bluuebunny/crossref_metadata_2025 huggingface dataset:
PC-4 The identification of a novel leukocyte population IMLEC unveils a critical role of mTORC1 in innate immune tolerance
Authors: Tang Fei , Zhang Peng , Liu Yang , Zheng Pan
Published: April 2019

Adaptive autoimmunity is restrained by controlling population sizes and pathogenicity of harmful clones, while innate destruction is controlled at effector phase. We report here that deletion of Rptor (an indispensable component of the mTOR complex 1) in hematopoietic stem/progenitor cells causes self-destructive innate immunity by massively increasing the population of previously uncharacterized innate myelolymphoblastoid effector cells (IMLECs). IMLECs are CD3-B220-NK1.1-Ter119-CD11c low/-CD115-F4/80low/-Gr-1- CD11b+, but surprisingly express high levels of PD-L1. Although they morphologically resemble lymphocytes and actively produce transcripts from Immunoglobulin loci, IMLECs have non-rearranged Ig loci, are phenotypically distinguishable from all known lymphocytes, and have a gene signature that bridges lymphoid and myeloid leukocytes. Rptor deletion unleashes differentiation of IMLECs from common myeloid progenitor cells by reducing expression of Myb. Importantly, IMLECs broadly overexpress pattern-recognition receptors and their expansion causes systemic inflammation in response to Toll-like receptor ligands.

Our data unveil a novel leukocyte population and an unrecognized role of Raptor/mTORC1 in innate immune tolerance. Our work challenges the strict dichotomy of myeloid and lymphoid lineages in the immune system, and suggests a new mode of immune regulation for innate effector cells. The identification of this new cell population may allow us to more effectively regulate inflammation under pathological conditions. These findings might help explain the inflammation caused by mTORC1 inhibitors treatments in some patients with cancers and transplantation. Moreover, since IMLECs constitutively express high levels of PD-L1, it is interesting to investigate their functions in cancer immunotherapy.
PC-8 Novel chemoimmunotherapy combinations for pancreatic cancer
Authors: Smith Peter , Capizzuto Valentina , Dalgleish Angus
Published: April 2019

Introduction:

Pancreatic cancer (PC) is a devastating malignancy. It is usually diagnosed at an incurable stage and has the poorest of prognoses of any cancer. Despite its relatively low incidence, it is the fourth leading cause of cancer-related death. A few chemotherapies have shown modest efficacy but are associated with significant toxicities and development of tumour resistance. For these reasons the median survival after diagnosis is about 4.6 months, 18% of patients survive one year and less than 5% survive for 5 years. Without improvement in PC therapy it may soon become the second leading cause of cancer related deaths. Immunotherapies are beginning to show efficacy as first line therapies for a number of cancers but have yet to prove effective against PC. This is due to the dense desmoplastic stroma and immune suppressive microenvironment characteristic of advanced disease. Thus novel chemo-immunotherapeutic combinations will likely be required to target the tumour and its microenvironment to create the conditions in which immunotherapies, such as checkpoint inhibition, will be effective. The data presented here details the development of combination chemotherapy capable of killing tumour cells whilst increasing the immunogenicity of the tumour.

Results:

Combinations based upon the chemotherapeutic drug Gemcitabine were studied. Gemcitabine was combined with Zolodronic acid, Pomalidomide, Oxaliplatin and mycobacterial adjuvants. These combinations demonstrated increased cytotoxicity of pancreatic cell lines compared to single agent treatment. Gemcitabine increased markers of immune recognition on these cell lines independently of its cytotoxic properties whilst Oxaliplatin increased markers of immunogenic cell death and uptake of tumour cells into dendritic cells. Combination treatment was able to enhance dendritic cell maturation and the activation of CD8+ T-cells, measured as increases in the expression of IFN-γ.

Discussion:

Taken together the data presented here shows that gemcitabine based combinations exhibit superior in vitro cytotoxicity and immunogenic properties compared to single agent therapy. Each of these agents has previously been paired with gemcitabine for treatment of pancreatic cancer, demonstrating low toxicity and potential clinical efficacy. This supports their development as 3 or 4 agent combinations. Further research using pre-clinical pancreatic cancer models is planned including the use of checkpoint inhibition in combination with Chemoimmunotherapy.
PC-10 Classical HLA alleles are associated with prevalent and persistent cervical high-risk HPV infection in African women
Authors: Adebamowo Sally , Adeyemo Adebowale , Adebamowo Clement
Published: April 2019

Background:

Persistent cervical high-risk human papillomavirus (hrHPV) infection is a necessary cause of cervical cancer. However, the genetic factors underlying its risk are not well understood. We hypothesized that immunogenetic variation plays a role in hrHPV infection and persistence. Therefore, we conducted a study of classical HLA alleles and their association with hrHPV infection and persistence.

Methods:

We characterized HPV infection using SPF25/LiPA10 in Nigerian women at baseline and at 6 months follow-up visits in 2014. hrHPV infection was prevalent if at least one carcinogenic HPV genotype was detected in a sample provided at the baseline visit and persistent if at least one carcinogenic HPV genotype was detected in each of the samples provided at the baseline and follow-up visits. Genotyping was performed with the Illumina Multi-Ethnic Genotyping Array. Classical HLA alleles were imputed from genotypes in the MHC region using the HLA genotype imputation with attribute bagging (HIBAG) algorithm. HLA association tests were conducted under additive genetic models. P values were adjusted for multiple comparisons with the false discovery rate (FDR) method.

