Genetic predisposition in acute leukaemia

A small but important proportion of patients with myelodysplasia (MDS) and acute leukaemia (AL) have underlying germline mutations in leukaemia susceptibility genes. The majority of these variants predispose to myeloid neoplasms with a smaller number associated with acute lymphoblastic leukaemia (ALL). The 2016 revision of the WHO classification of tumours of haematopoietic and lymphoid tissues has defined a number of myeloid neoplasms with germline predisposition (Blood, 127 , 2016, 2391) alerting clinicians to the importance of this underlying diagnosis. Advances in genetic technology and access to testing will undoubtably result in increased numbers of patients and families with leukaemia predisposition syndromes being identified. Here we summarize the salient biology and genetic and clinical features of a number of these conditions including some more recently described genetic variants.     

Nondisease-Specific Problems and All-Cause Mortality among Older Adults with CKD: The REGARDS Study

Background and objectives

The term “nondisease-specific” has been used to describe problems that cross multiple domains of health and are not necessarily the result of a single underlying disease. Although individuals with reduced eGFR and elevated albumin-to-creatinine ratio have many comorbidities, the prevalence of and outcomes associated with nondisease-specific problems have not been well studied.

Design, setting, participants, & measurements

Participants included 3557 black and white United States adults ≥75 years of age from the Reasons for Geographic and Racial Differences in Stroke Study. Nondisease-specific problems included cognitive impairment, depressive symptoms, exhaustion, falls, impaired mobility, and polypharmacy. Hazard ratios for mortality over a median (interquartile range) of 5.4 (4.2–6.9) years of follow-up associated with one, two, or three to six nondisease-specific problems were calculated and stratified by eGFR (≥60, 45–59, and <45 ml/min per 1.73 m²) and separately, albumin-to-creatinine ratio (<30, 30–299, and ≥300 mg/g). Secondary outcomes included hospitalizations and emergency department visits over 1.8 (0.7–4.0) and 2.3 (0.9–4.7) years of follow-up, respectively.

Results

The prevalence of nondisease-specific problems was more common at lower eGFR and higher albumin-to-creatinine ratio levels. Within each eGFR and albumin-to-creatinine ratio strata, the risk for mortality was higher among those with a greater number of nondisease-specific problems. For example, among those with an eGFR=45–59 ml/min per 1.73 m², the multivariable adjusted hazard ratios (95% confidence intervals) for mortality associated with one, two, or three to six nondisease-specific problems were 1.17 (0.78 to 1.76), 1.95 (1.24 to 3.07), and 2.44 (1.39 to 4.27; P trend <0.001). Risk for hospitalization and emergency department visits was higher among those with more nondisease-specific problems within eGFR and albumin-to-creatinine ratio strata.

Conclusions

Among older adults, nondisease-specific problems commonly co-occur with reduced eGFR and elevated albumin-to-creatinine ratio. Identification of nondisease-specific problems may provide mortality risk information independent of measures of kidney function.     

A randomized clinical trial of an interactive voice response and text message intervention for individuals with hypertension

Interactive voice response and text message (IVR‐T) technology may improve hypertension control in under‐resourced settings. We conducted a randomized clinical trial to determine whether an IVR‐T intervention would improve blood pressure (BP), medication adherence and visit keeping among adults with hypertension from multiple racial and ethnic groups in primary care at an Urban Indian Health Organization in Albuquerque, New Mexico. Two hundred and ninety‐five participants were randomly assigned to IVR‐T (N = 148) or to usual care (N = 147). The IVR‐T arm received reminders for clinic visits, messages to reschedule missed clinic visits, monthly medication refill reminders, weekly motivational messages, and a blood pressure cuff. The usual care arm received no messages. The primary outcome was change in systolic BP (SBP) between baseline and 12 months. Secondary outcomes included change in SBP between baseline and 6 months, change in diastolic BP (DBP) at 6 and 12 months, self‐reported adherence at 6 months, and the proportion of missed primary care clinic appointments. The intervention did not affect SBP or DBP at 6 or 12 months. The 12‐month change in SBP/DBP was 1.66/1.10 mm Hg in usual care and 0.23/1.34 mm Hg in the intervention group (P values = .57 and .88, respectively). Self‐reported medication adherence improved comparably in both groups, and there was no difference in percentage of kept visits. Several features of study design, clinic operations, and data transfer were barriers to demonstrating effectiveness.     

