Differences In Disease Progression Research Articles

Prognostic value of HPV DNA in Urothelial Carcinoma of the Bladder: A Preliminary Report of 2-Year Follow-up Results.

The association between the human papillomavirus (HPV) and anogenital carcinomas is well established. However, despite its anatomic adjacency, the relationship between HPV and urothelial carcinoma of the bladder (UCB) is less clear. Recent meta-analysis and case-control studies demonstrated a significant relationship between the presence of HPV DNA and UCB. The aim of this clinical study was to compare the 2-year follow-up results of HPV-positive and HPV-negative UCB patients to evaluate the prognostic value of HPV DNA positivity in UCB. The study included patients with stage pTa and pT1 UCB who underwent polymerase chain reaction (PCR) analysis of HPV DNA between January 1 and November 30, 2018. Based on their PCR results, 19 HPV-positive and 38 HPV-negative UCB patients who had regular follow-up in our clinic were evaluated in terms of tumor recurrence and disease progression over a 2-year follow-up period. There was no significant difference between the groups in terms of age, follow-up time, smoking, or tumor grade (P= .576, P= .368, P= .080, and P= .454). Tumor recurrence was observed at least once in 47.3% (n=9) of the 19 HPV-positive patients and 36.8% (n=14) of the 38 HPV-negative patients (P= .445). There was no difference in disease progression between the groups during follow-up. In our sample of UCB patients, the presence of HPV DNA was associated with a trend toward higher recurrence rate during the 2-year follow-up, though the difference was not statistically significant. No difference in disease progression was observed based on HPV DNA positivity.

Natural History of Post-Treatment Kidney Stone Fragments: A Systematic Review and Meta-Analysis

We assessed the literature around post-treatment asymptomatic residual stone fragments and performed a meta-analysis. The main outcomes were intervention rate and disease progression. We searched Ovid®, MEDLINE®, Embase™, the Cochrane Library and ClinicalTrials.gov using search terms: "asymptomatic", "nephrolithiasis", "ESWL", "PCNL", "URS" and "intervention." Inclusion criteria were all studies with residual renal fragments following treatment (shock wave lithotripsy, ureteroscopy or percutaneous nephrolithotomy). Analysis was performed using 'metafor' in R and bias determined using Newcastle-Ottawa scale. From 273 articles, 18 papers (2,096 patients) had details of intervention rate for residual fragments. Aggregate intervention rates for ≤4 mm fragments rose from 19% (20 months) to 22% (50 months), while >4 mm fragments rose from 22% to 47%. Aggregate disease progression rates for ≤4 mm rose from 25% to 47% and >4 mm rose from 26% to 88%. However, there was substantial difference in definition of "disease progression." Meta-analysis comparing >4 mm against ≤4 mm fragments: intervention rate for >4 mm (vs ≤4 mm): OR=1.50 (95% CI 0.70-2.30), p <0.001, I2=67.6%, tau2=0.48, Cochran's Q=11.4 (p=0.02) and Egger's regression: z=3.11, p=0.002. Disease progression rate for >4 mm: OR=0.06 (95% CI -0.98-1.10), p=0.91, I2=53.0%, tau2=0.57, Cochran's Q=7.11 (p=0.07) and Egger's regression: z=-0.75, p=0.45. Bias analysis demonstrated a moderate risk. Larger post-treatment residual fragments are significantly more likely to require further intervention especially in the long term. Smaller fragments, although less likely to require further intervention, still carry that risk. Notably, there is no significant difference in disease progression between fragment sizes. Patients with residual fragments should be appropriately counselled and informed decision-making regarding further management should be done.

Revisiting early-stage COVID-19 strategy options.

Background: Early-stage interventions in a potential pandemic are important to understand as they can make the difference between runaway exponential growth that is hard to turn back and stopping the spread before it gets that far. COVID19 is an interesting case study because there have been very different outcomes in different localities. These variations are best studied after the fact if precision is the goal; while a pandemic is still unfolding less precise analysis is of value in attempting to guide localities to learn lessons of those that preceded them. Methods: I examine two factors that could differentiate strategy: asymptomatic spread and the risks of basing strategy on untested claims, such as potential protective value of the Bacillus Calmette-Guerin (BCG) tuberculosis vaccine. Results: Differences in disease progression as well as the possibility of alternative strategies to prevent COVID-19 from entering the runaway phase or damping it down later can be elucidated by a study of asymptomatic infection. An early study to demonstrate not only what fraction are asymptomatic but how contagious they are would have informed policy on nonpharmaceutical interventions but could still be of value to understand containment during vaccine roll out. Conclusions: When a COVID-19 outbreak is at a level that makes accurate trace-and test possible, investigation of asymptomatic transmission is viable and should be attempted to enhance understanding of spread and variability in the disease as well as policy options for slowing the spread. Understanding mild cases could shed light on the disease in the longer term, including whether vaccines prevent contagiousness.

