Plasmodium falciparum-infected erythrocytes (IEs), where they mediate adhesion of IEs to a range of host receptors. Efficient PfEMP1-dependent IE sequestration often depends on soluble serum proteins, including IgM. Here, we report a comprehensive investigation of which of the about 60 var gene-encoded PfEMP1 variants per parasite genome can bind IgM via the Fc part of the antibody molecule, and which of the constituent domains of those PfEMP1 are involved. We erased the epigenetic memory of var gene expression in three distinct P. falciparum clones, 3D7, HB3, and IT4/FCR3 by promoter titration, and then isolated individual IEs binding IgM from malaria-unexposed individuals by fluorescence-activated single-cell sorting. The var gene transcription profiles of sub-clones measured by real-time qPCR were used to identify potential IgM-binding PfEMP1 variants. Recombinant DBL and CIDR domains corresponding to those variants were tested by ELISA and protein arrays to confirm their IgM-binding capacity. Selected DBL domains were used to raise specific rat anti-sera to select IEs with uniform expression of candidate PfEMP1 proteins. Our data document that IgM-binding PfEMP1 proteins are common in each of the three clones studied, and that the binding epitopes are mainly found in DBLε and DBLζ domains near the C-terminus.PfEMP1 is a family of adhesive proteins expressed on the surface of  Plasmodium. There are an estimated 219 million malaria cases annually, including about 435,000 fatal episodes, mainly caused by infection with P. falciparum1. The particular virulence of this species is related to its multiple strategies to evade acquired host immunity. Important among them is the capacity of P. falciparum-infected erythrocytes (IEs) to sequester in various tissues to avoid immune clearance in the spleen2. The P. falciparum erythrocyte membrane protein 1 (PfEMP1) family is essential for the adhesion of IEs to host cell membrane receptors , which in some cases requires soluble host proteins7.Malaria is caused by protozoan parasites of the genus var gene family8. The var genes can be divided into several groups based on genomic location, direction of transcription, and structural features10. Expression of PfEMP1 variants encoded by particular var gene groups (and their sub-groups) has been associated with discrete clinical presentations and IE adhesion to specific host receptors. Thus, PfEMP1 expression in parasites isolated from severe malaria patients with little or no pre-acquired immunity is often dominated by variants encoded by the relatively conserved Group A genes. The more diverse Group B and Group C genes are more commonly found among uncomplicated and asymptomatic infections, while the Group E genes that encode VAR2CSA-type PfEMP1 variants are responsible for the pathogenesis of placental malaria11. These different subsets of PfEMP1 proteins contain specific Duffy binding-like (DBL) domains and cysteine-rich inter-domain regions (CIDR). Both DBL and CIDR domains can be divided into structurally related classes 12. DBL and CIDR domains mediate IE adhesion to various host receptors, such as endothelial protein C receptor (EPCR), intercellular adhesion molecule 1 (ICAM-1), CD36, and oncofetal chondroitin sulfate18.The acquisition of PfEMP1-specific protective immunity to prevent IE sequestration is frustrated by the parasite’s ability to express a single PfEMP1 variant at the IE surface at a time, and to switch among the ~60 PfEMP1 proteins encoded by the 19 . We recently reported the existence of four additional non-immune IgM-binding PfEMP1 variants in P. falciparum 3D7 sub-clones. Relatively few sub-clones and PfEMP1 variants were tested, and the study thus probably underestimated the total number of non-immune IgM binders5. Furthermore, the study did not assess potential inter-clonal variation in the capacity for Fc-mediated binding of IgM to PfEMP1. To overcome these limitations, we report here results from single-cell sorting of parasite populations with highly heterogeneous var gene transcription to obtain a comprehensive mapping of non-immune IgM-binding PfEMP1 variants in the three distinct P. falciparum clones 3D7, HB3, and IT4/FCR3 (subsequently referred to as IT4). We also probed a multiplex array of PfEMP1 domains from P. falciparum 3D7 with non-immune IgM. Together with recombinant PfEMP1 proteins and specific rat anti-sera the study allowed us to identify several new PfEMP1 variants and constituent domains involved in non-immune IgM binding to IEs.A handful of PfEMP1 variants has been reported to bind IgM via the Fcµ region of the antibody rather than by the hypervariable, antigen-specific Fab fragmentP. falciparum clones 3D7, HB3, and IT4 dominantly transcribed one var gene each   gene under the control of a var promoter21. For each of the clones, selection by blasticidin pressure for high copy numbers of this plasmid markedly reduced transcription of the endogenous var genes , all the identified genes belong to Group B or Group C. Many did not encode any DBLε and DBLζ domains, which have previously been associated with non-immune IgM binding to PfEMP124 , HB3 (n = 10), and IT4 (n = 3) Figs . DomainsP. falciparum 3D7 for binding by non-immune IgM, in a manner similarly to that used previously in tests of PfEMP1 binding to the endothelial receptors ICAM-1, CD36, and αVβ3 and αVβ6 integrins27. By this method, evidence of non-immune IgM binding was found in constructs from 13 PfEMP1 variants in P. falciparum 3D7 , PF08_0141 (DBLζ5), PF08_0103 (DBLδ1-CIDRβ1), and PFC0005w (DBLδ1-CIDRβ1)  Fig. . Express051 Fig. . A weak 5, and the present data support that conclusion. Taken together, the data in sub-clones and selected parasites support the capacity of native PF07_0139, HB3VAR09, HB3VAR22, HB3VAR23, HB3VAR24, HB3VAR40, IT4VAR46, IT4VAR51, and IT4VAR67, to bind non-immune IgM.To further strengthen the link between IE surface-expression of particular native PfEMP1 variants and non-immune IgM binding to the IEs, we selected 12 recombinant domains (from 11 PfEMP1 variants) binding or not binding non-immune IgM in ELISA Table . The selP. falciparum clones.Overall, our data strongly support that binding of non-immune IgM to the surface of IEs is common , mediated by particular PfEMP1 variants, and can be found in genetically diverse P. falciparum causes the most severe form of malaria in humans. This is not least due to the evolution in this parasite species of multiple ways to evade host innate and acquired immune responses34. These include IE misappropriation of host plasma proteins36, endothelial sequestration of IEs38, and clonal antigenic variation40. The PfEMP1 family of adhesive proteins, expressed on the IE surface, are involved in all these processes42. In previous work, others and we have shown that Fcμ-mediated  binding of IgM to particular PfEMP1 variants can function to shield IEs from recognition by PfEMP1-specific IgG43, and may also serve to augment IE adhesion to endothelial receptors44. Whatever function PfEMP1-bound IgM serves, it appears to be of clinical significance. The phenotype has repeatedly been associated with severe malaria in children, caused by parasites expressing Group A PfEMP1 variants28 and with malaria in pregnant women, caused by parasites expressing Group E (VAR2CSA-type) PfEMP146. Furthermore, it has been proposed that IgM-binding to several Group B PfEMP1 variants5, which are otherwise generally associated with uncomplicated malaria and asymptomatic infections, serves to increase the adhesive strength between IEs and endothelial receptors44. This idea supports the importance of the non-immune IgM-binding phenotype.46 and C-terminal DBL domains47 have previously been implicated as the domains mediating non-immune binding of IgM to PfEMP1. In the single previous study assessing how many of the about 60 PfEMP1 variants encoded by a specific P. falciparum genome have the capacity to bind IgM that way, five were identified using the 3D7 clone5. In four of those, IgM bound to a C-terminal ε- or ζ-type DBL domain, whereas the PfEMP1 domain involved in the low-intensity IgM binding to PF07_0139 was not identified5. However, only a limited number of IgM-binding sub-clones were studied and the involvement of N-terminal domains was not systematically assessed. It is thus likely that additional IgM-binding PfEMP1 variants exist. Moreover, the study included only a single parasite clone.Both DBL and CIDR domains in the N-terminal head structureP. falciparum clones 3D748, HB349, and