for sepsis epidemiology surveillance due to the lack of clinical data and heterogeneity issues. The most reliable way to study trends in sepsis mortality seems to be based on clinical raw data derived from electronic healthcare data sets . In a reData from RCTs showed a declining trend in 28-day mortality in severe sepsis and septic shock patients during the years from 1991 to 2013. However, when controlling for severity at study inclusion by APACHE II, SAPS II and SOFA scores, there was no significant change in mortality over time. Only 4 of the 44 included trials showed any efficacy with regard to mortality, and none of their methods have been implemented in the current treatment regimen of sepsis. Considering the unsuccessful history of RCTs aiming to lower sepsis mortality, it seems reasonable for future trials to focus on treatments targeted to certain subgroups and to use outcome measures beyond 28-day mortality.Additional file 1:Figure S1. Meta-regression analysis of the temporal trend in Acute Physiology and Chronic Health Evaluation (APACHE) II score between 1991 and 2013 in the included sepsis trials. (DOCX 88 kb)Additional file 2:Table S1. Search strategy. (DOCX 14 kb)Additional file 3:Table S2. Summary of data from trials included in meta-regression analysis. (DOCX 22 kb)


N = 434) and experimental studies (N = 104) conducted in Mainland China support hypotheses that humble leadership enhances employee resilience through simultaneous increases in work-related promotion focus and perceived insider identity. Research implications are discussed, and directions for future research are offered.Although the topic of employee resilience has recently received increased attention, existing research has largely failed to explore its situational triggers. Drawing on social information processing theory, the current study integrates the literature of humility and resilience to theorize the underlying mechanism through which humble leadership facilitates employee resilience. This research proposes a potential heterogeneous effect that humble leadership catalyzes employee resilience through multiple pathways. Field ( Employee resilience is a capacity of employees that is supported and facilitated by organizations to positively cope, adapt, and even thrive in response to dynamic and challenging environments . LuthansLeadership substantially influences the work lives of employees  and can To address this issue, the current study sought to further elucidate employee resilience by examining its situational antecedents. Specifically, we complement the literature on resilience by testing whether humble leadership activates employee resilience. The impact of humble leadership on the development of others’ strengths has not received appropriate theoretical and empirical attention thus far . Second,Social Information Processing theory SIP;  argues tHumble leadership is defined as a leadership style in which a leader evaluates him/herself and subordinates through a multifaceted and objective lens, appreciating subordinates’ positive worth, strengths, and contributions . It cont Hypothesis 1 (H1): Humble leadership is positively associated with employee resilience.Work-related promotion focus influences employees’ approach and drive for desired work-related outcomes . EmployeHumble leadership is perceived by employees as a model of how to grow and leads employees to feel that their own growth and improvement processes are legitimate and necessary , 2016. F Hypothesis 2 (H2): Employee work-related promotion focus mediates the relationship between humble leadership and employee resilience.Perceived insider identity is critical to viewing one’s organization membership in a favorable light . Lapalme Hypothesis 3 (H3): Perceived insider identity mediates the relationship between humble leadership and employee resilience.We carried out two studies to test our theoretical model. In Study 1, a field study was conducted in which survey data were collected from Mainland China. In this study, all scales adopted were originally written in English and then translated into Chinese following back-to-back translation , 1986 prAll procedures performed were in accordance with the ethical standards of the Research Committee on Human Experimentation and with the Helsinki Declaration of 1964, as revised in 2000. In addition, our studies were approved by the Southwest University Ethics Review Board. All participants provided written informed consent, and all responses were anonymous.The data in Study 1 were collected from full-time working individuals through an exponential, non-discriminative “snowball sampling” method  in Mainlstrongly disagree) to 5 (strongly agree). We adopted a scale developed by Humble leadership was measured with a 9-item questionnaire in which participants rated each item from 1 (never) to 7 . We adopted the scale developed by Employee resilience was measured with a 9-item questionnaire in which participants rated each item from 1 (strongly disagree) to 5 (strongly agree). We adopted the scales developed by Work-related promotion focus was measured with a 9-item questionnaire. Respondents provided their agreement with each item from 1 (strongly disagree) to 5 (strongly agree). We adopted the scale developed by Perceived insider identity was measured with a 6-item questionnaire in which participants rated each item on a scale from 1 , we ran a set of confirmatory factor analyses in Mplus 7.2 to examine the distinctiveness among the measures for variables employed in this study and to assess the severity of CMV . If the p < 0.001; R2 = 0.18, p < 0.001) at the 95% confidence interval. Therefore, H1 was supported. Hypotheses 2 and 3 predicted mediating roles of work-related promotion focus (H2) and perceived insider identity (H3) between humble leadership and employee resilience. Using a bias-corrected confidence interval method, we applied bootstrapping (1000 samples) to test the indirect effects. The results support both the indirect effects of work-related promotion focus  and perceived insider identity . Therefore, H2 and H3 were supported. All of these effects (direct and indirect) are presented in Considering the nature of our data, we tested all the hypotheses with Mplus 7.2. We adopted the SEM approach, as it allows simultaneous estimation