Revisiting early-stage COVID-19 strategy options

Background: Early-stage interventions in a potential pandemic are important to understand as they can make the difference between runaway exponential growth that is hard to turn back and stopping the spread before it gets that far. COVID19 is an interesting case study because there have been very different outcomes in different localities. These variations are best studied after the fact if precision is the goal; while a pandemic is still unfolding less precise analysis is of value in attempting to guide localities to learn lessons of those that preceded them. Methods: I examine two factors that could differentiate strategy: asymptomatic spread and the risks of basing strategy on untested claims, such as potential protective value of the Bacillus Calmette-Guerin (BCG) tuberculosis vaccine. Results: Differences in disease progression as well as the possibility of alternative strategies to prevent COVID-19 from entering the runaway phase or damping it down later can be elucidated by a study of asymptomatic infection. An early study to demonstrate not only what fraction are asymptomatic but how contagious they are would have informed policy on nonpharmaceutical interventions but could still be of value to understand containment during vaccine roll out. Conclusions: When a COVID-19 outbreak is at a level that makes accurate trace-and test possible, investigation of asymptomatic transmission is viable and should be attempted to enhance understanding of spread and variability in the disease as well as policy options for slowing the spread. Understanding mild cases could shed light on the disease in the longer term, including whether vaccines prevent contagiousness.

Seasonality in extra-pulmonary tuberculosis notifications in Germany 2004-2014- a time series analysis

BackgroundSeasonality in tuberculosis (TB) has been found in different parts of the world, showing a peak in spring/summer and a trough in autumn/winter. The evidence is less clear which factors drive seasonality. It was our aim to identify and evaluate seasonality in the notifications of TB in Germany, additionally investigating the possible variance of seasonality by disease site, sex and age group.MethodsWe conducted an integer-valued time series analysis using national surveillance data. We analysed the reported monthly numbers of started treatments between 2004 and 2014 for all notified TB cases and stratified by disease site, sex and age group.ResultsWe detected seasonality in the extra-pulmonary TB cases (N = 11,219), with peaks in late spring/summer and troughs in fall/winter. For all TB notifications together (N = 51,090) and for pulmonary TB only (N = 39,714) we did not find a distinct seasonality. Additional stratified analyses did not reveal any clear differences between age groups, the sexes, or between active and passive case finding.ConclusionWe found seasonality in extra-pulmonary TB only, indicating that seasonality of disease onset might be specific to the disease site. This could point towards differences in disease progression between the different clinical disease manifestations. Sex appears not to be an important driver of seasonality, whereas the role of age remains unclear as this could not be sufficiently investigated.

T-cell responses in domestic pigs and wild boar upon infection with the moderately virulent African swine fever virus strain 'Estonia2014'.

Infection with African swine fever virus (ASFV) causes a highly lethal haemorrhagic disease in domestic and Eurasian wild pigs. Thus, it is a major threat to pig populations worldwide and a cause of substantial economic losses. Recently, less virulent ASFV strains emerged naturally, which showed higher experimental virulence in wild boar than in domestic pigs. The reason for this difference in disease progression and outcome is unclear but likely involves different immunological responses. Unfortunately, besides the importance of CD8α+ lymphocytes, little is known about the immune responses against ASFV in suids. Against this background, we used a multicolour flow cytometry platform to investigate the T-cell responses in wild boar and domestic pigs after infection with the moderately virulent ASFV strain 'Estonia2014' in two independent trials. CD4- /CD8α+ and CD4+ /CD8α+ αβ T-cell frequencies increased in both subspecies in various tissues, but CD8α+ γδ T cells differentiated and responded in wild boar only. Proliferation in CD8α+ T cells was found 10days post infectionem only. Frequencies of T-bet+ T cells increased in wild boar but not in domestic pigs. Of note, we found a considerable loss of perforin expression in cytotoxic T cells, 5 and 7dpi. Both subspecies established a regulatory T-cell response 10dpi. In domestic pigs, we show increasing levels of ICOS+ and CD8α+ invariant Natural Killer T cells. These disparities in T-cell responses might explain some of the differences in disease progression in wild boar and domestic pigs and should pave the way for future studies.

Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).

376 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p&lt;0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P&lt;0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]

Sex differences in disease progression and arrhythmic risk in patients with arrhythmogenic cardiomyopathy

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Research Area Network on Cardiovascular Diseases (ERA-CVD) Background Arrhythmogenic cardiomyopathy (AC) is an inheritable heart disease characterized by high risk of life-threatening ventricular arrhythmia. Male sex has been reported as a risk factor of high disease penetrance and arrhythmia, but data on sex-specific phenotype in AC are sparse. Purpose To assess sex-specific disease progression in AC patients and structural cardiac changes at time of arrhythmic event. Methods We included consecutive AC patients in a longitudinal cohort study. We performed echocardiography at baseline according to Task Force Criteria of 2010 with additional parameters including strain. Patients were followed with repeated echocardiographic examinations. Ventricular arrhythmia was defined as aborted cardiac arrest, sustained ventricular tachycardia or appropriate therapy by an implantable cardioverter-defibrillator. In patients with documented first time ventricular arrhythmias, echocardiographic findings obtained ±30 days around the event was noted separately. Results We included 191 AC patients (46% female, 51% probands, age 41 ± 17 years) of which 88% had ≥2 echocardiographic examinations during 6.9 (IQR 4.7-9.8) years of follow up. Females and males had similar progression rate of right ventricular dimensions and left ventricular function, but right ventricular function decreased more in females (Figure). Arrhythmic events occurred in 85 (45%) patients and 39 patients had an echocardiographic examination at the time of their first event. There was no difference in right ventricular diameters or right or left ventricular function between females and males at the time of first arrhythmic event (right ventricular outflow tract diameter: 35 ± 7 mm vs. 39 ± 7 mm, p = 0.16, right ventricular fractional area change: 34 ± 9 % vs. 29 ± 11 %, p = 0.26, left ventricular global longitudinal strain: -18.8 ± 3.0 % vs. 17.2 ± 2.2 %, p = 0.12, respectively). Conclusion Disease progression was similar in male and female AC patients indicating no accelerated disease progression in males. First arrhythmic event occurred at similar cardiac dysfunction and diameters in both sexes indicating no lower risk in females. Abstract Figure.

Infection with HIV-1 subtype D adversely affects the live expectancy independently of antiretroviral drug use.

HIV-1 subtypes have been associated with less favourable clinical profiles, differences in disease progression and higher risk of neurocognitive deficit. In this study we aimed to analyse the long term survival disparities between patients infected with the most common HIV-1 variants observed in Poland. For the study data from 518 Caucasian non-immigrant patients of Polish origin infected with divergent HIV subtypes and variants [subtype A (n=35, 6.8%), subtype B (n=386, 74.5%), subtype C (n=13, 2.5%), subtype D (n=58, 11.19%) or other non-A,B,C,D (n=26, 5.01%)variants] were analysed. Subtyping was performed using the partial pol (reverse transcriptase and protease) sequencing. HIV variant was coupled with clinical, virologic and survival data censored at 20years of observation. Overall survival and on antiretroviral treatment survival was analysed using Kaplan-Meyer as well as unadjusted and multivariate Cox proportional hazards models. Significantly higher mortality was observed among subtype D (28.8%) infected subjects compared to subtype B (11.7%, p=0.0004). Increased risk of death among subtype D cases remained significant when cART treated individuals were analysed, with on-treatment mortality of 26.9% for subtype D (p=0.006) compared to 10.73% in subtype B infected cases. Kaplan-Meyer survival estimates differed significantly across all investigated HIV-1 variant groups when overall 20year mortality was analysed (log rank p=0.029), being non-significant for the cART treated group. In multivariate model of overall 20year survival, adjusted for age at diagnosis, gender, HCV and AIDS status, lymphocyte CD4 count, transmission route and HIV viral load, only age and subtype D were independently associated with higher likelihood of death [HR: 1.08 (95%CI: 1.03-1.14, p=0.002) and HR: 7.91 (95%CI:2.33-26.86), p<0.001, respectively]. In the on-treatment (cART) multivariate model of 20year survival adjusted for the same parameters only subtype D remained as the independent factor associated with higher mortality risk [HR: 4.24 (95%CI:1.31-13.7), p=0.02]. Subtype D has an independent deleterious effect of survival, even in the setting of antiretroviral treatment. Observed effect indicated higher clinical vigilance for patients infected with this subtype even after long time of stable antiretroviral treatment.