“Not Just Right Experiences” in Adolescents: Phenomenology and Associated Characteristics

Efforts to understand the nature of “Not Just Right Experiences” (NJREs) have expanded the scientific understanding of obsessive–compulsive (OC) behavior. Approximately 80 % of unselected adults report experiencing NJREs and these experiences have been found to highly correlate with OC behavior. The purpose of this study was to assess NJREs in an unselected sample of adolescents (ages 14–17; N = 152), to compare their experience with adults (N = 237), and to assess the relation between NJREs and OC symptoms. Findings from questionnaires completed on the Internet were consistent with previous findings in adults, 81 % of adolescents endorsed recently having an NJRE. Some reactions differed according to age: adults reported NJREs as more frequent and adolescents endorsed feeling more compelled to respond. Surprisingly, OC symptoms were not significantly related to NJREs in the adolescents. Implications, limitations, and future directions for the study of NJREs in youth are discussed.     

A Retrospective Quasi-Experimental Study of a Transitional Housing Program for Patients with Severe and Persistent Mental Illness

Transitional housing programs aim to improve living skills and housing stability for tenuously housed patients with mental illness. 113 consecutive Transitional Housing Team (THT) patients were matched to 139 controls on diagnosis, time of presentation, gender and prior psychiatric hospitalisation and compared using a difference-in-difference analysis for illness acuity and service use outcomes measured 1 year before and after THT entry/exit. There was a statistically significant difference-in-difference favouring THT participants for bed days (mean difference in difference ?20.76 days, SE 9.59, p = 0.031) and living conditions (HoNOS Q11 mean difference in difference ?0.93, SE 0.23, p < 0.001). THT cost less per participant (I$14,024) than the bed-days averted (I$17,348). The findings of reductions in bed days and improved living conditions suggest that transitional housing programs can have a significant positive impact for tenuously housed patients with high inpatient service usage, as well as saving costs for mental health services.     

Contribution of voltage-dependent K⁺ channels to metabolic control of coronary blood flow

The purpose of this investigation was to test the hypothesis that K(V) channels contribute to metabolic control of coronary blood flow and that decreases in K(V) channel function and/or expression significantly attenuate myocardial oxygen supply-demand balance in the metabolic syndrome (MetS). Experiments were conducted in conscious, chronically instrumented Ossabaw swine fed either a normal maintenance diet or an excess calorie atherogenic diet that produces the clinical phenotype of early MetS. Data were obtained under resting conditions and during graded treadmill exercise before and after inhibition of K(V) channels with 4-aminopyridine (4-AP, 0.3mg/kg, iv). In lean-control swine, 4-AP reduced coronary blood flow ~15% at rest and ~20% during exercise. Inhibition of K(V) channels also increased aortic pressure (P<0.01) while reducing coronary venous PO(2) (P<0.01) at a given level of myocardial oxygen consumption (MVO(2)). Administration of 4-AP had no effect on coronary blood flow, aortic pressure, or coronary venous PO(2) in swine with MetS. The lack of response to 4-AP in MetS swine was associated with a ~20% reduction in coronary K(V) current (P<0.01) and decreased expression of K(V)1.5 channels in coronary arteries (P<0.01). Together, these data demonstrate that K(V) channels play an important role in balancing myocardial oxygen delivery with metabolism at rest and during exercise-induced increases in MVO(2). Our findings also indicate that decreases in K(V) channel current and expression contribute to impaired control of coronary blood flow in the MetS. This article is part of a Special Issue entitled "Coronary Blood Flow".     

A compact fiber-optic SHG scanning endomicroscope and its application to visualize cervical remodeling during pregnancy

We report the development of an all-fiber-optic scanning endomicroscope capable of high-resolution second harmonic generation (SHG) imaging of biological tissues and demonstrate its utility for monitoring the remodeling of cervical collagen during gestation in mice. The endomicroscope has an overall 2.0 mm diameter and consists of a single customized double-clad fiber, a compact rapid two-dimensional beam scanner, and a miniature compound objective lens for excitation beam delivery, scanning, focusing, and efficient SHG signal collection. Endomicroscopic SHG images of murine cervical tissue sections at different stages of normal pregnancy reveal progressive, quantifiable changes in cervical collagen morphology with resolution similar to that of bench-top SHG microscopy. SHG endomicroscopic imaging of ex vivo murine and human cervical tissues through intact epithelium has also been performed. Our findings demonstrate the feasibility of SHG endomicroscopy technology for staging normal pregnancy, and suggest its potential application as a minimally invasive tool for clinical assessment of abnormal cervical remodeling associated with preterm birth.