Results:

The mean (±SD) age of the study participants was 38 (±8) years, 48% (247/517) were HIV negative, 24% (125/517) were hrHPV positive at baseline and 10% (51/517) had persistent hrHPV infections. In multivariate regression models adjusted for age, HIV status and the first principal component, DQA1*01:02 (OR 1.46; 95% CI: 1.07 to 1.97; P = 0.03). and DQA1*02:01 (OR 1.89; 95% CI: 1.12 to 3.15; P = 0.03) were positively associated with prevalent but not persistent hrHPV infections, while DQA1*05:01 was negatively associated with prevalent hrHPV (OR 0.45; 95% CI: 0.24 to 0.85; P = 0.03) but positively associated with persistent cervical hrHPV infections (OR 2.46; 95% CI: 1.27 to 4.77; P = 0.04). Four haplotypes (A*30:01 - DQA1*05:01, B*07:02 - C*07:02, B*07:02 - DQA1*05:01 and C*07:02 - DQA1*05:01) were significantly associated with prevalent cervical hrHPV infections and several haplotypes that included the DQA1*05:01 allelic variant (including B*15:10 - DQA1*05:01, DQA1*05:01 - DQB1*02:01 and DQA1*05:01 - DRB1*03:01) were significantly associated with persistent cervical hrHPV infections. Six amino acids located on the DQA1 gene were associated with prevalent but not persistent cervical hrHPV infections.

Conclusions:

This study, the first to investigate the association between HLA alleles and persistent hrHPV risk in African women, has identified important risk alleles that merit further study. Our findings provide new insights into risk factors for hrHPV infection in women of African ancestry.
PC-12 Bone marrow microenvironment-induced miR-300 expression impairs natural killer cell proliferation and anti-tumor activity
Authors: Trotta Rosanna , Silvestri Giovannino , Stramucci Lorenzo , Marcucci Guido , Guimond Martin , Fan Xiaoxuanfan , Baer Maria , Perrotti Danila
Published: April 2019

Natural killer (NK) cells mediate immune responses against cancer; however, NK cell quantitative and functional defects are features of cancers including chronic myelogenous leukemia (CML). As increased numbers of activated NK cells were found in CML patients in treatment-free remission, the understanding of the molecular events inhibiting NK proliferation and function may lead to the development of NK cell-based therapies against drug-resistant cancer stem cells.

Because altered miRNA expression and inactivation of the protein phosphatase 2A (PP2A) tumor suppressor are also features of cancer, and SET-dependent PP2A inhibition is essential for NK cell function, we hypothesized that increased expression of miR-300, a miRNA with anti-proliferative activity, found inhibited in CML and targeting the PP2A inhibitor SET, accounts for impaired NK cell proliferation/activity.

An initial analysis revealed that miR-300 levels were significantly higher in peripheral blood (PB) CD56+CD3-NK cells from CML patients at diagnosis compared to healthy individuals. As NK cell activity is regulated by the bone marrow microenvironment (BMM), we evaluated whether hypoxic conditions and/or cell-to-cell interaction influence NK cell proliferation and cytotoxic activity by modulating miR-300 intracellular levels.

A marked and significant increase in miR-300 expression was detected in NK-92 and primary CD56+CD3-NK cells exposed to low O2 levels or cultured in the presence of conditioned medium (CM) or exosomes isolated from BM-derived primary mesenchymal stromal (MSC) and HS-5 MSC cells. As expected, increased miR-300 levels correlated with decreased SET levels and markedly reduced NK cell number. Interestingly, miR-300-induced growth inhibition was rescued in NK cells treated with CM/exosomes from HS-5 cells expressing an anti-miR-300 lentivirus. Notably, qRT-PCR indicated that miR-300 was contained in MSC exosomes. Functionally, exposure to MSCs (CM or exosomes) inhibited NK cell IL-12/IL-18-induced IFN-γ production and cytotoxic activity against K562 CML-BC cells in a miR-300-dependent manner. Accordingly, miR-300 lentiviruses and/or CpG-miR-300 oligonucleotides inhibited SET expression, reduced proliferation and suppressed spontaneous cytotoxicity of NK-92 and/or primary NK cells, likely through reactivation of PP2A.

Because BM hypoxic conditions and MSCs significantly contribute to decreased NK cell number and cytotoxic activity through upregulation of miR-300, its genetic or pharmacologic inhibition may result in reactivation of NK cell activity against leukemic stem/progenitor cells.
PF-2 Hepatitis B virus and risk factors among HIV+ and HIV− Nigerian men who have sex with men
Authors: Adeyemi Olusegun , Crowell Trevor , Peel Shelia , Ndembi Nicaise , Shutt Ashley , Baral Stefan , Charurat Man , Nowak Rebecca
Published: April 2019

Introduction:

Despite the advent of hepatitis B virus infection (HBV) vaccine since 1982, HBV prevalence among men who have sex with men (MSM) ranges between 8% and 18%, differing by population settings and geographic regions of Nigeria. Because of shared risk factors for viral acquisition, HBV is more common in HIV infected individuals and MSM are 2–4 times more likely to be infected with HBV as compared to the general population. We conducted a cross sectional study to estimate the prevalence and risk factors of HBV among HIV-infected and HIV-uninfected MSM.

Methods:

From March 2013 to December 2017, the TRUST/RV368 study recruited MSM into HIV care and treatment services in Abuja and Lagos, Nigeria using respondent driven sampling. Men were screened for Hepatitis B surface antigen using ELISA and confirmed to have active infection with PCR detection of HBV DNA. All participants with HBV and HIV diagnoses at baseline were included in the analysis (n = 717). Differences in demographics and behavioral characteristics were compared using Pearson χ2 test for categorical outcomes. Bivariate and multivariable analyses were conducted using logistic regression models.