Interaction between Cowpea Aphid-Borne Mosaic Virus Isolates and Its Effect on Passion Fruit Woodiness Disease on Passiflora edulis Sims and Passiflora ligularis Juss

In East Africa, passion fruit woodiness disease is caused by potyviruses, among which are Cowpea Aphid-Borne Mosaic Virus (CABMV) and Uganda Passiflora Virus (UPV). Previous studies suggest that synergistic interaction of viruses causes mild or severe outcomes of the disease. However, mixed infections of these viruses have not been documented. The aim of this study was to determine the effects of the interaction between two CABMV isolates causing passion fruit woodiness disease in Kenya. Healthy plants were mechanically inoculated at six-leaf stage. Four treatments were used: CABMV isolate 1, CABMV isolate 2, mixture of the two isolates, and noninoculated control. The test plants were maintained in a screen house, and data on symptom severity and rate of disease development were recorded. ELISA test was conducted to confirm virus presence and distribution. The results indicate that the CABMV isolates used are systemic. There were various differences in disease progression, which was faster in the sweet passion variety than in the purple variety. However, the latter had a higher disease severity. Coinfected plants expressed severe symptoms compared to the singly infected ones, indicating synergistic interaction between the viral isolates. This implies that coinfection has adverse impact resulting in higher economic losses.

Sex differences of innate immune activation in amyloid positive predementia cases

AbstractBackgroundInnate immunity is linked to Alzheimer’s disease, as shown by genome‐wide association studies and experimental data. There is, however, a sexual dimorphism in the activation of the innate immune system. Here, we investigate sex‐differences in immune activation by comparing glial activation markers in CSF from males and females with amyloid pathology as compared to healthy controls.MethodA total of 110 CSF Aβ‐ healthy controls (n=52 males and n=58 females), and 121 CSF Aβ+ (n=70 males and n=51 females) non‐demented cases with cognitive symptoms from the Dementia Disease Initiation (DDI) cohort were included in the analyses. CSF levels of sTREM2, YKL‐40 and MCP‐1 were determined using Mesoscale Discovery. Amyloid pathology was determined using CSF Aβ1‐42 threshold of 708 pg/mL. CSF total tau was included in our models to investigate potential sex differences of active neurodegeneration. We compared CSF concentrations using three‐way ANCOVA with age as a covariate, investigating main effects, two‐way interaction effects between sex and CSF Aβ status and three‐way APOE‐ε4 interactions with sex and CSF Aβ.ResultSignificant interaction effects between sex and CSF Aβ status showed lower CSF YKL‐40 (p&lt;.001), sTREM2 (p&lt;.05) and MCP‐1 (p&lt;.0001) levels in Aβ+ women as compared to males. No differences in levels were found between male and female healthy controls. Furthermore, we found that only Aβ+ males had increased YKL‐40 (p&lt;.001), sTREM2 (p&lt;.05) and MCP‐1 (p&lt;.05) levels compared to healthy controls, whilst Aβ+ females showed no significant differences in levels. Men had slightly higher levels of CSF total tau as compared to women, however, this difference did not reach the threshold for statistical significance (p=.07). No main effects or interaction effects with APOE‐ε4 were found.ConclusionWe found consistent differences in innate immune activation in Aβ+ females, but not related to APOE‐ε4 genotype. However, a slight non‐significant increase in a CSF marker of neurodegeneration in men may in part contribute to the observed differences in immune activation in our sample. The low level of innate immune activation has yet to be linked to differences in disease progression.

