Regional Variation in the Tumor Microenvironment, Immune Escape and Prognostic Factors in Breast Cancer in Sub-Saharan Africa.

The low overall survival rates of patients with breast cancer in sub-Saharan Africa (SSA) are driven by regionally differing tumor biology, advanced tumor stages at diagnosis, and limited access to therapy. However, it is not known whether regional differences in the composition of the tumor microenvironment (TME) exist and affect patients' prognosis. In this international, multicentre cohort study, 1,237 formalin-fixed, paraffin-embedded breast cancer samples, including samples of the "African Breast Cancer-Disparities in Outcomes (ABC-DO) Study," were analyzed. The immune cell phenotypes, their spatial distribution in the TME, and immune escape mechanisms of breast cancer samples from SSA and Germany (n = 117) were investigated using histomorphology, conventional and multiplex IHC, and RNA expression analysis. The data revealed no regional differences in the number of tumor-infiltrating lymphocytes (TIL) in the 1,237 SSA breast cancer samples, while the distribution of TILs in different breast cancer IHC subtypes showed regional diversity, particularly when compared with German samples. Higher TIL densities were associated with better survival in the SSA cohort (n = 400), but regional differences concerning the predictive value of TILs existed. High numbers of CD163+ macrophages and CD3+CD8+ T cells accompanied by reduced cytotoxicity, altered IL10 and IFNγ levels and downregulation of MHC class I components were predominantly detected in breast cancer samples from Western SSA. Features of nonimmunogenic breast cancer phenotypes were associated with reduced patient survival (n = 131). We therefore conclude that regional diversity in the distribution of breast cancer subtypes, TME composition, and immune escape mechanisms should be considered for therapy decisions in SSA and the design of personalized therapies. See related Spotlight by Bergin et al., p. 705.

Efficacy of Sensory Interventions on School Participation of Children With Sensory Disorders: A Systematic Review.

Research demonstrates lower school participation in children with sensory disorders. However, the scientific body of evidence supporting existing sensory intervention modalities is difficult to tackle. More specifically, the literature appears poorly organized, with a highly variable terminology, often with nonoverlapping definitions and lack of good keywords classification that would help organize the diversity of approaches. This systematic review organizes the body of evidence for 3 specific approaches (sensory based, sensorimotor, and sensory integration) and questions their efficacy in improving school participation for children with sensory disorders. Two methods were compared: first, a standard systematic review of the literature in 3 databases using appropriate keywords and descriptors, then an original method based on forward and backward citation connections. A total of 28 studies were retrieved, of which only 7 used the standard method for systematic reviews. For sensory-based approaches, the efficacy of weighted-vest varies according to different factors such as the protocol of use. For sensorimotor approaches, the efficacy of therapy balls, air cushions, platform swing, and physical exercise varies according to the child's sensory characteristics. The efficacy of the sensory integration approach remains mixed across studies.

Interaction between pulmonary vasculature and the patent ductus arteriosus in very premature infants.

BACKGROUND: The benefits of closing the ductus arteriosus in very preterm infants have not been convincingly shown in numerous clinical trials. Because a large untreated ductus arteriosus can cause death from congestive heart failure in infants born at term, we need to explain why this might not occur in premature infants born at <28 weeks' gestation. METHODS: Based on information in the literature, I have commented on the possible relationship between the pulmonary vasculature and the shunt through the patent ductus arteriosus. RESULTS: Many of these infants have bronchopulmonary dysplasia, in which animal and human studies have shown a reduced number of capillaries and small pulmonary arteries as well as reduction in vascular endothelial growth factor (VEGF) and platelet endothelial cell adhesion molecule-1 (PECAM-1). Both of these import angiogenic factors. Some who do not have bronchopulmonary dysplasia may have a restricted pulmonary vascular bed. CONCLUSIONS: The increased pulmonary vascular resistance in very premature infants may restrict pulmonary blood flow even if the ductus is large, thus reducing the urgency for ductus closure.

Pulse oximetry in neonates at high altitudes: a modified Colorado protocol.

Pulse oximetry for detecting critical CHD produces more false positive tests at high altitudes than at sea level, because at altitude the average resting saturation is lower and the variability is higher. This increases diagnostic difficulties, especially in small isolated communities without paediatric echocardio-graphy, and requires expensive transport to a regional medical centre. One way of reducing diagnostic errors is to measure arterial oxygen saturation while the infant is breathing 100% oxygen. In the absence of right-to-left shunting through the heart, the ductus, or the lungs, arterial oxygen tension will exceed 150 mmHg and arterial oxygen saturation will be 100%. With right-to-left shunting, arterial oxygen tension will be <100 mmHg, and thus <96% (usually much lower).

Effect of pain on deafferentation-induced modulation of somatosensory evoked potentials.