Results:

Median age was 24 years (Inter quartile range: 21–27) and the prevalence of HBV was similar between the HIV uninfected and HIV-infected (9% vs 10%, P = 0.60). Among the HIV-infected, prevalence was higher for those not on an ART regimen with anti-HBV activity (tenofovir, lamivudine, or emtricitabine) as compared to those with anti-HBV regimen (11% vs 5%), although not statistically significant (P = 0.12). In the multivariable analysis, HIV infection status was not associated with HBV prevalence (OR = 1.1, 95% CI: 0.6 to 2.0). Any condomless sex at last anal intercourse was associated with a 2-fold higher odds of HBV as compared to those always using condoms (OR = 2.3, 95% CI: 1.3 to 3.5). Those self-reporting as homosexual as compared to bisexual trended towards a higher odds of HBV (OR = 1.5, 95% CI: 0.9 to 2.5). Age, access to health care, concurrent STIs, receptive partnerships, and concurrency were not associated with HBV.

Conclusions:

HBV prevalence was modest in this high risk population and did not differ by HIV status. This lower than expected prevalence may be attributed to ART with anti-HBV activity. Although condomless sex continues to elevate the risk of HBV, reinforcing the need to increase communication and education on HBV and its potential complications.
PG-3 Assessment of internationally-available diagnostic test kits for their suitability to meet manufacturers' claims
Authors: Constantine Niel , Abouhmada Ahmed , Athwal Bhavneet , Saleh Ebtehal
Published: April 2019

Background:

Diagnostic test kits are used throughout the world as a primary measure to protect the blood supply and provide diagnosis to save lives. The US government purchases large numbers of HIV, syphilis, hepatitis, and other varieties of test kits from a number of manufacturers at considerable expense, and expects them to perform adequately when provided to countries.

Objective:

To assess a large number and variety of rapid test kits, purchased for many countries, to determine if they meet the claims of the manufacturers.

Methods:

From September 2010 through July 2018, a total of 1502 lots of rapid test kits from 16 manufacturers, representing 11 different types of tests from 26 countries, were received for evaluation at the IHV. The performance of each test kit was assessed for performance characteristics using panels of sera (n = 30–160) that included positives (n = 20–80), and negatives (n = 20–80). Greater than 1 false positive or false negative result constituted failure.

Results:

Of the 1502 rapid test kit lots, 1491 (99.3%) successfully passed the evaluation. Of the 11 lots from 5 manufacturers that did not pass, 3 lots were found to produce high background that interfered with reading, 2 lots performed inadequately with high-temperature testing, 4 lots gave 2 false-positive results, and 2 lots gave 2 false-negative results. In one case, the failure resulted in cessation of bulk purchase of test kits by the US Government and removal from WHO's e-catalogue. In another case, the manufacturer acknowledged that their internal lot release results indicated a less than usual level and that it was subsequently addressed.

Conclusions:

In our evaluation of a large number and variety of rapid test kit lots from 16 manufacturers that were sent to or targeted for 26 countries, nearly all performed as expected and met the manufacturers' claims. An evaluation system for the monitoring of test kit performance is essential to identify test kits that may not meet manufacturers' claims.
PG-8 Characterization of pre exposure prophylaxis (PrEP) cascade among Nigerian MSM
Authors: Omari Habib , Ayande Dorcas , Ndo-Ndombi Teclaire , Nowak Rebecca , Crowell Trevor , Baral Stefan , Ndembi Nicaise , Charurat Man
Published: April 2019

Introduction:

With an estimated HIV incidence of 15.4/100 person years, Nigerian men who have sex with men (MSM) account for one of the highest HIV incidence among members of key populations. Proven HIV biomedical intervention such as Pre exposure Prophylaxis (PrEP) will potentially decrease new HIV infections and likely benefit MSM in this setting. Here we characterize engagement in the HIV PrEP cascade and assess factors associated with PrEP initiation among Nigerian MSM.

Methods:

The TRUST/RV368 cohort employs respondent-driven-sampling (RDS) to recruit MSM into HIV/STI prevention and treatment services in Abuja and Lagos, Nigeria. HIV negative MSM at the Abuja site who completed a survey instrument on awareness and willingness to use PrEP were approached by telephone for PrEP initiation. Follow-up visits were one month after enrollment and quarterly thereafter. Bivariate logistic regression models were used to assess factors associated with PrEP initiation.

Results:

Between March 2013 and July 2018, 428 HIV negative MSM completed the survey instrument on awareness and willingness to use PrEP. Of these, 13 (3%) seroconverted during their initial follow up prior to PrEP initiation and were excluded, and the remaining 415 were included in these analyses. Participants had a median age of 25 (interquartile range [IQR]: 22–29) years. Among 415 HIV negative, 250 (60%) were successfully contacted, 144 (35%) screened and 133 (32%) initiated PrEP (Figure 1). Younger MSM, [≤19 years vs ≥ 25 years (OR 0.6; 95% CI 0.4 to 0.9)] and religion, (Muslims vs. Christians, (OR 0.5; 95% CI 0.3 to 0.9) were associated with decreased odds of PrEP initiation. Exposure to HIV education such as receiving information on HIV prevention in the past 12-months was associated with increased odds of PrEP initiation, (OR 1.7; 95% CI 1.1 to 2.7).

