The contribution of genotypes at the MEFV and SAA1 loci to amyloidosis and disease severity in patients with familial Mediterranean fever

OBJECTIVE: The clinical profile in familial Mediterranean fever (FMF), including its major manifestation, amyloidosis, is influenced by MEFV allelic heterogeneity and other genetic and/or environmental factors. In this study, we analyzed the contribution of genotypes at the MEFV and SAA1 loci to disease severity and to the development of amyloidosis, and further defined the factors affecting the clinical profile of FMF. METHODS: We investigated a sample of 277 FMF patients (154 men and 123 women), including 62 patients with nephropathic amyloidosis, in whom both FMF alleles had been identified. A detailed chart review, interview, and physical examination were undertaken to determine the patients' demographic characteristics, medical history, clinical manifestations, and treatment. The disease severity score was calculated from the Tel-Hashomer key. Genotypes at the SAA1 locus (isoforms alpha, beta, and gamma) were determined in all patients. The SAA1 13C/T polymorphism of the SAA1 promotor was analyzed in a subset of cases. RESULTS: The male:female ratio (154:123, or 1.3) was higher among patients with amyloidosis (40:22, or 1.8) compared with patients without amyloidosis (114:101, or 1.1). Logistic regression analysis showed that homozygosity for the M694V allele (odds ratio [OR] 4.27, 95% confidence interval [95% CI] 2.01-9.07), the presence of the SAAalpha/alpha genotype (OR 2.99, 95% CI 1.47-6.09), the occurrence of arthritis attacks (OR 2.43, 95% CI 1.17-5.06), and male sex (OR 1.73, 95% CI 0.90-3.33) were significantly and independently associated with renal amyloidosis. Disease severity was mainly influenced by MEFV mutations and was not associated with genotypes at the SAA1 locus. The SAA1 13T allele was rare, being associated mainly with the SAA gamma isoform, and not related to renal amyloidosis. CONCLUSION: Overall, disease severity and the development of amyloidosis in FMF are differentially affected by genetic variations within and outside the MEFV gene.     

Measuring Emergency Care Survival: The Implications of Risk Adjusting for Race and Poverty

Objectives

We determined the impact of including race, ethnicity, and poverty in risk adjustment models for emergency care–sensitive conditions mortality that could be used for hospital pay‐for‐performance initiatives. We hypothesized that adjusting for race, ethnicity, and poverty would bolster rankings for hospitals that cared for a disproportionate share of nonwhite, Hispanic, or poor patients.

Methods

We performed a cross‐sectional analysis of patients admitted from the emergency department to 157 hospitals in Pennsylvania with trauma, sepsis, stroke, cardiac arrest, and ST‐elevation myocardial infarction. We used multivariable logistic regression models to predict in‐hospital mortality. We determined the predictive accuracy of adding patient race and ethnicity (dichotomized as non‐Hispanic white vs. all other Hispanic or nonwhite patients) and poverty (uninsured, on Medicaid, or lowest income quartile zip code vs. all others) to other patient‐level covariates. We then ranked each hospital on observed‐to‐expected mortality, with and without race, ethnicity, and poverty in the model, and examined characteristics of hospitals with large changes between models.

Results

The overall mortality rate among 170,750 inpatients was 6.9%. Mortality was significantly higher for nonwhite and Hispanic patients (adjusted odds ratio [aOR] = 1.27, 95% confidence interval [CI] = 1.19–1.36) and poor patients (aOR = 1.21, 95% CI = 1.12–1.31). Adding race, ethnicity, and poverty to the risk adjustment model resulted in a small increase in C‐statistic (0.8260 to 0.8265, p = 0.002). No hospitals moved into or out of the highest‐performing decile when adjustment for race, ethnicity, and poverty was added, but the three hospitals that moved out of the lowest‐performing decile, relative to other hospitals, had significantly more nonwhite and Hispanic patients (68% vs. 11%, p < 0.001) and poor patients (56% vs. 10%, p < 0.001).

Conclusions

Sociodemographic risk adjustment of emergency care–sensitive mortality improves apparent performance of some hospitals treating a large number of nonwhite, Hispanic, or poor patients. This may help these hospitals avoid financial penalties in pay‐for‐performance programs.

     

Anticoagulation in patients with atrial fibrillation,thrombocytopenia and hematological malignancy

Journal of Thrombosis and Thrombolysis - Managing anticoagulation in hematological malignancy patients with atrial fibrillation and thrombocytopenia is a clinical challenge with limited data. We...     

Identification of BRaf-Sparing Amino-Thienopyrimidines with Potent IRE1α Inhibitory Activity

Amino-quinazoline BRaf kinase inhibitor 2 was identified from a library screen as a modest inhibitor of the unfolded protein response (UPR) regulating potential anticancer target IRE1α. A combination of crystallographic and conformational considerations were used to guide structure-based attenuation of BRaf activity and optimization of IRE1α potency. Quinazoline 6-position modifications were found to provide up to 100-fold improvement in IRE1α cellular potency but were ineffective at reducing BRaf activity. A salt bridge contact with Glu651 in IRE1α was then targeted to build in selectivity over BRaf which instead possesses a histidine in this position (His539). Torsional angle analysis revealed that the quinazoline hinge binder core was ill-suited to accommodate the required conformation to effectively reach Glu651, prompting a change to the thienopyrimidine hinge binder. Resulting analogues such as 25 demonstrated good IRE1α cellular potency and imparted more than 1000-fold decrease in BRaf activity.     