Virulence mismatches in index hosts shape the outcomes of cross-species transmission

Whether a pathogen entering a new host species results in a single infection or in onward transmission, and potentially an outbreak, depends upon the progression of infection in the index case. Although index infections are rarely observable in nature, experimental inoculations of pathogens into novel host species provide a rich and largely unexploited data source for meta-analyses to identify the host and pathogen determinants of variability in infection outcomes. We analyzed the progressions of 514 experimental cross-species inoculations of rabies virus, a widespread zoonosis which in nature exhibits both dead-end infections and varying levels of sustained transmission in novel hosts. Inoculations originating from bats rather than carnivores, and from warmer- to cooler-bodied species caused infections with shorter incubation periods that were associated with diminished virus excretion. Inoculations between distantly related hosts tended to result in shorter clinical disease periods, which are also expected to impede onward transmission. All effects were modulated by infection dose. Taken together, these results suggest that as host species become more dissimilar, increased virulence might act as a limiting factor preventing onward transmission. These results can explain observed constraints on rabies virus host shifts, describe a previously unrecognized role of host body temperature, and provide a potential explanation for host shifts being less likely between genetically distant species. More generally, our study highlights meta-analyses of experimental infections as a tractable approach to quantify the complex interactions between virus, reservoir, and novel host that shape the outcome of cross-species transmission.

Cerebrospinal Fluid Mitochondrial DNA in Rapid and Slow Progressive Forms of Alzheimer's Disease.

Alzheimer’s type dementia (AD) exhibits clinical heterogeneity, as well as differences in disease progression, as a subset of patients with a clinical diagnosis of AD progresses more rapidly (rpAD) than the typical AD of slow progression (spAD). Previous findings indicate that low cerebrospinal fluid (CSF) content of cell-free mitochondrial DNA (cf-mtDNA) precedes clinical signs of AD. We have now investigated the relationship between cf-mtDNA and other biomarkers of AD to determine whether a particular biomarker profile underlies the different rates of AD progression. We measured the content of cf-mtDNA, beta-amyloid peptide 1–42 (Aβ), total tau protein (t-tau) and phosphorylated tau (p-tau) in the CSF from a cohort of 95 subjects consisting of 49 controls with a neurologic disorder without dementia, 30 patients with a clinical diagnosis of spAD and 16 patients with rpAD. We found that 37% of controls met at least one AD biomarker criteria, while 53% and 44% of subjects with spAD and rpAD, respectively, did not fulfill the two core AD biomarker criteria: high t-tau and low Aβ in CSF. In the whole cohort, patients with spAD, but not with rpAD, showed a statistically significant 44% decrease of cf-mtDNA in CSF compared to control. When the cohort included only subjects selected by Aβ and t-tau biomarker criteria, the spAD group showed a larger decrease of cf-mtDNA (69%), whereas in the rpAD group cf-mtDNA levels remained unaltered. In the whole cohort, the CSF levels of cf-mtDNA correlated positively with Aβ and negatively with p-tau. Moreover, the ratio between cf-mtDNA and p-tau increased the sensitivity and specificity of spAD diagnosis up to 93% and 94%, respectively, in the biomarker-selected cohort. These results show that the content of cf-mtDNA in CSF correlates with the earliest pathological markers of the disease, Aβ and p-tau, but not with the marker of neuronal damage t-tau. Moreover, these findings confirm that low CSF content of cf-mtDNA is a biomarker for the early detection of AD and support the hypothesis that low cf-mtDNA, together with low Aβ and high p-tau, constitute a distinctive CSF biomarker profile that differentiates spAD from other neurological disorders.

Revisiting early-stage COVID-19 strategy options

Background: Early-stage interventions in a potential pandemic are important to understand as they can make the difference between runaway exponential growth that is hard to turn back and stopping the spread before it gets that far. COVID19 is an interesting case study because there have been very different outcomes in different localities. These variations are best studied after the fact if precision is the goal; while a pandemic is still unfolding less precise analysis is of value in attempting to guide localities to learn lessons of those that preceded them. Methods: I examine three factors that could differentiate strategy: asymptomatic spread, differences in use of the Bacillus Calmette-Guerin (BCG) tuberculosis vaccine and cloth face masks. Results: Differences in disease progression as well as the possibility of alternative strategies to prevent COVID-19 from entering the runaway phase or damping it down later can be elucidated by a study of asymptomatic infection. A study to demonstrate not only what fraction are asymptomatic but how contagious they are will also inform policy on universal mask wearing. Conclusions: While a COVID-19 outbreak is at a level that makes accurate trace-and test possible, investigation of asymptomatic transmission is viable and should be attempted to enhance understanding of spread and variability in the disease as well as policy options for slowing the spread.