IT450. The three parasite clones are representative of isolates from Africa, Central America, and Asia, respectively51. Furthermore, their var gene repertoires are highly divergent, with only two conserved genes (var1csa and var2csa) in common52.To overcome these limitations, the current study was undertaken to provide an exhaustive analysis of non-immune IgM-binding PfEMP1 variants in the three + IEs from each of the three parasite clones   Fig. . HoweverLε) Fig. , suggestP. falciparum genomes, and show that some PfEMP1 variants  appear to possess several IgM-binding domains. Finally, our investigation indicates that non-immune IgM-binding may also occur among DBLα-CIDRα, DBLδ1, DBLβ, and DBLγ-type domains. However their ability to bind IgM appears less pronounced than that of DBLε- and DBLζ-type domains, and the biological relevance of this part of the study should be assessed further. While we did not investigate the functional significance of non-immune IgM-binding in the present study, previous reports have indicated roles in immune-evasion as well as pathogenesis 44. Together, these findings support the idea that non-immune IgM binding confers survival advantages on parasites expressing PfEMP1 variants with IgM-binding domains, thereby rendering this phenotype of likely clinical importance.Overall, our study provides the first comprehensive overview of PfEMP1 proteins and domain classes that can bind IgM via its Fcµ domain. We document that the capacity for PfEMP1-dependent binding of IgM to the IE surface is prevalent in several distinct P. falciparum clones 3D7, HB3, and IT4 were maintained in vitro in blood group O erythrocytes and serum-free medium, essentially as described before53. The 3D7 clone, transfected with the plasmid pVBH to erase epigenetic memory and achieve heterogeneous var gene transcription54, was generated and kindly provided by Ron Dzikowski21. Corresponding HB3 and IT4 parasites were generated by us in a similar way, except that the blasticidin concentration was increased to 10 µg/mL to recover parasites carrying high plasmid copy numbers. The genotypic identity of the parasites and the absence of Mycoplasma infection in the cultures were regularly verified.The Erythrocytes infected with pVBH-transfected late-stage parasites, obtained 14 days after release from blasticidin drug pressure, were purified by magnetic-activated cell sorting (MACS) and labeled with non-immune human IgM . After thorough washes in sterile phosphate-buffered saline supplemented with fetal bovine serum (2%), IEs were stained with phycoerythrin-conjugated anti-human IgM  and washed as above. A BD FACSJazz cell sorter (BD Biosciences) was used to sort individual IgM-binding IEs into round-bottom 96-well plates (Thermo Fisher Scientific) containing serum-free culture medium (100 µL) and uninfected erythrocytes (1 µL). The parasites were maintained in the plates for 2-4 weeks as described above, changing medium twice weekly, alternating between medium alone and medium with erythrocytes as above. Parasite growth was monitored regularly by microscopy, testing small aliquots from 10 random wells per plate. Wells with microscopic evidence of parasite multiplication were transferred to culture flasks and maintained until stably growing parasite sub-clones were established.var gene-specific primers were used to assess var gene transcription profiles by real-time quantitative PCR on a Rotorgene RG-3000 thermal cycler (Corbett Research), as described in detail elsewhere57. The transcription levels for each var gene was calculated using the 2−ΔCT method, relative to the levels of the housekeeping gene seryl-tRNA synthetase.Total RNA was prepared from synchronous ring-stage IEs using TRIzol (Ambion). Genomic DNA was removed by DNase I treatment (Invitrogen) and cDNA was generated using SuperScript II reverse transcriptase and random primers (Invitrogen) according to the manufacturer’s instructions. The cDNA, QuantiTec SYBR Green PCR Master Mix (Qiagen), and three validated sets of Escherichia coli Shuffle C3030 cells (New England Biolabs). Constructs were amplified from parasite genomic DNA, using specific primer sets . The purity of each protein was analyzed by sodium-dodecyl-sulfate polyacrylamide gel electrophoresis, followed by Coomassie staining with InstantBlue (Expedeon) following the manufacturer’s instructions. His-tags were detected by western blot using HRP-coupled anti-his antibodies (Qiagen)  Fig. .Three male Wistar rats per domain were immunized by subcutaneous injection four times at two-weeks intervals with 30 μg (first injection) and 15 µg (subsequent injections) of selected recombinant PfEMP1 domains Table  emulsifi6. In brief, flat-bottomed 96-well plates (Thermo Fisher Scientific) were coated overnight (4 °C) with recombinant protein (18 nM) or non-immune IgM  in Tris saline magnesium buffer. After blocking and washing, plates were incubated  with non-immune human IgM (10 nM) or recombinant protein (18 nM). Bound IgM or protein was detected using HRP-coupled anti-human IgM antibody  and anti-His antibody , respectively, followed by TMB PLUS2 ready-to-use substrate (Kem-En-Tec Diagnostics) following the manufacturer’s instructions. Absorbance was read at 450 nm after stopping the colorimetric reaction by the addition of 0.2 M H2SO4. Binding was considered positive if the measured absorbance was higher than the average absorbance plus three standard deviations for the DBLγ13 (PFD1235w) expressed in an identical way as the constructs assessed in this study. This domain was chosen as a negative control, because erythrocytes infected by parasites expressing that particular variant do not bind non-immune IgM (our unpublished data).Non-immune IgM-binding to recombinant PfEMP1 domains was assessed by ELISA as previously describedP. falciparum 3D7 was also assessed by recombinant protein micro-array as previously described27. In brief, single- or multi-domain proteins were expressed in COS7 cells, purified and immobilized on BioPlex beads as described before25. In each experiment, a mixture of 53–55 bead regions with immobilized constructs was used. Beads with immobilized HisAdEx construct59 were used as negative control. The control contained all the same parts as recombinant domain constructs but short irrelevant 37-mer peptides instead of PfEMP1 domains. Some of the constructs, which showed consistent binding in these high throughput experiments (n = 4–7), were tested then in smaller sets of beads to confirm binding. PCR primers for constructs and protein domain boundaries are shown in Table 27. Binding of non-immune IgM to the constructs were determined by incubation with PE-conjugated anti-human IgM . The fluorescence signal  measured for each control construct was subtracted from the signal of each bead-bound construct, in each of duplicate well, and averaged. Experiments to test IgM binding to bead-immobilized domains were repeated at least three times with qualitatively similar results. Results of representative experiments are shown.Non-immune IgM-binding to recombinant PfEMP1 domains from 43. Briefly, late-stage IEs were purified by MACS and labeled with non-immune human IgM . IE-bound IgM was measured with a FITC-conjugated anti-human IgM  and ethidium bromide (2 µg/mL) using a Beckman Coulter FC500 flow cytometer for data acquisition. Analysis was performed using FlowLogic software .Non-immune IgM binding to native PfEMP1 expressed on the IE surface was detected by flow cytometry as previously described60. Monospecific PfEMP1 expression on IEs was verified by flow cytometry as previously described43. In brief, late-stage IEs were labeled with affinity-purified IgG (10 μg/mL) followed by FITC-conjugated goat anti-rat IgG . Parasite nuclei were stained with ethidium bromide (2 µg/mL) and antibody labeling of IEs quantified by flow cytometry as above.Antigen-specific IgG was purified from rat sera after immunization with recombinant PfEMP1 domains using HiTrap Protein G HP and NHS-activated HP (coupled to the antigen used for immunization) columns  following manufacturer’s instructions. IEs were selected for surface expression of particular IgM-binding PfEMP1 candidates by repeated immune-magnetic selection using PfEMP1-specific rat anti-sera or affinity-purified rat IgG coupled to protein G-Dynabeads (Invitrogen) as described befores) was used to assess the correlation between non-immune IgM-binding and labeling by PfEMP1-specific IgG. P-values < 0.05 were considered significant.Data were analyzed by using GraphPad Prism version 8.0.1 . Two-tailed one-sample t-test relative to construct control was used to analyze the Bioplex results. Spearman’s rank correlation (rSupplementary data


