Plasma circulating microRNAs associated with blood-based immune markers: a population-based study.

MicroRNAs (miRNAs) are small non-coding RNAs that post-transcriptionally regulate gene expression and different immune-related pathways. There is a great interest in identifying miRNAs involved in immune cell development and function to elucidate the biological mechanisms underlying the immune system, its regulation, and disease. In this study, we aimed to investigate the association of circulating miRNAs with blood cell compositions and blood-based immune markers. Circulating levels of 2083 miRNAs were measured by RNA-sequencing in plasma samples of 1999 participants from the population-based Rotterdam Study collected between 2002 and 2005. Full blood count measurements were performed for absolute granulocyte, platelet, lymphocyte, monocyte, white, and red blood cell counts. Multivariate analyses were performed to test the association of miRNAs with blood cell compositions and immune markers. We evaluated the overlap between predicted target genes of candidate miRNAs associated with immune markers and genes determining the blood immune response markers. First, principal component regression analysis showed that plasma levels of circulating miRNAs were significantly associated with red blood cell, granulocyte, and lymphocyte counts. Second, the cross-sectional analysis identified 210 miRNAs significantly associated (P < 2.82 × 10-5) with neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and systemic immune-inflammation index. Further genetic look-ups showed that target genes of seven identified miRNAs (miR-1233-3p, miR-149-3p, miR-150-5p, miR-342-3p, miR-34b-3p, miR-4644, and miR-7106-5p) were also previously linked to NLR and PLR markers. Collectively, our study suggests several circulating miRNAs that regulate the innate and adaptive immune systems, providing insight into the pathogenesis of miRNAs in immune-related diseases and paving the way for future clinical applications.

Developmental Dysplasia of the Hip Is Not Associated with Breech Presentation in Preterm Infants.

OBJECTIVES: The aim of the study is to (1) determine the incidence of developmental dysplasia of the hip (DDH) in preterm infants born prior to 35 completed weeks' gestation in a breech presentation, and (2) evaluate if the association between breech presentation and DDH in full-term infants holds for premature infants. STUDY DESIGN: This study design comprises retrospective review of infants born between January 1, 2008, and December 31, 2017, at <35 weeks' gestation and admitted to the NICU. Infants had hip ultrasounds at 4 to 6 weeks' corrected age if they were born in a breech presentation with a stable hip examination. We excluded infants born in a presentation other than breech or vertex, had no documentation of presentation at birth, or if they died within the first year. RESULTS: We included 1,533 infants. Preterm infants <35 weeks' gestation born in the breech versus vertex position had an incidence of DDH of 0.47% (2/428) and 0.36% (4/1,105), respectively. There was no significant difference in the incidence of DDH between infants born in the breech versus vertex position (Chi-square and Fisher's exact tests). The sensitivity, specificity, and positive and negative predictive values of breech presentation in detecting DDH were 33, 72, 0.47, and 99.6%, respectively. CONCLUSION: There is no association between breech presentation and DDH in preterm infants <35 weeks' gestation. Obtaining hip ultrasounds on preterm infants <35 weeks' gestation born in the breech presentation with a normal hip examination is not recommended. KEY POINTS: · Breech position is a risk factor for DDH in term newborns.. · Preterm infants are often in the breech position until 37 weeks' gestation.. · This study shows that breech presentation is not a risk factor for DDH in preterm infants..

Reproductive genetic screening for information: evolving paradigms?

Reproductive genetic screening has introduced the possibility for pregnant women to learn, during the pregnancy or sometimes earlier, about the likelihood of their baby being affected with certain genetic conditions. As medicine progresses, the options afforded by this early information have expanded. This has led to a shifting paradigm in prenatal screening, wherein the early knowledge is seen as useful not solely for its inherent value to the pregnant woman, but also as enabling an expansion of conditions whose identification may allow early intervention and clinical impact. This article discusses this paradigm against the backdrop of prenatal genetic screening that is available today.

Blunt traumatic brachial plexus injuries in a northern rural US setting: increased likelihood in unshielded motor-powered crashes.

BACKGROUND: Blunt traumatic brachial plexus injuries (BTBPI) are severe peripheral nerve injuries which present in a small portion of trauma patients but can result in long-term neurological disability and severe chronic pain. OBJECTIVE: The goal of this study was to describe the epidemiology of BTBPI in a northern rural setting caused by motor-powered collisions, and to determine the relative risk of these injuries in shielded (cars, trucks, vans, and so on) and unshielded vehicles (snowmobiles, all-terrain vehicles and motorcycles). METHODS: This retrospective study describes the epidemiology of BTBPI caused by motor-powered collisions and treated at two level II trauma centers in northeast Minnesota and determines the relative risk of these injuries in shielded (cars, trucks, vans, and so on) and unshielded vehicles (snowmobiles, all-terrain vehicles and motorcycles). We hypothesized unshielded motor vehicle crashes in rural areas are at an increased risk of incurring BTBPI. RESULTS: Out of all injuries resulting from motor-powered collisions in a 20-year period (9951), BTBPIs were found in 63 trauma patients, a prevalence of 0.6%. The rate of BTBPI involving unshielded vehicles (1.0%) was significantly higher than those involving a shielded vehicle (0.4%) and primarily occurred in rural areas (70%). CONCLUSIONS: Unshielded vehicle crashes, particularly snowmobiles, have the highest risk for BTBPI in our rural region. The overall incidence of these injuries appears to be declining. LEVEL OF EVIDENCE: Level III.