Conclusions:

Engagement in PrEP in this population is relatively low with younger individuals less likely to engage in PrEP. Reinforcing HIV prevention education and facilitating young MSM to engage in PrEP programs is critical in order to prevent onward HIV transmission.
PG-9 Predictors of final HIV status outcome for HIV-exposed infants at 18 months of age in 10 Nigerian states
Authors: Adelekan Babatunde , Harry-Erin Abidemi , Sam-Agudu Nadia , Okposo Martha , Ndembi Nicaise , Mensah Charles , Dakum Patrick , Aliyu Ahmad
Published: April 2019

Introduction:

There were an estimated 37,000 new child HIV infections in Nigeria in 2016, the highest globally. For Nigeria, 6 week and final mother-to-child transmission of HIV (MTCT) rates are estimated at 13.1% and 23.0%, respectively. The UNAIDS has targeted final MTCT rates of <2% and <5% among non-breastfeeding and breastfeeding infants, respectively. Data on 18-month final outcomes among HIV-Exposed Infants (HEI) in Nigeria is scarce. We evaluated for predictors of HIV status among HEI at 18 months of life in 10 Nigerian states.

Methods:

This retrospective, cross-sectional study collected data from 96 PEPFAR-supported health facilities supported by the Institute of Human Virology Nigeria in 10 Nigerian states between October 2014 and September 2015. Only HEI with a first DNA PCR result at ≥4–6 weeks, and a rapid HIV antibody test result at ≥18 months of age were included. Data including residence, birth weight, breastfeeding status, and maternal ART access were collected for analysis. Multivariate logistic regression (adjusted odds ratios [aORs] evaluated for predictors of HIV test positivity at 18 months.

Results:

A total of 2405 HEI from the 96 facilities were included in the study. Median birthweight was 3 kg (IQR 1.2–6.1), and at final testing was 10 kg (IQR 5.5–15). Of the 2405 HEI negative at first DNA PCR test and tested at ≥18 months, 68 (2.8%) were positive. After a minimum of 18 months of age, 51 (75%) of the 68 HIV-positive infants were alive on ART; 7 (10%) had died, 4 (6%) were lost to follow-up and 6 (9%) had transferred out to other facilities for care. Infant birth weight of ≥2.5 kg (AOR 0.40, P = 0.009), urban residence (OR 0.45, P = 0.008) and exclusive breastfeeding (OR 0.04, P < 0.001) protected against MTCT; maternal non-initiation/utilization of antenatal/in-labor ART (OR 9.59, P < 0.001) correlated with MTCT.

Conclusions:

The final HIV positivity rate of 2.8% in our cohort is lower than the national estimates, which is encouraging. However, this should be interpreted with caution: the HIV status of HEI seen at the study facilities who did not present for early and/or final testing was not available and thus not evaluated. Nevertheless, supported by our findings, we recommend strengthening universal maternal access to ART, ideally in the pre-conception and prenatal stages. This should be prioritized especially for rural women living with HIV. Furthermore, our findings correlate with the nationally-recommended 6-months of exclusive infant breastfeeding. We acknowledge that data from non-presenting HEI are also needed to devise interventions for universal uptake of early and final HIV testing. We expect that as Option B plus is scaled up in Nigeria, more women would access and be maintained on ART through their first and subsequent pregnancies, thereby reducing the gaps in maternal-infant HIV service uptake.
PI-4 Trogocytosis of viral immune complexes in the context of HIV-1 infection
Authors: Orlandi Chiara , Flinko Robin , Ray Krishanu , Hu Yi , Mamede Joao , Maric Danijela , Hope Thomas , Lewis George
Published: April 2019

Fc-mediated Ab functions rely on multiple mechanisms of action that include the recruitment of complement and Fc receptor-bearing cellular subsets that can mediate trogocytosis, phagocytosis, and cellular cytotoxicity. Monocytes-mediated trogocytosis is defined as the active exchange of membrane fragments between cells tightly interacting through an immunological synapse. Here, we propose to define the trogocytic activity of anti-Envelope human monoclonal antibodies in the context of HIV-1 infection. With this aim we employ the optimized RFADCC, adding a new one-step anti-CD14 and Live/dead staining. Combining flow cytometry and high-resolution confocal microscopy, we were able to follow the movement of fragments of membrane from the targets to the effectors, specifically to monocytes. Particularly, in the presence of monoclonal IgGs specific for Cluster A epitopes (A32 and C11) exposed on HIV-1 envelope, we were able to visualize the formation of stable immune synapses that include a Ba-L gp120-coated target and one or multiple monocytes. During the interaction, the whole immune complex, formed by Ba-L gp120 Ag and IgG, migrated and clustered towards the points of contact with monocyte(s) and transferred onto the surface of the effectors by trogocytosis. This phenomenon is very fast and it is strictly dependent on the formation of stable immunological synapses between HIV-1 sensitized cells and monocytes, since trogocytosis is not observed in the case of Synagis, which lacks its specific antigen and, in turns the ability of bridging Targets and Effectors. These findings support a new role for monocytes, potentially being the mediators of a new mechanism for clearance of viral antigens from target cells or potentially being new targets for the immune response against the virus after the acquisition viral IC from HIV-1 sensitized cells.
From Tramadol to Methadone
Authors: Friedrichsdorf Stefan J.
Published: April 2019

Background:

More than 15,000 children die annually in the United States due to an underlying life-limiting disease and the majority of those children experience distressing symptoms, which are not adequately relieved, such as pain and dyspnea. Multimodal analgesia, that is multiple agents, interventions, rehabilitation, psychological modalities, and integrative (nonpharmacologic) therapies, act synergistically for more effective pediatric pain and symptom control with fewer side effects than a single analgesic or modality. However, opioids, such as morphine, fentanyl, hydromorphone, oxycodone, and methadone (in the United Kingdom: diamorphine) remain the mainstay medication to effectively treat pain and dyspnea in children with serious illness.