We assessed IgM detection in Zika patients from the 2016 outbreak in Miami-Dade County, Florida, USA. Of those with positive or equivocal IgM after 12–19 months, 87% (26/30) had IgM 6 months later. In a survival analysis, ≈76% had IgM at 25 months. Zika virus IgM persists for years, complicating serologic diagnosis. Diagnosis of Zika virus infection is accomplished by testing for viral RNA or IgM and neutralizing antibodies (We included persons residing in Miami-Dade County who had confirmed Zika virus disease with symptom onset during June‒October 2016 and had participated in a previous prospective cohort study (https://www.sas.com) to manage and analyze the data and performed a nonparametric survival analysis  for interval-censored data to estimate the duration of Zika virus IgM detection. For this procedure, we considered survival to be the detection of Zika virus IgM . We included the IgM results of specimens from all 62 original participants collected 12‒19 months after symptom onset and the IgM results from all follow-up specimens acquired in the survival analysis. The Florida Health Institutional Review Board  approved this study.We used SAS version 9.4  provided a follow-up specimen. The median time of specimen collection after symptom onset was 21 (range 18–25) months; 5 (17%) patients provided a specimen at 18 months after symptom onset, 1 (3%) at 19 months, 6 (20%) at 20 months, 9 (30%) at 21 months, 3 (10%) at 22 months, 3 (10%) at 23 months, 1 (3%) at 24 months, and 2 (7%) at 25 months.Demographics and clinical characteristics of the 62 participants in the original study were previously reported  were positive for Zika virus IgM, 7 (23%) had an equivocal result, and 4 (13%) were IgM seronegative. Compared with results from the specimen collection 6 months earlier, 20 (67%) remained positive for Zika virus IgM, 2 (7%) remained Zika virus IgM equivocal, 4 (13%) transitioned from Zika virus IgM positive to equivocal, and 4 (13%) transitioned from Zika virus IgM equivocal to negative; no participants switched from Zika virus IgM positive to negative. Because of the small sample size, we were unable to assess whether age group, race, or ethnicity was associated with Zika virus IgM results. When we used all available test results from the 62 participants, a survival analysis indicated that 93% (95% CI 82%‒97%) of participants had detectable  Zika virus IgM at 14 months after symptom onset, 91% (95% CI 81%‒96%) at 17 months, 81% (95% CI 69%‒89%) at 22 months, and 76% (95% CI 57%‒88%) at 25 months .Our findings suggest that approximately three quarters of persons with PCR-confirmed symptomatic Zika disease still have detectable IgM at 25 months after initial illness onset. The prolonged detection of IgM after Zika virus infection is consistent with previous findings for related flaviviruses (


In 2015, an earthquake killing 9,000 and injuring 22,000 people hit Nepal. The Tribhuvan University Teaching Hospital (TUTH), a reference tertiary hospital, was operational immediately after the earthquake. We studied the profile of earthquake victims admitted in TUTH and assessed what factors could influence hospital length of stay.An earthquake victim dataset was created based on patient records, with information on sex, age, date of admission and discharge, diagnosis, and surgical intervention. We performed an initial descriptive overview of the earthquake victims followed by a time-to-event analysis to compare length of hospital stay in different groups, using log rank test and cox regression to calculate Hazard Ratios.There were in total 501 admitted victims, with the peak of admissions occurring on the fifth day after the earthquake. About 89% had injury as main diagnosis, mostly in lower limbs, and 66% of all injuries were fractures. Nearly 69% of all patients underwent surgery. The median length of hospital stay was 10 days. Lower limb and trunk injuries had longer hospital stays than injuries in the head and neck . Plastic surgeries had longer hospital stays than orthopaedic surgeries (HR = 0.57 p = 0.006). Having a crush injury and undergoing an amputation also increased time to discharge .Hospital stay was particularly long in this sample in comparison to other studies on earthquake victims, indirectly indicating the high burden TUTH had to bear to treat these patients. To strengthen resilience, tertiary hospitals should have preparedness plans to cope with a large influx of injured patients after a large-scale disaster, in particular for the initial days when there is limited external aid. Earthquakes are large-scale, sudden-onset disasters, which cause widespread damage . BetweenInjuries are the most important cause of earthquake-related morbidity, consisting mostly of soft tissue and orthopaedic injuries, particularly fractures. These injuries are more frequent in the extremities, mostly lower limbs, and are also prone to wound infections . Crush iOn Saturday April 25th 2015, at 11:56 in the morning, Nepal was hit by an earthquake with a magnitude of 7.8 on the Richter scale, killing 9,000 people and injuring 22,000. The epicentre was in the Gorkha district, about 76 km northwest of the capital Kathmandu, but neighbouring districts were heavily affected . SeveralUnderstanding the profile of admitted earthquake victims is crucial to gain insight not only on health consequences of earthquakes, but also to understand what type of resources are mostly needed, in order to better prepare for such events. Literature on earthquake victims in low resource settings is mostly from foreign field teams who only arrive some days after the disaster, failing to picture the victims who reach the local health services in the first days after the earthquake , 13. SinEarthquake victims were defined as those patients admitted in TUTH with a clinical condition that could be directly related to the earthquake. These patients had records that identified them as such so the hospital could claim financial compensation from the Nepali government. The hospital staff later compiled these records into a database. In parallel, the government of Nepal created a standardized matrix to ensure comparability among different hospitals, and posteriorly filled it with TUTH patients’ information, but had a more conservative definition of earthquake victim, excluding cases such as acute stress disorder, deprivation syndromes, or acute exacerbation of chronic diseases. Some variables were reported in both datasets, but each dataset also contained unique information. In order not to lose this information, we linked both datasets based on six variables: Name, age, sex, living district, date of admission, and date of discharge. If there was a match in at least four out of six variables, we considered them the same subject. If there was a match in three of the six variables, we would verify the compatibility of diagnosis and treatment. If this was the same, we still considered the patient a match, otherwise not. Inconsistencies in variables between datasets  were verified by hand search in patient records. If these records were not available, we used the information from the dataset generated by the hospital staff, as it collected data at an earlier stage. We included all victim admissions, including referrals from other hospitals, which occurred until October 2015. Readmissions and duplications were identified independently by two researchers, and those they agreed upon were removed from the victims dataset, as our study only intended to look at first admissions.th, and the admission. Length of hospital stay was computed by calculating number of days between admission and discharge. The main diagnosis for admission was entered as free text in the original files, and coded into the International Classification of Diseases, 10th revision (ICD-10), by two independent researchers. If the coding did not coincide, they would discuss in order to reach a consensus. Only the first and main diagnosis was taken into account. Diagnoses were further converted into additional categorical variables, such as location of injury, presence of fracture, presence of crushing injury. Main body region of injury was classified in head and neck, lower limb, trunk , and upper limb. If a person sustained several injuries in one same region, the injuries would be classified under