Creating a Rural Surgery Track and a Review of Rural Surgery Training Programs.

OBJECTIVE: The objective of this study was to present the process of developing a rural surgery training track within an established residency program and review the current rural surgery training programs in the nation. DESIGN: This study reviews current rural surgery training opportunities at Accreditation Council for Graduate Medical Education accredited surgical residencies in the United States and presents the process of creating the University of Minnesota's rural surgery training track. SETTING: This study was performed at the University of Minnesota, in Minneapolis, Minnesota, and at Essentia Health-Saint Mary's Medical Center, in Duluth, Minnesota. PARTICIPANTS: Accredited general surgery residencies were reviewed. The creation of a designated rural surgery training track added an additional rural-designated surgical resident during each postgraduation year and created a required postgraduation year 2 rural surgery rotation for all categorical surgical residents. RESULTS: Two hundred sixty-eight surgery residency programs were reviewed. Twenty-seven had required rural rotations, 10 offered only elective rural rotations, and 4 had dedicated National Resident Matching Program codes for rural training tracks. After review of national rural surgery training opportunities, the University of Minnesota's process of creating a designated rural surgery training program required attention to 5 main components: needs assessment and review of local opportunities, surgery residency review committee approval, funding, surgical education, and clinical/operative education. CONCLUSIONS: Increasing opportunities for surgical residents to train in rural settings may help with recruitment of medical students and retention of surgeons pursuing careers in rural surgery.

Static cerebrovascular pressure autoregulation remains intact during deep hypothermia.

BACKGROUND: Clinical studies measuring cerebral blood flow in infants during deep hypothermia have demonstrated diminished cerebrovascular pressure autoregulation. The coexistence of hypotension in these cohorts confounds the conclusion that deep hypothermia impairs cerebrovascular pressure autoregulation. AIM: We sought to compare the lower limit of autoregulation and the static rate of autoregulation between normothermic and hypothermic piglets. METHODS: Twenty anesthetized neonatal piglets (5-7 days old; 10 normothermic and 10 hypothermic to 20°C) had continuous measurements of cortical red cell flux using laser Doppler flowmetry, while hemorrhagic hypotension was induced without cardiopulmonary bypass. Lower limit of autoregulation was determined for each subject using piecewise regression and SRoR was determined above and below each lower limit of autoregulation as (%change cerebrovascular resistance/%change cerebral perfusion pressure). RESULTS: The estimated difference in lower limit of autoregulation was 1.4 mm Hg (lower in the hypothermic piglets; 95% C.I. -10 to 14 mm Hg; P=0.6). The median lower limit of autoregulation in the normothermic group was 39 mm Hg [IQR 38-51] vs 35 mm Hg [31-50] in the hypothermic group. Intact steady-state pressure autoregulation was defined as static rate of autoregulation >0.5 and was demonstrated in all normothermic subjects (static rate of autoregulation=0.72 [0.65-0.87]) and in 9/10 of the hypothermic subjects (static rate of autoregulation=0.65 [0.52-0.87]). This difference in static rate of autoregulation of 0.06 (95% C.I. -0.3 to 0.1) was not significant (P=0.4). CONCLUSION: Intact steady-state cerebrovascular pressure autoregulation is demonstrated in a swine model of profound hypothermia. Lower limit of autoregulation and static rate of autoregulation were similar in hypothermic and normothermic subjects.

Critical points for an accurate human genome analysis.

Next-generation sequencing is radically changing how DNA diagnostic laboratories operate. What started as a single-gene profession is now developing into gene panel sequencing and whole-exome and whole-genome sequencing (WES/WGS) analyses. With further advances in sequencing technology and concomitant price reductions, WGS will soon become the standard and be routinely offered. Here, we focus on the critical steps involved in performing WGS, with a particular emphasis on points where WGS differs from WES, the important variables that should be taken into account, and the quality control measures that can be taken to monitor the process. The points discussed here, combined with recent publications on guidelines for reporting variants, will facilitate the routine implementation of WGS into a diagnostic setting.

Known unknowns: building an ethics of uncertainty into genomic medicine.