Isogenic models of hypertrophic cardiomyopathy unveil differential phenotypes and mechanism-driven therapeutics

BackgroundHypertrophic cardiomyopathy (HCM) is a prevalent and complex cardiovascular condition. Despite being strongly associated with genetic alterations, wide variation of disease penetrance, expressivity and hallmarks of progression complicate treatment. We aimed to characterize different human isogenic cellular models of HCM bearing patient-relevant mutations to clarify genetic causation and disease mechanisms, hence facilitating the development of effective therapeutics. MethodsWe directly compared the p.β-MHC-R453C and p.ACTC1-E99K HCM-associated mutations in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) and their healthy isogenic counterparts, generated using CRISPR/Cas9 genome editing technology. By harnessing several state-of-the-art HCM phenotyping techniques, these mutations were investigated to identify similarities and differences in disease progression and hypertrophic signaling pathways, towards establishing potential targets for pharmacological treatment. CRISPR/Cas9 knock-in of the genetically-encoded calcium indicator R-GECO1.0 to the AAVS1 locus into these disease models resulted in calcium reporter lines. ResultsConfocal line scan analysis identified calcium transient arrhythmias and intracellular calcium overload in both models. The use of optogenetics and 2D/3D contractility assays revealed opposing phenotypes in the two mutations. Gene expression analysis highlighted upregulation of CALM1, CASQ2 and CAMK2D, and downregulation of IRF8 in p.β-MHC-R453C mutants, whereas the opposite changes were detected in p.ACTC1-E99K mutants. Contrasting profiles of nuclear translocation of NFATc1 and MEF2 between the two HCM models suggest differential hypertrophic signaling pathway activation. Calcium transient abnormalities were rescued with combination of dantrolene and ranolazine, whilst mavacamten reduced the hyper-contractile phenotype of p.ACTC1-E99K hiPSC-CMs. ConclusionsOur data show that hypercontractility and molecular signaling within HCM are not uniform between different gene mutations, suggesting that a ‘one-size fits all’ treatment underestimates the complexity of the disease. Understanding where the similarities (arrhythmogenesis, bioenergetics) and differences (contractility, molecular profile) lie will allow development of therapeutics that are directed towards common mechanisms or tailored to each disease variant, hence providing effective patient-specific therapy.

Differences in clinical characteristics and outcomes between white (W) and non-white (NW) patients with metastatic germ cell tumor (mGCT) treated at Indiana University (IU).

e19053 Background: Patients (pts) with mGCT are curable even when presenting at advanced stages, however its incidence is rising in NW populations. There is lack of data evaluating differences in disease characteristics and outcomes between W and NW pts. Methods: 701 pts with mGCT treated at IU with first-line chemotherapy (FLC) and 462 patients with relapsed mGCT treated with HDCT (high-dose chemotherapy) between 2004 and 2017 at IU were evaluated. Results: Pts treated with FLC had a median follow-up since diagnosis of 4.9 (0.03-19.46) years. 660 (94.1%) W pts and 41 (5.9%) NW (49% Hispanic, 26% Asian, 20% African American and 5% Native American). There were no significant differences in median age at diagnosis, rates of primary tumor site, pathology type (seminoma vs non-seminoma), metastasis sites, mortality, median hCG levels pre-chemotherapy, rates of progression after FLC, or late relapse rates. Higher rates of good risk disease and lower rates of poor risk disease were present among W compared to NW, as well as higher median AFP levels pre-chemotherapy and rates of platinum refractory disease in NW (p &lt; 0.05). Patients treated with HDCT had a median follow up time of 2.08 (0.02-14.49) years since diagnosis. 412 (89.1%) were W and 50 (10.1%) were NW (48% Hispanic, 18% Asian, 26% African American, 2% Native American and 6% other). There were no significant differences in rates pathology type, disease risk, tumor markers, platinum refractory disease, completion of 2 cycles of HDCT, progression after HDCT or status at last follow up. W pts were more likely to receive HDCT as initial salvage chemotherapy compared to NW (P &lt; 0.05). Conclusions: This single-institution study demonstrates that amongst patients undergoing FLC for mGCT, there were higher rates of poor risk disease and platinum refractory disease amongst NW patients. W patients were more likely to receive HDCT as initial salvage chemotherapy compared to NW patients. However these findings did not reflect a significant difference in disease progression or mortality. [Table: see text]