that region. The medical specialty performing primary surgery was classified from an open text into a categorical variable. We created a binary variable for amputations and in-hospital deaths.We first performed a descriptive analysis of selected variables, followed by a more thorough analysis of hospital length of stay. Statistical analysis of hospital length of stay is not straightforward. In general, the distribution curve is right-skewed and does not meet assumptions of Normality. In addition, in-hospital deaths make it uncertain when the discharge would have occurred. Time-to-event analysis, often known as survival analysis, allows inclusion of such cases . As repoData analyses were conducted using Stata 15.1 . We considered a level of significance of p < 0.05.For the purpose of this study, we only used secondary data from the hospital records. Identifiers were only used to merge the datasets, and were removed immediately after. In compliance with local requirements, we submitted this study protocol to the ethics committee of the Institute of Medicine of the Tribhuvan University. The requirement for an informed consent was waived, and we received clearance to undertake this study (Ref. 381(6-11-E)2/074/075).Our final victims dataset contained 501 individuals, with a mean age of 36.18 years (SD 21.58), ranging from 2 months to 87 years of age. th. The median was five days with an interquartile range of three to 15 days, and the peak occurred on the fifth day after the earthquake, with 77 admissions , with a maximum of 106 days. The median length of stay was ten days, with an interquartile range of five to 18 days .Of all 501 admitted victims, 494 had diagnostic information . The vasFractures represented nearly two thirds of all injury cases , with 49 compound fractures . Crushing injury was primary diagnosis for 21 admissions. About one third of all crushing injuries affected the upper limb (n = 6), one third affected the lower limb (n = 7), and one third occurred in an unspecified body region (n = 8).About 69% of all admitted victims underwent at least one surgery (n = 345); this share was about 76% for fracture cases (n = 218). The majority of surgical interventions were orthopaedic, followed by neurosurgery, and plastic surgery . About 6For 7% of the cases (n = 37), death was reported as an outcome, of which 20 were males and 17 were female. Most people who died were admitted one day after the earthquake (n = 10), and half were admitted within four days. Deaths occurred on average thirteen days after the admission, with a median of nine days of admission. Among in-patient deaths, 14 had a lower limb injury, seven sustained a head and neck injury, six a trunk injury, and four an upper limb injury. One person had a postsurgical state (craniotomy), and two were due to earthquake-related diseases of the nervous system.In the bivariate log rank tests, time to discharge was not associated with sex, age group, nor fracture. In contrast, it was significantly associated with main body region affected (p = 0.0026), presence of crush injury (p = 0.0093), having undergone an amputation (p = 0.0361), and surgery type (p = 0.0168).The four presented variables were incorporated in a multivariate model to calculate adjusted HR, which only included 291 observations due to missing values. The only significant finding was that injuries in the trunk region had lower hazards of discharge compared to head and neck (p = 0.005). However, this model did not meet the proportional hazards assumptions , and there was significant evidence of a poor fit (p = 0.047). We checked for interaction terms between all variables, but these models were not significantly better.The majority of the literature describing the profiles of treated victims from the Nepal earthquake is from foreign field teams, who usually arrive on site several days after the event , 18–20. More than half of victims with a reported mechanism of injury were hurt by an object falling on them. As described in the literature, building collapse is associated with higher mortality, and such victims are hence less frequently admitted, as they often die before reaching a health facility . DespiteAs expected, the vast majority of the earthquake victims were admitted primarily because of injuries, mostly orthopaedic, with fractures representing almost two thirds of all injuries. Lower limbs were the most common body location of injuries, and 17% of all fractures were compound. These findings are in line with previous studies on earthquake victims , 22, 23.Children and adolescents under 15 years of age only accounted for 17.2% of the admissions, a share lower than the country’s age distribution in 2014, where they represented 33.4% of the population . The earThe mean and median length of hospital stay of earthquake victims in TUTH, which were equal to 14.7 and ten days, respectively, are higher than in other studies. A study in a rural hospital in Nepal showed that earthquake victims had a median length of stay of eight days, as opposed to five days in non-earthquake patients. In another study comprising 1,878 admitted victims of the Wenchuan earthquake, their mean length of hospital stay was seven days, ranging from one to 120 days . EarthquOur survival analysis indicates that trunk and lower limb injuries, crush injuries, undergoing plastic surgery, or undergoing an amputation, were associated with longer hospital stays. Injuries in the trunk region include pelvic and spine fractures, and such patients are generally more unstable and usually require definite treatment before being sent home. Lower limbs are relatively less vascularized than upper limbs , and neeLength of hospital stay is often described as the result of complex interactions between patients, accompanying physicians, and hospital management characteristics , 33. OurThis study had some limitations. Data were collected in chaotic conditions, primarily aimed at reporting to the government for financial compensation. We limited our analyses to the most reliable information available, which underwent several verifications. Completeness was lower for some specific variables, decreasing the power of statistical tests, and preventing us from including additional information, such as subsequent surgeries or co-morbidities, which could have enriched our analyses. Furthermore, we only analysed the main diagnosis as reported in the patient records. Although some conditions could be jointly classified as one ICD-10 code (e.g. multiple fractures in upper limb), some were left out from the analysis due to limitations in categorization, which was done by two independent researchers. As a consequence, it is likely that a relevant share of injuries were not taken into account.We included earthquake victims who were admitted at TUTH at any stage, and our analysis contains referrals from other hospitals. However, because this information was not systematically collected, we cannot be entirely certain of which individuals were referrals. It is also not possible to affirm with certainty which victims were affected during the first earthquake or in its aftershocks. In addition, we lacked reliable information on posterior readmissions, which would have provided more insights on the long-term consequences for patients.Our study attempted to use existing data from a unique setting in the most efficient way possible, providing useful information for tertiary hospitals to improve preparedness and response in the event of an earthquake. There was a high influx of earthquake victims coming to TUTH for several days, with the peak occurring on the fifth day only. With an increased length of hospital stay for earthquake victims compared to other settings, and some conditions that specifically need higher levels of care requiring longer admissions, TUTH faced an extremely high burden after the 2015 earthquake. To strengthen resilience, tertiary hospitals in countries with seismic risks should have preparedness plans to cope with large numbers of injured patients after earthquakes, anticipating that they will need considerable resources. In particular, there should be a strong focus on the initial days following the disaster, since there is a sustained influx of patients, but limited external aid.In order to improve our understanding of this disaster and of how it affected hospital functioning, we are conducting additional studies focusing on gender differences, changes in patterns of hospital admissions, and on hospital staff experiences.