Perspectives of Ketamine Use in COVID-19 Patients

Hospitalized coronavirus disease 2019 (COVID-19)-infected patients suffer from both physical impairments and mental stress. Respiratory insufficiency and cardiovascular disturbances require most of the intensive care interventions, but they are also accompanied by depressive conditions, sadness and fear of dying. Sedatives are mostly respiratory and cardiovascular depressants and do not provide resistance to the pro-inflammatory burst induced by the virus. Ketamine is a unique and safe drug that enables well-controlled sedation and anesthesia, attenuates depression and mitigates suicidal thoughts, without depressing respiratory or cardiovascular mechanics. This brief communication highlights the benefits potentially provided by ketamine to patients hospitalized for COVID-19 infection.     

Chronic Pain and Premature Aging – The Moderating Role of Physical Exercise

Chronic pain induces a multitude of harmful effects; recently it has been suggested that chronic pain is also associated with premature aging, manifested in shortened telomere length (TL). However, evidence for this hypothesis is scarce and inconsistent. The aim was twofold: 1) Investigate whether chronic pain is associated with premature aging, and 2) Determine whether physical exercise (PE) moderates this association if it exists. Participants were 116 male subjects, with (n = 67) and without chronic pain (n = 49). Blood samples for TL analysis were collected and participants were interviewed and completed questionnaires. As a part of the cohort, we included people with physical disability; this variable was controlled in the analysis. The TL of individuals with chronic pain was significantly shorter than that of pain-free individuals. Regression analysis revealed a significant moderating effect of PE on chronic pain and TL, above and beyond the effects of disability, age, and weight. Whereas chronic pain was associated with shorter telomeres in participants who did not exercise, this association was nonsignificant among participants who did exercise. The results suggest that chronic pain is associated with premature ageing; however, PE may mitigate this association and may protect individuals against the harmful effects of chronic pain.PerspectiveThe study suggests that it is important to monitor signs of premature ageing among chronic pain patients as they are at risk. However, chronic pain patients may benefit from regular PE in this respect as it may moderate premature ageing.     

Initial experience of videocapsule endoscopy for diagnosing small-bowel tumors in patients with GI polyposis syndromes

BACKGROUND: Small-bowel tumors frequently occur in familial adenomatous polyposis and other GI polyposis syndromes. These tumors are difficult to detect with conventional techniques. Our aim was to assess the utility of videocapsule endoscopy in the detection of small-bowel tumors in this setting. METHODS: We examined 19 familial adenomatous polyposis patients and 3 patients with either Peutz-Jeghers syndrome, hyperplastic polyposis, or Cowden disease. OBSERVATIONS: Prevalence of small-bowel polyps on videocapsule endoscopy was 59% in all patients, 52.6% in familial adenomatous polyposis patients, and 75% in a subgroup of familial adenomatous polyposis patients with exon 15 mutations. Videocapsule endoscopy was safe and well tolerated in all patients. CONCLUSIONS: Videocapsule endoscopy has a high yield in detecting small-bowel tumors in patients with GI polyposis syndromes. It may be especially indicated in familial adenomatous polyposis patients with the aggressive phenotype of the disease, e.g., mutations in exon 15.     

Radiotherapy for head and neck cancer in nonagenarian patients: a possible cornerstone?

European Archives of Oto-Rhino-Laryngology - In the field of radiotherapy, there is very little scientific data on the management of nonagenarians, especially in patients aged 90&nbsp;years or...     

A Novel Non-Invasive Adjuvant Biomechanical Treatment for Patients with Altered Rehabilitation after Total Knee Arthroplasty: Results of a Pilot Investigation

Background

Many factors contribute to suboptimal results after total knee arthroplasty (TKA) but little is known regarding the value of postsurgical rehabilitation after TKA. We examined the effects of an enhanced closed kinematic chain exercises program (AposTherapy) on gait patterns and clinical outcomes among patients with a lack of progress in their postsurgical rehabilitation.

Methods

Twenty-two patients were prospectively followed during the study. Gait spatiotemporal parameters were measured at the initial evaluation, after 15 minutes of therapy, and after 3 months of therapy. The Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the short form (SF) 36 health survey were completed by patients before treatment and after 3 months of treatment.

Results

The WOMAC and SF-36 scores improved significantly after 3 months of treatment. Gait velocity, single limb support, and step length of the operated leg improved significantly even after a single 15 minutes treatment. Normal gait velocity was observed in 36% of patients after 3 months of treatment.

Conclusions

A physiotherapy program that included enhanced closed kinematic chain biomechanical therapy was beneficial for patients who experienced a suboptimal rehabilitation course after TKA.