Methods:

This article reviews commonly used opioids in Pediatric Palliative Care, which a special emphasis on 2 potentially particularly effective multimechanistic opioids: tramadol and methadone.

Results:

Methadone, due to its multimechanistic action profile, is possibly among the most effective and most underutilized opioid analgesics in children with severe unrelieved pain at end of life. However, methadone should not be prescribed by those unfamiliar with its use: Its effects should be closely monitored for several days, particularly when it is first started and after any dose changes.

Conclusions:

Tramadol appears to play a key role in treating episodes of inconsolability in children with progressive neurologic, metabolic, or chromosomally based condition with impairment of the central nervous system. However, the recent 2017 United States Food and Drug Administration (FDA) warning against pediatric use of tramadol does not seem to be based on clinical evidence, and therefore puts children at risk for unrelieved pain or increased respiratory depression.
The Use of Opioids for Treatment of Pediatric Neuropathic Pain
Authors: Windsor Robert B. , Tham See Wan , Adams Trevor L. , Anderson Annette
Published: April 2019

Pediatric neuropathic pain is caused by a spectrum of disorders that are generally challenging to treat. Many of the underlying altered neurological processes are being elucidated through mechanistic studies. Few randomized control trials have evaluated the use of opioids for the treatment of adult neuropathic pain conditions, and there have been none in pediatric populations. With sparse data to provide guidance and an incomplete understanding of the underlying mechanisms, the use of opioids remains unclear. Our clinical experience and typical risk versus benefit considerations suggest a limited, if any, role for using opioids to treat pediatric neuropathic pain. In this literature review, we review the available adult and pediatric data and provide general guidance on this subject matter.
Blood Loss of Posterior Lumbar Interbody Fusion on Lumbar Stenosis in Patients With Rheumatoid Arthritis
Authors: Xu Shuai , Liang Yan , Wang Jing , Yu Guanjie , Guo Chen , Zhu Zhenqi , Liu Haiying
Published: April 2019

Study Design.

Case–control study.

Objective.

To compare intraoperative bleeding, drainage, and hidden blood loss (HBL) of posterior lumbar interbody fusion (PLIF) on lumbar spinal stenosis (LSS) in patients with rheumatoid arthritis (RA) and non-RA and identify the risk factors of HBL with RA.

Summary of Background Data.

Exploration on PLIF on LSS and HBL has been reported before while the comparison on total blood loss (TBL), especially HBL of PLIF or PLF on LSS between patients with RA and without RA has not been studied.

Methods.

Sixty-one patients diagnosed LSS with RA (RA group) and 87 matched patients without RA (NRA group) were enrolled and demographic characteristics, RA-related parameters, operation and blood loss information were extracted. Intraoperative blood loss, drainage, and HBL were primary outcomes and secondary measures included operation time, hematocrit (Hct) and hemoglobin (Hb), the number of anemia and blood transfusion.

Results.

There was no statistical difference in total blood loss (TBL), intraoperative blood loss, and postoperative drainage while HBL and the proportion of HBL in TBL were lower in NRA group (P < 0.001 and P = 0.012, respectively). Stratified analysis based on the number of surgical levels suggested HBL and the proportion of HBL in NRA group was superior in long-segment surgery (>2 segments). The secondary outcomes showed the change of Hct was lower in NRA group (P = 0.021) but not the reduction of Hb. In addition, there was no significant difference in neoformative and grade-aggravated anemia, as well as the number of allogeneic blood transfusion and operation time showed Steinbroker classification, disease-modifying anti-rheumatic drugs (DMARDs), hange of Hb and allogeneic blood transfusion were risk factors for HBL with RA.

Conclusion.

There was no difference in TBL, intraoperative bleeding, and operation time, but HBL were higher in RA patients particularly in long-segmental operation. Steinbroker classification, DMARDs, the change of Hb, and allogeneic blood transfusion were independent risk factors for HBL in RA patients.

Level of Evidence: 3
Risk and Prognostic Factors of Low Back Pain
Authors: Halonen Jaana I. , Shiri Rahman , Magnusson Hanson Linda L. , Lallukka Tea
Published: April 2019

Study Design.

Prospective longitudinal cohort study.

Objective.

To determine the associations for workload and health-related factors with incident and recurrent low back pain (LBP), and to determine the mediating role of health-related factors in associations between physical workload factors and incident LBP.

Summary of Background Data.

It is not known whether the risk factors for the development of LBP are also prognostic factors for recurrence of LBP and whether the associations between physical workload and incident LBP are mediated by health-related factors. We used data from the Swedish Longitudinal Occupational Survey of Health study. Those responding to any two subsequent surveys in 2010 to 2016 were included for the main analyses (N = 17,962). Information on occupational lifting, working in twisted positions, weight/height, smoking, physical activity, depressive symptoms, and sleep problems were self-reported. Incident LBP was defined as pain limiting daily activities in the preceding three months in participants free from LBP at baseline. Recurrent LBP was defined as having LBP both at baseline and follow-up. For the mediation analyses, those responding to three subsequent surveys were included (N = 3516).

Methods.

Main associations were determined using generalized estimating equation models for repeated measures data. Mediation was examined with counterfactual mediation analysis.

Results.