OR 8.20; 95% Confidence Interval, 95% CI 1.30–51.80), cerebrovascular thrombosis , chronic kidney disease , and acute heart failure  hospitalizations were statistically significantly associated with carvedilol choice. Analogously, human insulin , fondaparinux  or strontium ranelate  redeemed prescriptions. In conclusion, this study suggests the absence of beta-blockers exchangeability and a preferential choice of carvedilol in patients with heart failure, COPD and concurrent chronic kidney disease, atrioventricular block, cerebrovascular thrombosis, acute heart failure or redeeming human insulin, fondaparinux or strontium ranelate prescriptions. Therefore, it suggests that choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments.Clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease (COPD), metoprolol/bisoprolol/nebivolol should be preferred over carvedilol. However, studies suggest a high proportion of carvedilol usage that remains unexplained. Therefore, we aimed to investigate the predictors of carvedilol choice in patients with heart failure and COPD that were naïve to carvedilol or metoprolol/bisoprolol/nebivolol. Caserta Local Health Unit databases  were used as data sources. Age, sex, chronic/acute comorbidities, and co-medications were included in a logistic regression model to assess predictors of carvedilol choice. Chronic comorbidities include those defined in the Elixhauser comorbidity index and all hospitalizations within two years prior to the first beta-blocker prescription. Comedications include all redeemed prescriptions within one year prior to the beta-blocker prescription. Kernel density estimations were used to assess the overlap in propensity and preference scores distributions for receiving carvedilol and thereby potential beta-blocker exchangeability. Totally, 10091 patients composed the study population; 2011 were exposed to carvedilol. The overlapping of propensity scores distributions was 57%. Accordingly, the exchangeability was not reached. Atrioventricular block (Odds Ratio,  The benefits of beta-blockade in heart failure are due to their mitigation of the negative pathological consequences associated with adrenergic nervous system hyperactivity that gradually occurs in a chronically failing heart2. The sympathetic overdrive in heart failure is associated with an increased risk of arrhythmias, progressive dysfunction of the left ventricle, and myocardial insult, phenomena that have a negative impact on disease progression and prognosis3. In fact, adrenergic nervous system hyperactivity determines increased peroxidative and lipoperoxidative metabolism and demands of oxygen in the myocardium leading to the overproduction of reactive oxygen species that in turn determines local inflammation, apoptosis, and necrosis resulting in interstitial fibrosis and heart remodelling5. In Europe, four beta-blockers are currently indicated for heart failure, three beta-1 adrenoceptor selective, metoprolol, bisoprolol and nebivolol, and a non-selective, carvedilol. Metoprolol and bisoprolol are both second generation beta-blockers or rather they have high beta-1 adrenoceptor selectivity and they both lack intrinsic sympathomimetic activity. Bisoprolol has 20 times higher selectivity for the beta-1 adrenoceptor than metoprolol and it has a longer half-life (9–12 hours versus 3–7 hours) and bioavailability (90 versus 12%). Due to its high selectivity for the beta-1 adrenoceptor, bisoprolol has minimal effects on insulin sensitivity while, on the other hand, metoprolol has an additional membrane-stabilizing activity on the heart. Carvedilol and nebivolol are third generation beta-blockers with additional vasodilatation properties. Nebivolol is beta-1 adrenoceptor selective beta-blockers with a long half-life and bioavailability (12–96%) which, through a mechanism mediated by nitric oxide, is able to provide a reduction of the arteries tone that when targeted on the coronaries guarantees additional cardioprotective and anti-ischemic effects. Carvedilol is a non- beta-1 adrenoceptor selective beta-blockers with an intrinsic sympathomimetic activity, long half-life (7–10 hours) and additional vasodilatation properties mediated by the alpha-1 adrenoceptor blockade. It has anti-oxidant properties, it mitigates calcium overload by modulating ryanodine channels, and it ameliorates insulin sensitivity6. Despite a clinical and pharmacological rationale suggest the use of beta-blockers in heart failure, reluctance to prescribe beta-blockers in patients with the concurrent chronic obstructive pulmonary disease has been observed in multiple clinical settings. The leading factor for under-prescription of beta-blockers in this subpopulation is the concern of adverse respiratory effects mediated by beta-blockers through beta-2 adrenoceptors in the airway. The magnitude of the bronchoconstriction is strongly correlated with beta-1 adrenoceptor selectivity7. For this reason, current clinical guidelines suggest that for patients with heart failure and concurrent chronic obstructive pulmonary disease, metoprolol, bisoprolol or nebivolol should be preferred9. However, studies suggest a high proportion of carvedilol usage that is in opposition to above-mentioned recommendations10. Several adverse clinical consequences have been associated with carvedilol usage in patients with heart failure and concurrent chronic obstructive pulmonary disease such as a reduction in the lung function11 that may lead to subclinical effects on respiratory parameters13. Additionally, carvedilol may lead to a higher rate of unfavourable hemodynamic alterations leading to an increased risk of heart failure hospitalization, on both short and long-term following treatment commencement12. In virtue of the potential negative clinical consequences associated with carvedilol choice in patients with heart failure and chronic obstructive pulmonary disease naïve to beta-blockers, understanding key factors that may lead to a preferential choice of such prescriptions is crucial and, in this regard, the evidence is scarce. Our hypothesis is that concurrent chronic/acute comorbidities and comedications may have driven the choice of carvedilol over metoprolol/bisoprolol/nebivolol and this may have led to the absence of exchangeability of these beta-blockers in this subpopulation. To overcome this gap in knowledge, the current study aims to investigate carvedilol and metoprolol/bisoprolol/nebivolol exchangeability and the predictors of carvedilol choice in patients with heart failure and chronic obstructive pulmonary disease that were naïve to beta-blockers. The investigated predictors included chronic comorbidities defined in the Elixhauser comorbidity index14, all hospitalizations and redeemed prescriptions within two and one years prior to the first beta-blocker prescription, respectively.Beta-blockade is a crucial pharmacological therapy to improve survival and to reduce morbidity in patients with heart failure and concurrent chronic obstructive pulmonary diseaseHealth data sources of the Caserta Local Health Unit were used to identify the study population. These data sources cover approximately 1,000,000 citizens living in the catchment area of Caserta . For reimbursement purposes, the data sources store information on socio-demographic characteristics of residents, redeemed prescriptions, inpatient and outpatient hospitalizations and hospital contacts. Data contained in Caserta Local Health Unit administrative databases are pseudonymized to comply with current law on data protection and privacy.ATC R03) prior to the redemption of the first prescription of aforementioned beta-blockers  during the period December 31, 2010 to September 30, 2017 had a hospitalization/hospital contact for heart failure, (2) redeemed their first carvedilol, metoprolol, bisoprolol or nebivolol prescription after this hospitalization for heart failure , and (3) redeemed drugs for obstructive airway diseases 15. According to Walker and colleagues, the predicted value from the above-mentioned logistic regression was used to compute a preference score as following: ln {A/(1 − A)} = ln (B/(1 − B) − ln (C/(1 − C)) where A is the preference score, B is the propensity score and C is the prevalence of exposure to carvedilol16. To assess beta-blocker exchangeability among beta-blockers, a Kernel density estimation was used to assess the overlap in propensity scores areas for carvedilol and metoprolol/bisoprolol/nebivolol users. Additionally, as suggested by Walker and colleagues, by using a Kernel density estimation, we tested if half of the distributions of the preference score was between 0.3 and 0.7 between carvedilol and metoprolol/bisoprolol/nebivolol users16. Baseline characteristics of the two cohorts were compared using the t-tests for continuous variables and χ2 test for categorical variables.A prevalence proportion  for all primary diagnosis for hospital contact/hospitalization and redeemed prescriptions that occurred 2 and 1 year/s prior to the redemption of the first carvedilol, metoprolol, bisoprolol, or nebivolol prescription was computed and the 500 event most prevalent among carvedilol users were selected. This is a crucial preliminary step to identify the most relevant variables for propensity score assessment in highly dimensional datasets. The 500 top-ranked potential predictors selected with the abovementioned method were used as independent variables in a logistic regression model to compute the propensity score for receiving carvedilol rather than metoprolol, bisoprolol, and nebivolol. The predicted probability of receiving carvedilol given the set of potential predictors was used to assess the exchangeability between treatments groups given their covariate distributions. The null hypothesis was the absence of clinical or demographic differences between recipients of carvedilol versus metoprolol, bisoprolol, or nebivolol or rather beta-blocker exchangeability  of statistically significant predictors for carvedilol prescription over metoprolol/bisoprolol/nebivolol prescriptions are provided in Fig. This study suggests that among patients with heart failure and chronic obstructive pulmonary disease, the choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol is driven by differences in comorbidities and co-treatments. Predictors of carvedilol choice were chronic comorbidities and co-treatments including chronic kidney disease, human insulin, fondaparinux, strontium ranelate or recent acute episode of acute heart failure, cerebrovascular thrombosis or atrioventricular block.European clinical guidelines on chronic