of multiple indirect paths. To test the main effect, we modeled humble leadership as the predictor and employee resilience as the outcome and then conducted a regression analysis. The direct-path model provided the results for H1, which predicted that there was a significantly positive relationship between humble leadership and employee resilience , as well as the mediating roles of work-related promotion focus (H2) and perceived insider identity (H3). Participants in the present study were full-time staff working in Mainland China. Participation was voluntary, and confidentiality was guaranteed. In the first round, 104 participants, who were enrolled in a Master of Public Administration Program (part-time) in a large university in the southwestern region of China, were invited to participate in our study. These individuals were then randomly assigned to one of the two conditions. These two conditions represented two different humble leadership levels. Four participants were omitted from analysis due to a substantial amount of missing data . To make sure cell sizes for the two conditions were equal , we then invited another four individuals to participate by using the “snowball sampling” method. All of them were compensated with prepaid mobile phone cards value of RMB 30 Yuan (approximately 4.35 US dollars) for their participation. All participants held a bachelor’s degree or higher, 51% were female, and the mean age was 30.25 years (SD = 3.59).n = 52) and humble leadership (n = 52). Participants received all materials in paper-and-pencil form. Participants were asked to put themselves into the situation described and were told that they needed to make their own decisions. To ensure the reliability and confidentiality of the participants’ responses, all were told that there were no right or wrong answers and that all information was given anonymously and would only be used for research purposes. The manipulation of humble leadership was achieved by inserting a vignette characterizing the leader as behaving in a humble way. We created the scenarios based on the seminal definition and items of humble leadership proposed by We created scenarios that resembled real encounters in workplace contexts. Following seminal works in the field of humble leadership e.g.,  that genstrongly disagree to 7 = strongly agree). As a result, the humble leadership manipulation was considered successful.We did a twofold manipulation check to control for alternative explanations of our results. First, we used a panel of two university faculty members who were experts in the domain of leadership to assess the definition of leadership versions of our scenarios. Both experts rated the humble leadership version as a case of very intense humility and rated the control group version as an example of which the leader does not show any qualities reminiscent of humble leadership. In addition, participants were asked to respond to a manipulation check: “I would characterize the leader as a humble leader” (from 1 = strongly disagree to 7 = strongly agree). Other measures adopted were well-established scales. We adopted the 9-item scale used by Participants were required to “assume the part” of the employee in each vignette they read. They were then asked to complete a serial scale, which was used to reflect their likely reactions if they were to encounter the situations described. Participants reported the extent to which they considered the leader to be humble on a 7-point Likert scale . Our manipulation in eliciting participants in imagining themselves working with a humble leader was effective. The participants placed in the humble leadership group (n = 52) rated work-related promotion focus as significantly higher compared to those placed in the control group (n = 52). We conducted a regression analysis to test H1. Results supported that the effect was positive and significant . To test H2 and H3, we conducted a bias-corrected bootstrap analysis (1000 samples) with Mplus 7.2. Results indicated that humble leadership had a positive and significant indirect influence on employee resilience via increased work-related promotion focus  and exerted a positive and significant indirect effect on employee resilience via enhanced perceived insider identity . All of these effects (direct and indirect) are presented in The manipulation check showed that participants in the humble leadership group reported the leader as humbler than those in the control group  to empirically test the hypotheses by manipulating humble leadership, in an effort to increase internal validity. Study 2 replicated the results of Study 1. We combined a field study with an experimental study, which provided us with the advantages of both methods, with a consequent increase in both the generalizability and internal validity of our research .Our research makes several theoretical contributions. First, our inquiry helps fill the theoretical gap related to the scarcity of studies about the situational stimuli of employee resilience in the workplace. So far, very little is known about the relationship between leadership and employee resilience. The present research provides evidence regarding the power of humble leadership in facilitating employee resilience. Furthermore, the current results reinforce the contagious nature of humility within the Eastern cultural context and empirically confirm that the virtue of humble leadership is an underpinning for developing employees’ strengths. This finding illuminate’s leadership as a new activator of employee resilience that can be developed. This can be achieved by increasing appreciation of employees’ contributions and exhibiting openness to new ideas, which goes beyond traditional resilience-building channels . Second,Our findings also provide some managerial implications. First, our research shows the impact of humble leadership on catalyzing employee resilience in work organizations. Employee resilience can be facilitated in any work environment . UnderstDespite its strengths, our research has potential limitations that offer promising directions for future research. The first limitation is rooted in the cultural context within which both studies were conducted. Humility is culturally bound . AlthougAll authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.