Bilateral Acute Macular Neuroretinopathy in a Young Patient: Imaging and Visual Field during Two-Year-Follow-Up

Acute macular neuroretinopathy (AMN) is a rare disorder. We report a case of bilateral AMN in a young female patient, without any risk factors. She referred a positive scotoma in both eyes after flu-like symptoms. Fundus examination revealed parafoveal dark-reddish oval lesions in both eyes. Therefore, we performed visual field, optical coherence tomography (OCT), fluorescein angiography (FA) and indocyanine green angiography (ICG) at baseline and several times during the two years of follow-up. The infrared (IR) imaging showed one rounded hyporeflective lesion in the left eye and two similar lesions in the right eye. The OCT demonstrated the characteristic alterations in the outer retina. The visual field also demonstrated scotomas corresponding with these lesions. The OCT and IR features disappeared at the end of the follow-up except for the left eye, which continued to have hyperreflective spots in the outer plexiform layer. The patient complained about a residual scotoma only in the left eye after two years. Our case shows a difference in disease progression in the two eyes of the same patient, suggesting that several mechanisms can be implicated in the pathology of AMN.

CLINICAL CHARACTERISTICS AND NATURAL HISTORY OF RHO-ASSOCIATED RETINITIS PIGMENTOSA: A Long-Term Follow-Up Study.

To investigate the natural history of RHO-associated retinitis pigmentosa (RP). A multicenter, medical chart review of 100 patients with autosomal dominant RHO-associated RP. Based on visual fields, time-to-event analysis revealed median ages of 52 and 79 years to reach low vision (central visual field <20°) and blindness (central visual field <10°), respectively. For the best-corrected visual acuity (BCVA), the median age to reach mild impairment (20/67 ≤ BCVA < 20/40) was 72 years, whereas this could not be computed for lower acuities. Disease progression was significantly faster in patients with a generalized RP phenotype (n = 75; 75%) than that in patients with a sector RP phenotype (n = 25; 25%), in terms of decline rates of the BCVA (P < 0.001) and V4e retinal seeing areas (P < 0.005). The foveal thickness of the photoreceptor-retinal pigment epithelium (PR + RPE) complex correlated significantly with BCVA (Spearman's ρ = 0.733; P < 0.001). Based on central visual fields, the optimal window of intervention for RHO-associated RP is before the 5th decade of life. Significant differences in disease progression are present between generalized and sector RP phenotypes. Our findings suggest that the PR + RPE complex is a potential surrogate endpoint for the BCVA in future studies.

Pediatric Extrapolation in Type 2 Diabetes: Future Implications of a Workshop.

Extrapolation from adults to youth with type 2 diabetes (T2D) is challenged by differences in disease progression and manifestation. This manuscript presents the results of a mock‐team workshop focused on examining the typical team‐based decision process used to propose a pediatric development plan for T2D addressing the viability of extrapolation. The workshop was held at the American Society for Clinical Pharmacology and Therapeutics (ASCPT) in Orlando, Florida on March 21, 2018.

Integration Analysis of m6A-SNPs and eQTLs Associated With Sepsis Reveals Platelet Degranulation and Staphylococcus aureus Infection are Mediated by m6A mRNA Methylation.

Sepsis is a major threat with high mortality rate for critically ill patients. Response to pathogen infection by the host immune system is a key biological process involved in the onset and development of sepsis. Heterogeneous host genome variation, especially single nucleotide polymorphisms (SNPs), has long been suggested to contribute to differences in disease progression. However, the function of SNPs located in non-coding regions remains to be elucidated. Recently, m6A mRNA modification levels were revealed to differ at SNPs. As m6A is a crucial regulator of gene expression, these SNPs might control genes by changing the m6A level on mRNA. To investigate the potential role of m6A SNPs in sepsis, we integrated m6A-SNP and expression quantitative trait loci (eQTLs) data. Analysis revealed 15,720 m6A-cis-eQTLs and 381 m6A-trans-eQTLs associated with sepsis. We identified 1321 genes as locations of m6A-cis-eQTLs. These were enriched in platelet degranulation and Staphylococcus aureus infection pathways, which are vital for the pathophysiological process of sepsis. We conclude that m6A modification of mRNA plays a very important role in sepsis, with m6A-cis-eQTLs potentially having the most effect on individual variation in sepsis progression.