heart failure released during the study period do not state any preference among beta-blockers in the aforementioned clinical conditions and they do not provide recommendations in the clinical setting of multiple comorbidities. However, clinical evidence seems to support the choice of carvedilol over other beta-blockers in the clinical scenario listed above.17. These effects, along with to the ability of all beta-blockers in reducing sympathetic over-activity, were found associated with attenuation in the increase of albuminuria and hyperkalaemia, but also to an absence of an increase in serum creatinine, events typically observed in patients with chronic kidney disease. In addition, the aforementioned effects were found associated with high effectiveness in protecting from cardiovascular events in patients with chronic kidney disease19.Carvedilol was found beneficial for patients with chronic kidney disease due to its ability to reduce cardiac output and renin release, as to its ability to reduce renovascular constriction through its alfa-1 and beta-1 receptor antagonism. Additional, carvedilol was useful due to its enhanced renovascular dilation through beta2-receptor antagonism21.With regards to diabetes mellitus and in particular human insulin as a predictor for carvedilol choice, evidence suggests a favourable effect of carvedilol on glycaemic control in diabetic patients when compared to metoprolol. In particular, in the Glycaemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensive (GEMINI) trial, patients treated with carvedilol had a lower probability of new onset diabetes mellitus, microalbuminuria  and an increased insulin sensitivity compared to patients treated with metoprolol. Additionally, a recent systematic review suggested even more beneficial effect of carvedilol in diabetes mellitus, including a reduced risk of new onset of atherogenic dyslipidaemia or weight gain among treated with carvedilol22. In Italy, during the study period, strontium ranelate was indicated for “the treatment of severe osteoporosis in postmenopausal women and in adult men at high risk of fracture”. Observational studies suggest an association between beta-blocker treatments, and in particular carvedilol, and reduced risk of bone fracture and an inherent protective effect of this drug class. On the other hand, pooled data from clinical trials that investigate the effect of carvedilol on congestive heart failure do not seem to support this hypothesis24. Mechanistic studies performed in pre-clinical models support the hypothetic involvement of β-adrenoceptor in the aforementioned phenomena by showing that beta-blocker treatment improves bone density and mass while β-adrenoceptor agonists led to the opposite effect. In particular, the effect seems mediated by the β2-adrenoceptor on osteoblasts and the sympathetic nervous system25. It should be mentioned that no formal potential drug-drug interactions were found between strontium ranelate and carvedilol or metoprolol/bisoprolol/nebivolol by using Micromedex®26. Therefore we excluded potential drug-drug interaction as a plausible explanation for carvedilol choice in these patients.Regarding the role of strontium ranelate as a predictor for carvedilol choice, it should be mentioned that our study population had a mean age of 77.8 years with a proportion of women of 49.8% and, therefore, at high risk of osteoporosis. Additionally, patients with chronic obstructive pulmonary disease have an increased risk of all-cause and site-specific fractures27. Alternatives to fondaparinux in the aforementioned clinical scenario are the direct acting oral anticoagulants27. However, while carvedilol has no potential drug-drug interactions with fondaparinux26, it has with direct acting oral anticoagulants, and in particular dabigatran and edoxaban. Given carvedilol’s ability to inhibit the glycoprotein-P, it may induce an increased plasma concentration of the aforementioned direct acting oral anticoagulants with a consequent increased risk of bleeding26. Therefore, we speculate that the occurrence of these clinical scenarios may have led the choice of carvedilol in patients exposed to fondaparinux.In relation to fondaparinux as a predictor of carvedilol prescription, we need to mention that during the study period, fondaparinux was indicated for the prevention of venous thromboembolism in multiple clinical scenarios. We believe that a plausible explanation for the higher proportion of fondaparinux use in patients treated with carvedilol may be due to the fear of potential drug-drug interactions. In particular, clinical guidelines advocate the use of fondaparinux for venous thromboembolism prophylaxis in patients with a history of heparin-induced thrombocytopenia29.In relation to acute heart failure, previous studies have found different effects on the cardiovascular system among beta-blockers with different β-1 adrenoceptor selectivity in patients that experienced acute heart failure and that were exposed to inotropic agents (i.e. dobutamine). In this subpopulation, metoprolol did not modify the cardiac index, heart rate, and systemic vascular resistance providing only a modest effect on the pulmonary artery and systemic arterial pressures within the first 12 months of treatment. In contrast, substantial differences were observed for carvedilol. The aforementioned effects were attributed to the blockade of β-2-receptors in the vascular system and to the other pharmacological properties of carvedilol30. In pre-clinical and in-vitro models, authors found neuroprotective effects of beta-blockers with additional vasodilatation properties, like carvedilol and nebivolol. Notably, for carvedilol, a study suggests that these effects may be mediated also by the β2 adrenal receptors antagonism and cyclooxygenase 2 isozyme/prostacyclin pathways32. Additionally, clinical evidence seems to support the hypothesis of a reduced risk of mortality due to stroke in patients exposed to carvedilol versus those exposed to metoprolol33.It should be mentioned that clinical evidence exists on the beneficial effect of beta-blockers on the risk of early death in patients with ischemic stroke35.Regarding the choice of carvedilol in patients with a recent episode of atrioventricular block, it should be highlighted that clinically relevant differences were observed among beta-blockers indicated for heart failure on the heart rate. In particular, among aforementioned beta-blockers, carvedilol provided a weaker effect on heart rate at rest when compared to other beta-blockers especially in patients with a low sympathetic tone which may be beneficial in patients with a recent episode of atrioventricular block. It was hypothesized that this effect might be caused by the increased sympathetic drive consequent to the peripheral vasodilation resulting from the accessories vasodilatation properties of carvedilol36. Additionally, beta-blockers are relatively contraindicated in asthma.A major limitation of this study is the lack of information on the indication of use for redeemed prescriptions. For drugs having ATC code R03, it may have led to a misclassification of the exposure. In fact, these drugs are mainly indicated for both asthma and chronic obstructive pulmonary diseases. Therefore, we may have classified patients with asthma as having chronic obstructive pulmonary disease. We believe that the magnitude of this type of misclassification is very low because Caserta Local Health unit databases contain information on drugs reimbursed by the national health system, and most of the reimbursed drugs in this ATC group are indicated for chronic obstructive pulmonary disease as shown elsewhere37. Another limitation of this study is the potential misclassification of chronic comorbidities identified through hospitalizations/hospital contacts. In fact, we lack information for those patients hospitalized and/or with a hospital contact outside the catchment area of Caserta local health unit. However, we believe that the magnitude of this bias is low because these patients will receive in most of the cases a pharmacological treatment that is tracked in Caserta Local health unit databases.The second major limitation of this study is the lack of information on over-the-counter drugs/drugs not requiring a medical prescription. In particular, we may have not detected predictors for carvedilol choice among acute comorbidities. In the Italian healthcare system, over-the-counter drugs/drugs not requiring a medical prescription are generally not indicated for chronic and/or invalidating diseases with a high burden for the patient and they are usually used as symptomatic treatments39. However, we believe that this limitation may have introduced a negligible bias. In fact, during the study period, the number of immigrants in the catchment area of Caserta was between 3000–4000, or rather 0.3–0.4% of the study population and, mostly with an age lower than 60 years and, therefore, with a lower probability of having heart failure40.The third major limitation of this study is the lack of information on the ethnicity/race of the study population for which, recent studies found an association with a differential response to beta-blockers treatment42, to date, in Europe, none of the summaries of product characteristics of medicinal products containing carvedilol include polymorphisms of the gene codifying this enzyme as a “contraindications”/“special warnings and precautions for use” for its prescription. Therefore, we believe that even in the setting of poor, rapid or ultra-rapid metabolizers, it should not have influenced the prescription choice.Regarding the lack of information on the cytochrome P450 2D6 polymorphisms in the study population, despite carvedilol is extensively metabolized by this enzymeFinally, as for all observational studies, we cannot exclude the presence of unmeasured confounders that may have introduced biases in our analysis. Strengths include the use of the entire population of patients enlisted in Caserta local health unit databases reducing the risk of selection bias and the possibility of providing results based on real-world data from routine clinical practice.In conclusion, this study showed that no beta-blocker exchangeability was found among carvedilol and metoprolol/bisoprolol/nebivolol in patients with heart failure and chronic obstructive pulmonary disease. In this subpopulation, concurrent chronic (i.e. chronic kidney disease) and acute comorbidities  or concurrent pharmacological treatments  may drive the choice of prescribing carvedilol over metoprolol/bisoprolol/nebivolol.