All risk factors at baseline but smoking and physical activity were associated with incident LBP after adjustment for confounders. The strongest associations were observed for working in twisted positions (risk ratio  = 1.52, 95% CI 1.37, 1.70) and occupational lifting (risk ratio  = 1.52, 95% CI 1.32, 1.74). These associations were not mediated by health-related factors. The studied factors did not have meaningful effects on recurrent LBP.

Conclusion.

The findings suggest that workload and health-related factors have stronger effects on the development than on the recurrence or progression of LBP, and that health-related factors do not mediate associations between workload factors and incident LBP.

Level of Evidence: 3
Presepsin As a Biomarker for Evaluating Prognosis and Early Innate Immune Response of Out-of-Hospital Cardiac Arrest Patients After Return of Spontaneous Circulation
Authors: Qi Zhijiang , Zhang Qiang , Liu Bo , Shao Fei , Li Chunsheng
Published: April 2019

Objectives:

After return of spontaneous circulation, patients who experienced out-of-hospital cardiac arrest present an impaired innate immune response that resembles sepsis. Presepsin, a new biomarker for sepsis, has not been studied in out-of-hospital cardiac arrest patients. This study explored the role of presepsin in evaluating the prognosis and early innate immune alteration of out-of-hospital cardiac arrest patients after return of spontaneous circulation by observing presepsin levels, CD14, and human leukocyte antigen-DR expression on monocytes.

Design:

Retrospective analysis.

Setting:

The emergency department of an urban university tertiary hospital.

Participants:

One hundred sixty-five out-of-hospital cardiac arrest patients with return of spontaneous circulation more than 12 hours, and 100 healthy individuals.

Interventions:

None.

Measurements and Main Results:

Plasma presepsin and procalcitonin levels were tested after resuscitation (day 0) and on days 1 and 3 after return of spontaneous circulation. Presepsin levels were higher in out-of-hospital cardiac arrest patients than in healthy individuals. In the first 3 days, presepsin and procalcitonin levels were persistently lower in 28-day survivors and patients with favorable neurologic outcome patients than in 28-day nonsurvivors and patients with unfavorable neurologic outcome. On days 0, 1, and 3, different cut-off values of presepsin showed prognostic value for 28-day mortality and favorable neurologic outcomes similar to procalcitonin. CD14 and human leukocyte antigen-DR expression on monocytes were analyzed by flow cytometry. Compared with controls, CD14 expression in out-of-hospital cardiac arrest patients increased on day 1 and began to decrease on day 3, whereas human leukocyte antigen-DR+ monocyte percentages decreased on days 1 and 3. Presepsin and procalcitonin had a low positive correlation with CD14 expression and a strong negative correlation with human leukocyte antigen-DR+ monocyte percentages on day 1.

Conclusions:

Plasma presepsin concentrations are independent prognostic factors for out-of-hospital cardiac arrest patients after return of spontaneous circulation and are correlated with abnormal CD14 and human leukocyte antigen-DR expression on monocytes. Monitoring presepsin levels may be helpful for evaluating the prognosis and impaired innate immune response in the early period after return of spontaneous circulation.
Cost-Effectiveness Studies in the ICU: A Systematic Review*
Authors: Wilcox M. Elizabeth , Vaughan Kelsey , Chong Christopher A. K. Y. , Neumann Peter J. , Bell Chaim M.
Published: April 2019

Objectives:

Cost-effectiveness analyses are increasingly used to aid decisions about resource allocation in healthcare; this practice is slow to translate into critical care. We sought to identify and summarize original cost-effectiveness studies presenting cost per quality-adjusted life year, incremental cost-effectiveness ratios, or cost per life-year ratios for treatments used in ICUs.

Design:

We conducted a systematic search of the English-language literature for cost-effectiveness analyses published from 1993 to 2018 in critical care. Study quality was assessed using the Drummond checklist.

Setting:

Critical care units.

Patients or Subjects:

Critical care patients.

Interventions:

Identified studies with cost-effectiveness analyses.

Measurements and Main Results:

We identified 97 studies published through 2018 with 156 cost-effectiveness ratios. Reported incremental cost-effectiveness ratios ranged from –$119,635 (hypothetical cohort of patients requiring either intermittent or continuous renal replacement therapy) to $876,539 (data from an acute renal failure study in which continuous renal replacement therapy was the most expensive therapy). Many studies reported favorable cost-effectiveness profiles (i.e., below $50,000 per life year or quality-adjusted life year). However, several therapies have since been proven harmful. Over 2 decades, relatively few cost-effectiveness studies in critical care have been published (average 4.6 studies per year). There has been a more recent trend toward using hypothetical cohorts and modeling scenarios without proven clinical data (2014–2018: 19/33 [58%]).

Conclusions:

Despite critical care being a significant healthcare cost burden there remains a paucity of studies in the literature evaluating its cost effectiveness.
Sleep and Work in ICU Physicians During a Randomized Trial of Nighttime Intensivist Staffing*
Authors: Bakhru Rita N. , Basner Mathias , Kerlin Meeta Prasad , Halpern Scott D. , Hansen-Flaschen John , Rosen Ilene M. , Dinges David F. , Schweickert William D.
Published: April 2019

Objectives:

To compare sleep, work hours, and behavioral alertness in faculty and fellows during a randomized trial of nighttime in-hospital intensivist staffing compared with a standard daytime intensivist model.

Design:

Prospective observational study.

Setting:

Medical ICU of a tertiary care academic medical center during a randomized controlled trial of in-hospital nighttime intensivist staffing.

Patients:

Twenty faculty and 13 fellows assigned to rotations in the medical ICU during 2012.