There is a large body of evidence showing substantial sensorimotor reorganizations after an amputation. These reorganizations are believed to contribute to the development of phantom limb pain, but alternatively, pain might influence the plasticity triggered by the deafferentation. The aim of this study was to test whether pain impacts on deafferentation-induced plasticity in the somatosensory pathways. Fifteen healthy subjects participated in 2 experimental sessions (Pain, No Pain) in which somatosensory evoked potentials (SSEPs) associated with electrical stimulation of the ulnar nerve were assessed before and after temporary ischemic deafferentation induced by inflation of a cuff around the wrist. In the Pain session capsaicin cream was applied on the dorsum of the hand 30 minutes prior to cuff inflation. Results show that pain decreased the amplitude of the N20 (main effect of condition, p = 0.033), with a similar trend for the P25. Temporary ischemic deafferentation had a significant effect on SSEPs (main effect of time), with an increase in the P25 (p = 0.013) and the P45 amplitude (p = 0.005), together with a reduction of the P90 amplitude (p = 0.002). Finally, a significant time x condition interaction, reflecting state-dependent plasticity, was found for the P90 only, the presence of pain decreasing the reduction of amplitude observed in response to deafferentation. In conclusion, these results show that nociceptive input can influence the plasticity induced by a deafferentation, which could be a contributing factor in the cortical somatosensory reorganization observed in chronic pain populations.

A Preliminary Study of Left Ventricular Rotational Mechanics in Children with Noncompaction Cardiomyopathy: Do They Influence Ventricular Function?

BACKGROUND: Current diagnostic criteria for noncompaction cardiomyopathy (NCC) lack specificity, and the disease lacks prognostic indicators. Reverse apical rotation (RAR) with abnormal rotation of the cardiac apex in the same clockwise direction as the base has been described in adults with NCC. The aim of this study was to test the hypothesis that RAR might differentiate between symptomatic NCC and benign hypertrabeculations and might be associated with ventricular dysfunction. METHODS: Echocardiograms from 28 children with NCC without cardiac malformations were prospectively compared with those from 29 age-matched normal control subjects. A chart review was performed to identify the patients' histories and clinical characteristics. Speckle-tracking was used to measure longitudinal strain, circumferential strain, and rotation. RESULTS: RAR occurred in 39% of patients with NCC. History of left ventricular (LV) dysfunction or arrhythmia was universal in, but not exclusive to, patients with RAR. Patients with RAR had lower LV longitudinal strain but similar ejection fractions compared with patients without RAR (median, -15.6% [interquartile range, -12.9% to -19.3%] vs -19% [interquartile range, -14.5% to -21.9%], P < .01; 53% [interquartile range, 43% to 68%] vs 61% [interquartile range, 58% to 67%], P = .08). Only a pattern of contraction with RAR, early arrest of twisting by mid-systole, and premature untwisting was associated with lower ejection fraction (46%; interquartile range, 43% to 52%; P = .006). CONCLUSIONS: RAR is not a sensitive but is a specific indicator of complications in children with NCC. Therefore, RAR may have prognostic rather than diagnostic value. Premature untwisting of the left ventricle during ejection may be an even more worrisome indicator of LV dysfunction.

The Ratio Fallacy, with Special Reference to the Cardiac Index.

When comparing cardiac outputs in children of different sizes, or deciding on the normality of these outputs, we often convert the absolute output to the output per m2 body surface area-the cardiac index. For small infants, this leads to potentially large errors. The best way to evaluate these outputs is to determine their z values.

The challenge in diagnosing coarctation of the aorta.

Critical coarctation of the aorta in neonates is a common cause of shock and death. It may be the most difficult of all forms of critical congenital heart disease to diagnose because the obstruction from the coarctation does not appear until several days after birth (and after discharge from the hospital), and because there are no characteristic murmurs. Some of these patients may be detected by neonatal screening by pulse oximetry, but only a minority is so diagnosed. Older patients are usually asymptomatic but, although clinical diagnosis is easy, they are frequently undiagnosed.

Will the real ventricular architecture please stand up?

Ventricular twisting, essential for cardiac function, is attributed to the contraction of myocardial helical fibers. The exact relationship between ventricular anatomy and function remains to be determined, but one commonly used explanatory model is the helical ventricular myocardial band (HVMB) model of Torrent-Guasp. This model has been successful in explaining many aspects of ventricular function, (Torrent-Guasp et al. Eur. J. Cardiothorac. Surg., 25, 376, 2004; Buckberg et al. Eur. J. Cardiothorac. Surg., 47, 587, 2015; Buckberg et al. Eur. J. Cardiothorac. Surg. 47, 778, 2015) but the model ignores important aspects of ventricular anatomy and should probably be replaced. The purpose of this review is to compare the HVMB model with a different model (nested layers). A complication when interpreting experimental observations that relate anatomy to function is that, in the myocardium, shortening does not always imply activation and lengthening does not always imply inactivation.

The history of the microsphere method for measuring blood flows with special reference to myocardial blood flow: a personal memoir.