Conflicts of interest (COI) between industry and surgeons frequently introduce biases into surgical research. The abstracts submitted for presentation in scientific congresses are usually vetted for any indication of commercial bias. Members of review program committees regularly have recognized qualifications, and therefore certain COI are unavoidable. This study aims to determine the prevalence and magnitude of possible COI among those responsible for the selection of presentations at two important international conferences on spine surgery during a five-year period.COI declarations by those responsible for the final programs of the annual SRS (Scoliosis Research Society) and IMAST  conferences from 2010 to 2014 were collected and analyzed from data published by the corresponding scientific programs. The SRS’s disclosure index did not contain financial amounts; therefore, this aspect could not be analyzed.Five scientific committees and 117 members  were studied. Of these 76, 41 (53.9%) participated in more than one conflict of interest (>1 COI). Scientific committee members were from 11 countries across 4 continents, but most were from the Unites States (76.9%). Of the 117 program reviewers, 65.8% declared >1 COI and 34.2% reported no COI. The 77 program reviewers who disclosed a potential COI declared a total of 273 COI (mean = 3.54 COI/member). Overall, 36.0%, 26.1%, 10.7%, and 10.7% of the COI corresponded to consultancies, research funds, bureau participation, and advisory board panel participation, respectively. Stockholder reimbursement corresponded to 8.8% of the disclosed COI, and financial or material support were mentioned in 7.4% of COI. Among the COI disclosures, 55 companies were mentioned, and 5 of the top 10 companies involved in spinal device markets were responsible for 65.2% of the COI.More than two thirds of the members of the SRS and IMAST scientific committees reported COI. Consultancies and research grants account for two thirds of these. Most of the grants and major COI are related to the five companies leading the spinal implant market. Links between the medical device industry and surgeons are crucial for the development of new therapeutic surgical procedures. In recent decades, the role of industry support in different areas of surgical research has expanded significantly; further, support is now directed toward individuals instead of institutions . These fOrthopedic surgery is heavily dependent on implants that are often designed, improved, or developed by surgeons in conjunction with industry. It is relatively common for surgeons to hold or participate in the patent of a device because they have a particular interest in its use. These close bonds between industry and surgeons could be a source of potential bias in clinical research and may affect both scientific presentations at clinical meetings and published data –4. A recAll orthopedic societies require conflict of interest (COI) disclosure statements from contributors before any presentation or discussion of research results at their scientific meetings, and this information is published in the conference proceedings. Indeed, some surgical specialties in orthopedics have already released audits of the COI disclosures at their congresses ,4,6.In spinal surgery, the policy concerning COI disclosures for authors varies significantly. For example, the self-reported disclosure information of authors attending three major annual spine conferences in 2008  has been compiled and analyzed, and discrepancies or irregularities in the COI disclosures oscillated from 9% among authors whose data were listed at the NASS and SRS conferences to 51% among authors who presented at the NASS and CSRS meetings .Within orthopedics, the SRS is a leading provider of policies to improve transparency and clarify the relationships between surgeons and industry. The SRS’s website provides the following information to authors: “It is the policy of SRS to ensure balance, independence, objectivity, and scientific rigor in all of their educational activities. In accordance with this policy, SRS identifies conflicts of interest with instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by SRS to ensure that all scientific research referred to, reported, or used in a continuing medical education (CME) activity conforms to the generally accepted standards of experimental design, data collection, and analysis. Complete faculty disclosures will be included in the final program” .The process of selecting abstracts for presentation at different scientific meetings is a challenge for medical societies. Abstract presentations at SRS meetings are CME accredited activities, and it is therefore essential that submissions be free from commercial influence. Before presentation, all contributions must clear a review by the SRS CME Committee to ensure that no bias issues are included in the final program. In addition, the SRS strongly recommends that authors use generic descriptions of their instrumentation or techniques, with no specific names of implants or surgical devices.Both abstracts submitted for presentation in scientific congresses and manuscripts submitted for publication in journals are usually vetted for indications of commercial bias. However, members of review program committees and journal review boards regularly have recognized qualifications, and therefore certain COI are unavoidable. Recently, a study analyzed the prevalence and financial magnitude of potential COI among the editorial board members of five leading spinal journals . The perThe first purpose of this study was to determine the prevalence and magnitude of COI reported by members of the review program responsible for the selection of works to be presented at two prestigious international congresses of spinal surgery over a five-year period: the SRS Annual Meeting and the International Meeting of Advanced Spine Technologies (IMAST). Interestingly, review of abstracts submitted to these two meetings is entrusted to a single committee. This fact makes analysis of COI disclosures among committee members even more interesting from merely an observational perspective. The second objective was to measure the type of and variability in COI reported by review committee members and to examine members’ financial relationships with leading medical device companies.COI disclosures of members of the review committee responsible for the final program of the annual congresses of the SRS and IMAST during the years 2010–2014 were analyzed. Data were collected from the disclosure index published in the final program of each congress. These meetings were chosen because of their exclusive focus on spinal topics, their single review committee, and the availability of disclosure statement indexes. Disclosure for these meetings was mandatory not only for authors but also for committee and board members.As per the SRS policy concerning COI, disclosures were categorized according to one of the following: (1) nothing to disclose/no conflict reported and (2) potential conflict of interest. Relationships disclosed were categorized as follows: (a) grant/research support; (b) consultant; (c) stock/shareholder (self-managed); (d) speakers bureau; (e) advisory board or panel; (f) salary/contractual services; and (g) other financial or material support . The disclosure indexes of the SRS and IMAST do not contain the financial amount per disclosure; therefore, this aspect could not be analyzed.Consultant fees, stock options, and royalties were considered major financial COI . To be aU test. The level of significance was set at p<0.05.The total number of individuals reporting COI and the types of COI were tabulated. COI frequencies were calculated for each year. As one of the main objectives of this study was to analyze the ratio and type of COI of those reviewers who declared COI, this group was subsequently analyzed more in detail. Statistics were calculated on the basis of reviewer participation and not on individuals, since the same individual could participate multiple years in the Program Committee and the COI might change. Data for all measured variables were examined using descriptive statistical analysis. Contrast analyses were performed using Fisher’s exact test and a Mann–Whitney A total of 117 program reviewers of 5 scientific program committees were identified. These corresponded to 76 unique individuals, of whom 41 (53.9%) participated in more than one committee . Subsequent statistics will be done in the scientific committee members (117), even if they can correspond to participations of the same individual, since their COI could have changed from time to time. Scientific committee members were from 11 countries, but most were from the United States . Twelve were from the United Kingdom, Spain, Germany, and Turkey; six were from Japan, Singapore, and Malaysia; five were from Egypt; three were Canadian; and one was from Australia.p<0.05)  reported a potential COI, whereas 40 (34.2%) reported nothing to disclose/no conflict. When reviewers were analyzed by origin, those from the United States disclosed COI at a significantly higher proportion than reviewers from other countries (Fisher’s exact test p<0.05) . Analysip = 0.02), consultancy being more frequent in non-U.S. members. The mean ratio of disclosed COI to reviewers (of those who disclosed COI) was 3.54 (range per year: 1.62–3.93). The United States had a twofold greater COI to reviewer ratio than did other countries , followed by research funds (26.1%). ountries .During the same 2010–2014 SRS-IMAST meetings, there was a total of 2728 authors excluding some of the reviewers that also participated in the oral presentations. Of these authors, a total of 592 disclosed COI (21.7%). The percentage of authors declaring COI showed small variations along the period of study, ranging from 20.6% in 2012 to 24.5% in 2011. Differences in COI declarations between program reviewers and authors we statistically significant along the years of study (p<0.001) . The numWhen consultant fees, stock options, and royalties were considered together as a major financial COI of reviewers, they accounted for 52.0% of COI. Minor COI  represented 22.0% of disclosures. Grants that support research were 26.0% of the reported COI. The