Interventions:

As part of the parent study, there was weekly randomization of staffing model, stratified by 2-week faculty rotation. During the standard staffing model, there were in-hospital residents, with a fellow and faculty member available at nighttime by phone. In the intervention, there were in-hospital residents with an in-hospital nighttime intensivist. Fellows and faculty completed diaries detailing their sleep, work, and well-being; wore actigraphs; and performed psychomotor vigilance testing daily.

Measurements and Main Results:

Daily sleep time (mean hours [sd]) was increased for fellows and faculty in the intervention versus control (6.7 [0.3] vs 6.0 [0.2]; p < 0.001 and 6.7 [0.1] vs 6.4 [0.2]; p < 0.001, respectively). In-hospital work duration did not differ between the models for fellows or faculty. Total hours of work done at home was different for both fellows and faculty (0.1 [< 0.1] intervention vs 1.0 [0.1] control; p < 0.001 and 0.2 [< 0.1] intervention vs 0.6 [0.1] control; p < 0.001, respectively). Psychomotor vigilance testing did not demonstrate any differences. Measures of well-being including physical exhaustion and alertness were improved in faculty and fellows in the intervention staffing model.

Conclusions:

Although no differences were measured in patient outcomes between the two staffing models, in-hospital nighttime intensivist staffing was associated with small increases in total sleep duration for faculty and fellows, reductions in total work hours for fellows only, and improvements in subjective well-being for both groups. Staffing models should consider how work duration, sleep, and well-being may impact burnout and sustainability.
Novel Risk Factors for Posttraumatic Stress Disorder Symptoms in Family Members of Acute Respiratory Distress Syndrome Survivors*
Authors: Lee Robert Y. , Engelberg Ruth A. , Curtis J. Randall , Hough Catherine L. , Kross Erin K.
Published: April 2019

Objectives:

Family members of ICU survivors report long-term psychologic symptoms of posttraumatic stress disorder. We describe patient- and family-member risk factors for posttraumatic stress disorder symptoms among family members of survivors of acute respiratory distress syndrome.

Design:

Prospective cohort study of family members of acute respiratory distress syndrome survivors.

Setting:

Single tertiary care center in Seattle, Washington.

Subjects:

From 2010 to 2015, we assembled an inception cohort of adult acute respiratory distress syndrome survivors who identified family members involved in ICU and post-ICU care. One-hundred sixty-two family members enrolled in the study, corresponding to 120 patients.

Interventions:

None.

Measurements and Main Results:

Family members were assessed for self-reported psychologic symptoms 6 months after patient discharge using the Posttraumatic Stress Disorder Checklist-Civilian Version, the Patient Health Questionnaire 9-item depression scale, and the Generalized Anxiety Disorder 7-item scale. The primary outcome was posttraumatic stress disorder symptoms, and secondary outcomes were symptoms of depression and anxiety. We used clustered multivariable logistic regression to identify patient- and family-member risk factors for psychologic symptoms. Posttraumatic stress disorder symptoms were present in 31% (95% CI, 24–39%) of family participants. Family member risk factors for posttraumatic stress disorder symptoms included preexisting mental health disorders (adjusted odds ratio, 3.22; 95% CI, 1.42–7.31), recent personal experience of serious physical illness (adjusted odds ratio, 3.07; 95% CI, 1.40–6.75), and female gender (adjusted odds ratio, 5.18; 95% CI, 1.74–15.4). Family members of previously healthy patients (Charlson index of zero) had higher frequency of posttraumatic stress disorder symptoms (adjusted odds ratio, 2.25; 95% CI, 1.06–4.77). Markers of patient illness severity were not associated with family posttraumatic stress disorder symptoms.

Conclusions:

The prevalence of long-term posttraumatic stress disorder symptoms among family members of acute respiratory distress syndrome survivors is high. Family members with preexisting mental health disorders, recent experiences of serious physical illness, and family members of previously healthy patients are at increased risk for posttraumatic stress disorder symptoms.
The Clinical Spectrum of New-Onset Status Epilepticus
Authors: Chakraborty Tia , Hocker Sara
Published: April 2019

Objectives:

There is a paucity of data on patients with new-onset status epilepticus in patients without a prior history of epilepsy; we aimed to describe clinical characteristics and assess variables predictive of outcomes.

Design:

Retrospective cohort.

Setting:

Quaternary academic medical center.

Patients:

Adult patients with new-onset status epilepticus.

Methods:

Retrospective review of adults with new-onset status epilepticus admitted to Mayo Clinic, Rochester MN between January 1, 1990, and December 31, 2015, was performed. Patient demographics, status epilepticus etiology, Status Epilepticus Severity Score, and status epilepticus classification per the Status Epilepticus Severity Score were recorded. Six-month mortality and functional outcomes defined as modified Rankin scale (≥3 at last follow-up was considered poor) were primary outcomes. Refractory status epilepticus was a secondary outcome.

Interventions:

None.

Measurements and Main Results:

One-hundred seventy-seven patients were included. Status epilepticus was convulsive in 124 (70.1%) and nonconvulsive in 53 (29.9%); 96 cases (54.2%) were refractory status epilepticus. Mean age at onset was 63 ± 18 years; 52.5% were greater than or equal to 65 years. Etiologies were acute in 50.8%, progressive in 18.1%, remote in 19.2%, and unknown in 11.9% patients. Six-month mortality was 32.2%, and 70.1% had poor modified Rankin scale at mean follow-up 3.1 ± 3.5 years. Age greater than or equal to 65 was a significant predictor of poor functional outcome and 6-month mortality. Loss of consciousness, status epilepticus classification, or age greater than or equal to 65 did not predict progression to refractory status epilepticus. Progression to refractory status epilepticus did not impact functional outcome or mortality at last follow-up.