BACKGROUND: Genomic testing has reached the point where, technically at least, it can be cheaper to undertake panel-, exome- or whole genome testing than it is to sequence a single gene. An attribute of these approaches is that information gleaned will often have uncertain significance. In addition to the challenges this presents for pre-test counseling and informed consent, a further consideration emerges over how - ethically - we should conceive of and respond to this uncertainty. To date, the ethical aspects of uncertainty in genomics have remained under-explored. DISCUSSION: In this paper, we draft a conceptual and ethical response to the question of how to conceive of and respond to uncertainty in genomic medicine. After introducing the problem, we articulate a concept of 'genomic uncertainty'. Drawing on this, together with exemplar clinical cases and related empirical literature, we then critique the presumption that uncertainty is always problematic and something to be avoided, or eradicated. We conclude by outlining an 'ethics of genomic uncertainty'; describing how we might handle uncertainty in genomic medicine. This involves fostering resilience, welfare, autonomy and solidarity. CONCLUSIONS: Uncertainty will be an inherent aspect of clinical practice in genomics for some time to come. Genomic testing should not be offered with the explicit aim to reduce uncertainty. Rather, uncertainty should be appraised, adapted to and communicated about as part of the process of offering and providing genomic information.

Dermatomyositis presenting as a paraneoplastic syndrome with resolution of symptoms following surgical management of underlying breast malignancy.

Breast cancer is the most common cancer in women in the USA, with the lifetime incidence of 1 in 8 women. Dermatomyositis (DM) is an uncommon idiopathic inflammatory myopathy that can manifest as a paraneoplastic syndrome of an underlying malignancy. Here, we report a case of a patient who presented with breast cancer and DM symptoms. The patient's rash and muscle weakness progressed during the workup of her breast cancer, while she was already started on medical treatment of these symptoms with oral prednisone. Her cutaneous and musculoskeletal improved dramatically following the treatment of her breast cancer. Our case report describes the rapid progression and regression of her symptoms emphasizing the benefit of early diagnosis and treatment of DM as well as the underlying breast cancer.

Distal 10q monosomy: new evidence for a neurobehavioral condition?

Pure distal monosomy of the long arm of chromosome 10 is a rare cytogenetic abnormality. The location and size of the deletions described in this region are variable. Nevertheless, the patients share characteristic facial appearance, variable cognitive impairment and neurobehavioral manifestations. A Minimal Critical Region corresponding to a 600 kb Smallest Region of deletion Overlap (SRO) has been proposed. In this report, we describe four patients with a distal 10q26 deletion, who displayed attention-deficit/hyperactivity disorders (ADHD). One of them had a marked behavioral profile and relatively preserved cognitive functions. Interestingly, the SRO was not included in the deleted segment of this patient suggesting that this deletion could contain candidate genes involved in the control of neurobehavioral functions. One of these candidates was the CALY gene, known for its association with ADHD patients and whose expression level was shown to be correlated with neurobehavioral disturbances in varying animal models. This report emphasizes the importance of the behavioral problems as a cardinal feature of the 10q microdeletion syndrome. Haploinsufficiency of CALY could play a crucial role in the development of the behavioral troubles within these patients.

Symmetrical enchondromatosis is associated with duplication of 12p11.23 to 12p11.22 including PTHLH.

We describe a patient with striking generalized symmetrical enchondromatosis of the tubular bones and a de novo duplication of chromosome 12p11.23 to 12p11.22. The PTHLH gene within this region encodes a ligand for PTHR1: mutations in the gene encoding this receptor are associated with some cases of Ollier disease, several skeletal dysplasias including Blomstrand, Eiken, and Jansen and down-regulation of PTHLH expression in brachydactyly type E. Our findings suggest that abnormal PTHLH-PTHR1 signaling may underly this unusual form of enchondromatosis and indicate that unlike most cases of Ollier disease it is dominantly inherited.

Childhood genetic testing for familial cancer: should adoption make a difference?

Professional guidelines and practice in clinical genetics generally counsel against predictive genetic testing in childhood. A genetic test should not be performed in a child who is too young to choose it for himself unless that test is diagnostic, will lead to an intervention to prevent illness, or enable screening. It is therefore generally considered unacceptable to test young children for adult-onset cancer syndromes. However, these guidelines are challenged when clinical genetics services receive requests from adoption agencies or pre-adoptive parents for predictive genetic tests in children being placed for adoption. Testing will foreclose a pre-adoptive child's future autonomous right to choose, yet those commissioning these tests argue that adoption should form a special case. In this paper, we argue that predictive genetic testing as part of a pre-adoptive 'work-up' should be discouraged when the same test would not generally be carried out in a child who is not being adopted. We present an argument based on a principle of consistency and question those claims that privilege the adoptive process, whilst acknowledging the array of uncertainties faced by pre-adoptive parents. We suggest that if pre-adoptive testing is considered, this should only take place after prospective adoptive parents have had the opportunity to meet the clinical genetics team and fully understand the implications of the testing process.