evolution of COI declarations from 2010 to 2014 is shown in In the study period, 55 different companies were mentioned in COI disclosures. Five of the top companies in the global spinal implant and device markets were responsible for 65,2% of all disclosed COI. Eighteen companies were involved in research grants, with five of the leading companies overall accounting for more than two thirds of such COI (77.4%) . The numAs for major COI, the same five leading companies were cited in 110 of the 142 COI disclosed (77.4%). Consultant activities related to the big five companies were more commonly disclosed among COI with major relevance . Minor COI were spread among 25 different companies, with four of the five leading companies overall involved in 51.6% of this type of disclosure. K2M was never referred among minor COI. An important change in the involvement of the big companies in. minor COI was observed along the period of study. Four big companies were responsible of 77.8% of the minor COIs in 2010, and 81.3% in 2011. However, the contribution of these four companies to minor COIs decreased notably in 2011 (11.8%) and in 2012 (22.2%). There were no minor COI related with these companies in 2012. Overall, the distribution of the type of COI declares by the program reviewers in relation to the five big companies of the spine implant market are shown in To our knowledge, this study is the first to examine the amount and type of COI disclosed by reviewers of the program committees of five consecutive SRS annual meetings. Importantly, this program committee also decides to accept or reject abstracts submitted to IMAST meetings. According to the disclosure statement index provided each year by SRS, almost two thirds  of reviewers declared potential COI, and more than half of the disclosures were considered as major COIs ; these increased from 44.6% in 2010 to 66.0% in 2014. The mean disclosed COI per reviewer (of those who disclosed COI) was 3.54. These statistics reflect the strong interactions between industry and review program members.When reviewers from USA were compared to those of the rest of the world, a significantly higher proportion of COI were declared by the USA reviewers (71.1% vs 48.1%). Interestingly, the percentage of reviewers declaring COI was significantly higher than that found in the authors participating in the different meetings. which never exceeded 24.5%. This disproportion between reviewers and authors could be understood by the fact that most of the reviewers use to be recognized surgeons with a longer professional career and, therefore, with more potential bounds to industry.In 2008, Ju et al.  analyzedA potential explanation for these high rates of industry relationships of SRS program reviewers is the relatively small nature of the scoliosis community and the field’s heavy reliance on implant technology. Advances in the surgical treatment of spinal deformities are usually related only to surgeon expertise. As such, the industry must develop new technologies. Furthermore, as reputed spine surgeons, a significant number of review program members unsurprisingly show interactions with industry, resulting in frequently unavoidable COI.This is the first study analyzing separately the COI of meeting program reviewers. Therefore, comparisons with other studies are not possible. In the current study, the percentage of spinal surgery program reviewers with potential COI (65.8%) is substantially higher than that found for reviewers of spine journals 29%) [% [9]. ObThe reasons are unknown from outside the companies. These findings indicate that the policy of companies concerning relationships with spine surgeons are progressively changing. More specifically, this data reflects that the interactions of reviewers with industry are more intense over time.One interesting finding is the progressive increment of major COI along the period of study (58.5% in 2014), especially those related to consultant activities. In the last year analyzed, consultant activities corresponded with almost half of the declared COI. Analyzing the frequency and type of COI declared by authors in the 2006 SRS annual meeting, grants accounted for 51.1% of the disclosures and consultant relationships only for the 20.8% . The incRegarding the source of COI, two thirds of the declared relationships were related with only five big companies covering the spine implant market. Considering only major COI, 86.4% of the disclosures were due to consultant activities for the five top companies. Three of these companies were not involved in minor COI after 2012. according to the current data, five big companies are supporting most of the research and consultant activities of the SRS program reviewers. These findings are similar in arthroplasty research. Authors presenting arthroplasty-focused research at the 2012 annual meeting of the American Academy of Orthopaedic Surgeons (AAOS) and declaring COI reported also paid consultancy (51.5%), and research support (43.0%) from industry . AccordiThese interactions can have both beneficial and negative effects. On one hand, ties between the spinal device industry and reviewers could be essential for sharing state-of-the-art scientific knowledge and advancing spinal surgery. On the other hand, these strong financial bonds might harm the impartiality of the review process to a certain extent, resulting in unintentional selection bias ,15. ThesThe process of deciding which abstracts are presented at scientific meetings is certainly a source for concern among medical societies. As have other scientific societies, the SRS has made a great and commendable effort to ensure that abstract selection not be biased by potential COI among program review members. The SRS CME Committee is one of the mechanisms that guarantee the ethical integrity of this process. However, the process could likely be improved by publishing the names of program committee members together with their potential COI before the submission process. The scientific society’s board of directors could contemplate the possibility that some authors may reject reviewers at the time of abstract submission because of COI disclosed by those reviewers. This might reinforce the value of COI disclosure requirements.Medical associations should be aware of the potential bias that could be caused even unintentionally by program reviewers and should strive to improve transparency during the selection process. Current recommendations proposed for medical journals to avoid altered conclusions or outright rejection of submitted manuscripts could be adapted and incorporated by program review committees of scientific meetings ,14–18. SThe scientific method attempts to make science as free from bias as possible ,20, but This study is not free from limitations; therefore, the findings should be interpreted carefully. The most obvious limitation is that the financial COI extracted from the index published by SRS were self-reported, which implies irregularities, inconsistencies, and inadequate disclosures. This limitation was demonstrated in a relatively recent study that quantified the variability in self-reported disclosures of individual authors who presented at three of the leading spinal conferences  held in 2008 . Among aThese results confirm that members of the SRS and IMAST scientific committees have a high percentage of COI. Two thirds of the reviewers (65.8%) disclosed COI, which is high compared to authors (27.1%). The average of disclosed COI was 3.54 per reviewer who declare COI. Consultancies and research grants account for two thirds of COI. Most of the grants and major COI are related to five of the leading companies in the spinal implant market. As expected, this study shows that SRS review program members have significant relationships with the spine implants industry. The diagnosis and treatment of spine diseases and deformities are highly dependent on new technologies; therefore, relationships with industry are completely understandable, not necessarily unethical, and unavoidable in many instances. Scientific societies should minimize the potential bias that COI disclosed by program reviewers could introduce during the abstract selection process. To improve transparency in that process, scientific societies should select as many reviewers as possible without relationships with medical device or implant companies. These independent reviewers could assess the scientific and methodological data of submissions. All of these suggestions aim to improve transparency in the abstract review process and scientific independency from industry.


Approximately 80% of older adults have chronic illness which requires complex care. Primary care providers require special training to improve the care they provide older adults. As primary care shortages increase, and the older adult population swells, physician assistants (PA) will increasingly be relied upon to provide care and advocacy for older adults. The purpose of this presentation is to describe the development of a dual degree program that facilitates enhanced gerontological training for students pursuing a Masters of PA Studies degree. The Gerontology Interdisciplinary Program and the PA Program at the University of Utah collaborated to assess program objectives, competencies, and coursework, while identifying student interest in this dual MS venture. Students were interested in increasing their skills to meet the growing need for geriatric care while also saving time and money. In addition, it was important that the combined program of study did not overburden students and accommodated participants off-site. Faculty and administrative buy-in was sought from within departments and colleges. Revisions to the proposed program of study included altering course offerings, changing program start dates, and removing course overlap. A 30-month dual MS was developed that incorporates 87 PA Program credits, 25 Gerontology Credits, and 6 credits shared through practicum, geriatric content, and evidence based practice. Students who graduate will complete a Gerontology focused Masters Project that combines their work from the two programs. This dual MS program prepares students to be competitive in the job market, while also targeting an area of need in primary care.