Conclusions:

Poor outcomes in new-onset status epilepticus were associated with older age as well as predominantly progressive or remote symptomatic disease. Further prospective investigations assessing the course and outcomes of these patients would be useful in management and prognostication.
Double-Blind Randomized Clinical Trial to Examine the Pharmacokinetic and Clinical Impacts of Fixed Dose versus Weight-based Enoxaparin Prophylaxis: A Methodologic Description of the FIxed or Variable Enoxaparin (FIVE) Trial
Authors: Pannucci Christopher J. , Fleming Kory I. , Bertolaccini Corinne , Prazak Ann Marie , Stoddard Gregory J. , Momeni Arash
Published: April 2019

Venous thromboembolism is an important patient safety in plastic surgery, and multiple clinical trials in the past 10 years have provided increased understanding of the risks and benefits of venous thromboembolism prevention strategies. This paper provides an exhaustive discussion of the rationale behind and methodology for an in progress randomized double-blind clinical trial in plastic surgery inpatients, in which the 2 study arms are enoxaparin 40 mg twice daily and enoxaparin 0.5 mg/kg twice daily. The trial’s primary aims are to: (1) demonstrate whether enoxaparin 0.5 mg/kg twice daily is superior to enoxaparin 40 mg twice daily for the pharmacokinetic endpoint of overanticoagulation (anti-Factor Xa > 0.4 IU/mL) and (2) demonstrate whether enoxaparin 0.5 mg/kg twice daily is not inferior to enoxaparin 40 mg twice daily for the pharmacokinetic endpoint of underanticoagulation (anti-Factor Xa < 0.2 IU/mL). The results of this trial will provide Level I evidence to help guide plastic surgeon’s choice of postoperative prophylactic anticoagulation.
Repeatability and Agreement of a Swept-Source Optical Coherence Tomography–Based Biometer IOLMaster 700 Versus a Scheimpflug Imaging–Based Biometer AL-Scan in Cataract Patients
Authors: Chan Tommy C.Y. , Wan Kelvin H. , Tang Fang Yao , Wang Yu Meng , Yu Marco , Cheung Carol
Published: April 2019

Purpose:

To compare the repeatability and agreement between a swept-source biometer and a Scheimpflug biometer in cataract patients.

Methods:

Three consecutive measurements were obtained using a swept-source biometer (IOLMaster 700) and a Scheimpflug biometer (AL-Scan) in 52 eyes of 52 patients. Keratometry, central corneal thickness (CCT), anterior chamber depth (ACD), axial length, and white-to-white (WTW) distance were recorded. Astigmatism values were transformed into vector components of J0 and J45. Intraoperator repeatability was analyzed using intraclass correlation coefficients (ICCs) and reproducibility coefficients (RCs). Agreement of measurements between the two devices was evaluated using the Bland–Altman method.

Results:

The IOLMaster 700 showed higher ICCs and lower RCs for the mean keratometry (Km) (P≤0.018), CCT (P≤0.027), and ACD (P≤0.001) measurements, whereas the AL-Scan showed higher ICC and lower RC for the J45 vector component of astigmatism at the 2.4-mm zone (P≤0.034). Both the devices had excellent repeatability (ICC=0.999) in axial length measurement. Systematic differences were found in Km, CCT, ACD, and WTW (P≤0.018) between the devices. The mean difference for Km was −0.196 and −0.144 D measured at the 2.4-mm zone and 3.3-mm zone, respectively. The corresponding mean difference for CCT, ACD, and WTW distance was 14.92 μm, −0.017 mm, and 0.283 mm, respectively. These differences led to a statistically significant but clinically insignificant difference in the prediction of intraocular lens power.

Conclusions:

This study showed significant differences in anterior segment measurement repeatability and agreement between a swept-source biometer and a Scheimpflug biometer in eyes with cataract.
The Clinical Use of Eyelash Manipulation in the Diagnosis of Demodex folliculorum Blepharitis
Authors: Murphy Orla , O' Dwyer Veronica , Lloyd-McKernan Aoife
Published: April 2019

Objectives:

To compare the efficacy of using an eyelash manipulation technique to the traditional eyelash epilation and subsequent microscopic examination technique, when investigating for the presence of Demodex folliculorum in a clinical setting.

Methods:

Four hundred twenty-eight eyelashes of 107 subjects were chosen to compare the quantity of D. folliculorum visible on eyelash manipulation with the slitlamp biomicroscope to that counted on microscopic examination of the same epilated eyelash. One eyelash from each eyelid was rotated with sterile forceps in situ, and the number of D. folliculorum seen emerging from the follicle was counted. The same eyelash was then epilated, and the number of D. folliculorum on the epilated eyelash was counted. Data were analyzed to check for agreement between the two techniques.

Results:

Intraclass correlation coefficient showed moderately good agreement for assessing the quantity of D. folliculorum (0.78) between the techniques. However, the Bland–Altman plot suggested that consistently higher quantities were found on eyelash manipulation. The overall mean quantity of D. folliculorum was also greater on eyelash manipulation (1.45 mites; range, 0–13 mites) than on microscopic examination of the epilated eyelash (0.81 mites; range, 0–16; P= <0.001). Weighted kappa (κw=0.56) indicated weak levels of agreement between the two methods for addressing severity of infestation.

Conclusion:

Eyelash manipulation exhibited larger quantities of D. folliculorum than complete epilation of the eyelash. In a clinical setting, complete eyelash epilation is not necessary to accurately detect Demodex blepharitis requiring treatment.