Convolutional neural networks (CNN) have enabled significant improvements in pedestrian detection owing to the strong representation ability of the CNN features. However, it is generally difficult to reduce false positives on hard negative samples such as tree leaves, traffic lights, poles, etc. Some of these hard negatives can be removed by making use of high level semantic vision cues. In this paper, we propose a region-based CNN method which makes use of semantic cues for better pedestrian detection. Our method extends the Faster R-CNN detection framework by adding a branch of network for semantic image segmentation. The semantic network aims to compute complementary higher level semantic features to be integrated with the convolutional features. We make use of multi-resolution feature maps extracted from different network layers in order to ensure good detection accuracy for pedestrians at different scales. Boosted forest is used for training the integrated features in a cascaded manner for hard negatives mining. Experiments on the Caltech pedestrian dataset show improvements on detection accuracy with the semantic network. With the deep VGG16 model, our pedestrian detection method achieves robust detection performance on the Caltech dataset. Object detection is a fundamental problem in computer vision and has wide applications in video surveillance  for feature extraction. Compared to hand-craft features, CNN has better capability of feature representation. On the observation that CNN feature maps can be successfully used for the semantic segmentation task    based classifiers  from one image. RPN outputs proposals high quality pedestrian proposals. With 100 proposals per image, the PRN can achieve >99% recall at an intersection of union (IoU) of 0.5, and >95% recall at an IoU of 0.7. At test time, RPN outputs top-ranked 100 proposals for classification, while for training RPN outputs the top-ranked 1, 000 proposals.The RPN network is fine-tuned using the Caltech dataset by fixing the first four convolutional layers. The number of total iterations is 805 so that the output feature maps are of size 15 × 6. It is required to map the low resolution feature maps into higher resolutions for pixel-wise semantic labeling.Semantic segmentation requires dense classification result of the same resolution as the input image. However, CNNs feature maps are of much smaller resolution than the input image due to the effects of pooling layers. Therefore, an upsampling module is required in order to recover spatial resolution of the CNN feature maps. Take VGG16 network for instance, the output feature maps throughout five max-pooling layers of VGG16 are of very low resolution. For example, for an input image of size 480 × 360, the output feature maps throughout five max-pooling layers will shrink by 2Motivated by the success of SegNet , henceforth. CNN features are extracted from multi-layers of the CNN as illustrated in Figure Conv3 and Conv4 gives the best performance.The VGG16 network consists of five convolutional blocks, i.e., Conv4 to achieve better semantic segmentation performance. An atrous feature map is obtained by dilating the original filter size by a factor of 2 so that the stride of the original feature map can be reduced by 2. Using the a trous convolution enables a higher feature resolution while preserving the same feature representation ability. This is crucial for small object detection. Hence, we also perform experiments on the dilated version of Conv4 and Conv5 features and refer to them as Conv4a and Conv5a henceforth. Unlike in Ren et al. , which represent the Xth upsampling block of the semantic network. We extracted semantic features from both Dconv1 and Dconv2 which provide the best performance (as it will be shown in section 4.2).Semantic features are extracted from multi-layers of the semantic upsampling network as illustrated in Figure We use RoI pooling  is an ensemble learning method which can achieve fast and accurate classification. Owing to high accuracy and low computation cost, decision forests have been widely used in computer vision tasks such as object recognition  and 10−4 to 100  false positive per image (FPPI) for evaluation . As we can see, the best two performances are achieved by using Conv3 and Conv4a features. The best two performances are achieved by using Conv3 and Conv4a features  pixels in height, which is generally a harder case for the pedestrian detection (see Table We compare the proposed pedestrian detector with the state-of-the-art pedestrian detection methods, including ACF (Dollár et al., MR−2 of 5.7%, which is a improvement of 0.8% beyond the state-of-the-art method (Zhang et al., Detection results on the proposed pedestrian detector on trained using Caltech3x set is given in Figure Figure In this paper, we proposed a pedestrian detector which makes use of semantic image segmentation information. Basis on the Faster-RCNN framework, we have unified the detector with a semantic segmentation network. Semantic features extracted from the semantic network are used jointly with convolutional features for improved pedestrian detection. Some ambiguous pedestrian hypotheses that may be difficult to classify from the convolutional feature maps can be discriminated with the help of semantic information on and around each hypothesis. Experiments on the Caltech dataset indicate that the proposed detector make improvement on the baseline detector by enforcing the consistency between the detection network and the semantic network. The proposed solution provides a more powerful pedestrian detector achieving competitive results on pedestrian detection benchmarks at 0.21 s per frame on single TITAN-X Pascal GPU. In the future, we can explore the proposed method with more advanced deep neural network such as the residual network (He et al., All authors listed have made a substantial, direct and intellectual contribution to the work, and approved it for publication.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.