We use many types of equipment and technologies to make our measurements but give little thought to how they developed. Evolution was once described as a series of recoils from blind alleys, and this is exemplified by the gradual development of the microsphere method of measuring blood flows. The microsphere method is one of the most frequently used methods for measuring blood flow to organs and portions of organs. The method can measure myocardial blood flow with reasonable accuracy (within 10%) down to samples weighing >50 mg but probably will not do so for samples weighing 1-10 mg. Microspheres with diameters from 10 to 15 µm provide the best compromise between accurate flow measurement and retention in tissue. Radioactive labels have been almst entirely replaced by fluorescent labels, but colored microspheres and neutron-activated labels are also used.NEW & NOTEWORTHY The contributions of the various individuals who developed the microsphere method of measuring regional blood flows and how these advances took place are brought to light in this paper.

At what age should tetralogy of Fallot be corrected?

Tetralogy of Fallot can be corrected with very low mortality at any age, even in neonates, but this does not necessarily mean that it should be corrected in the neonatal period. Although there are many advantages to early correction, a high proportion of these neonates have residual stenosis or pulmonary regurgitation that impairs ventricular function and may require further surgery or implantation of a pulmonary valve. Before we had the ability to correct this anomaly with low mortality in small children, a variety of palliative procedures had to be performed. Today, with better understanding of the anatomy of tetralogy of Fallot, we should consider what forms of palliation will increase growth of the right ventricular outflow tract in order to reduce the complications of very early surgery.

Is spontaneous closure of a patent arterial duct common?

As closing a patent arterial duct is relatively simple, safe, and successful, most children with a patent arterial duct have it closed soon after diagnosis. The larger ducts are closed to prevent congestive heart failure, pulmonary vascular disease, or aneurysmal dilatation of the ductus, and smaller ducts are closed to prevent infective endocarditis. Consequently, there is no opportunity to determine whether spontaneous closure or diminution in size of the patent arterial duct is common. If the duct does become smaller, flow through it may be so low that no murmur is produced - the silent ductus. The frequency and best management of the silent patent arterial duct are unknown, and we do not know whether these tiny ducts are the last stage before spontaneous closure.

The Effects of Acute Intense Physical Exercise on Postural Stability in Children With Cerebral Palsy.

This study evaluated the effects of intense physical exercise on postural stability of children with cerebral palsy (CP). Center of pressure (CoP) was measured in 9 typically developing (TD) children and 8 with CP before and after a maximal aerobic shuttle-run test (SRT) using a single force plate. Anteroposterior and mediolateral sway velocities, sway area, and sway regularity were calculated from the CoP data and compared between pre- and postexercise levels and between groups. Children with CP demonstrated significantly higher pre-SRT CoP velocities than TD children in the sagittal (18.6 ± 7.6 vs. 6.75 1.78 m/s) and frontal planes (15.4 ± 5.3 vs. 8.04 ± 1.51 m/s). Post-SRT, CoP velocities significantly increased for children with CP in the sagittal plane (27.0 ± 1.2 m/s), with near-significant increases in the frontal plane (25.0 ± 1.5m/s). Similarly, children with CP evidenced larger sway areas than the TD children both pre- and postexercise. The diminished postural stability in children with CP after short but intense physical exercise may have important implications including increased risk of falls and injury.

Is Pulse Oximetry Useful for Screening Neonates for Critical Congenital Heart Disease at High Altitudes?

Now that pulse oximetry is used widely to screen for critical congenital heart disease, it is time to consider whether this screening method is applicable to those who live at high altitudes. Consideration of basic physical principles and reports from the literature indicate that not only is the 95 % cutoff point for arterial oxygen saturation incorrect at high altitudes, but the lower saturations are accompanied by greater variability and therefore there is the possibility of a greater percentage of false-positive screening tests at high altitudes. Because of ethnic differences in response to high altitudes, normative data will have to be collected separately in different countries and perhaps for different ethnic groups.

Acute Physical Exercise Affects Cognitive Functioning in Children With Cerebral Palsy.

Little is known about the effects of acute exercise on the cognitive functioning of children with cerebral palsy (CP). Selected cognitive functions were thus measured using a pediatric version of the Stroop test before and after maximal, locomotor based aerobic exercise in 16 independently ambulatory children (8 children with CP), 6-15 years old. Intense exercise had: 1) a significant, large, positive effect on reaction time (RT) for the CP group (preexercise: 892 ± 56.5 ms vs. postexercise: 798 ± 45.6 ms, p < .002, d = 1.87) with a trend for a similar but smaller response for the typically developing (TD) group (preexercise: 855 ± 56.5 ms vs. postexercise: 822 ± 45.6 ms, p < .08, d = 0.59), and 2) a significant, medium, negative effect on the interference effect for the CP group (preexercise: 4.5 ± 2.5%RT vs. postexercise: 13 ± 2.9%RT, p < .04, d = 0.77) with no significant effect for the TD group (preexercise: 7.2 ± 2.5%RT vs. postexercise: 6.9 ± 2.9%RT, p > .4, d = 0.03). Response accuracy was high in both groups pre- and postexercise (>96%). In conclusion, intense exercise impacts cognitive functioning in children with CP, both by increasing processing speed and decreasing executive function.