UBC-Nepal Expedition: Cerebrovascular Responses to Exercise in Sherpa Children Residing at High Altitude.

Understanding the process of successful adaptation to high altitude provides valuable insight into the pathogenesis of conditions associated with impaired oxygen uptake and utilization. Prepubertal children residing at low altitude show a reduced cerebrovascular response to exercise in comparison to adults, and a transient uncoupling of cerebral blood flow to changes in the partial pressure of end-tidal CO2 (PETCO2); however, little is known about the cerebrovascular response to exercise in high-altitude native children. We sought to compare the cerebral hemodynamic response to acute exercise between prepubertal children residing at high and low altitude. Prepubertal children (n = 32; 17 female) of Sherpa descent (Sherpa children [SC]) at high altitude (3800 m, Nepal) and maturational-matched (n = 32; 20 female) children (lowland children [LLC]) residing at low altitude (342 m, Canada). Ventilation, peripheral oxygen saturation (SpO2), PETCO2, and blood velocity in the middle and posterior cerebral arteries (MCAv and PCAv) were continuously measured during a graded cycling exercise test to exhaustion. At baseline (BL), PETCO2 (-19 ± 4 mmHg, p < 0.001), SpO2 (-6.0% ± 2.1%, p < 0.001), MCAv (-12% ± 5%, p = 0.02), and PCAv (-12% ± 6%, p = 0.04) were lower in SC when compared with LLC. Despite this, the relative change in MCAv and PCAv during exercise was similar between the two groups (p = 0.99). Linear regression analysis demonstrated a positive relationship between changes in PETCO2 with MCAv in SC (R2 = 0.13, p > 0.001), but not in LLC (R2 = 0.03, p = 0.10). Our findings demonstrate a similar increase in intra-cranial perfusion during exercise in prepubertal SC, despite differential BL values and changes in PETCO2 and SpO2.

Perceptions of Parenting Residents Among Family Medicine Residency Directors.

BACKGROUND AND OBJECTIVES: Parenting during residency is increasingly common, and resident parents face unique demands on their time and emotional and cognitive resources. Physicians at all levels of training perceive negative impacts of parenting on career and family life. Surveys of program directors (PDs) in other specialties reveal concern about performance and quality of life of parenting residents. The primary aims of this study were to examine family medicine PDs' perceptions of parenting residents' performance and the adequacy of parenting support structures. METHODS: Data were collected from the 2017 Council of Academic Family Medicine (CAFM) Educational Research Alliance (CERA) Family Medicine Residency Program Directors survey. Directors provided the number and status of parenting residents and rated adequacy of parenting resources, resident performance, and impact of parenting on residents using a Likert scale. Results were compared between male/female PDs and male/female residents. RESULTS: Response rate was 57.1%. Less than half of PDs reported adequate parenting support structures in their program (46%). Over 40% of PDs reported that 81%-100% of female residents who take parental leave end up extending their residency training, the most common response category. PDs did not report gender-based differences in performance of parenting residents. PDs most often reported significantly worse well-being for female parenting residents but perceived improved well-being of male parents. CONCLUSIONS: Less than half of family medicine PDs feel their program has adequate parenting resources. Female parenting residents commonly extend residency training. PDs perceive parenting negatively impacts well-being of female residents, but not male residents.

Effect of healthy aging on cerebral blood flow, CO2 reactivity, and neurovascular coupling during exercise.

We sought to make the first comparisons of duplex Doppler ultrasonography-derived measures of cerebral blood flow during exercise in young and older individuals and to assess whether healthy aging influences the effect of exercise on neurovascular coupling (NVC) and cerebral vascular reactivity to changes in carbon dioxide (CVRco2). In 10 healthy young (23 ± 2 yr; mean ± SD) and 9 healthy older (66 ± 3 yr) individuals, internal carotid artery (ICA) and vertebral artery (VA) blood flows were concurrently measured, along with middle and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean). Measures were made at rest and during leg cycling (75 W and 35% maximum aerobic workload). ICA and VA blood flow during dynamic exercise, undertaken at matched absolute (ICA: young 336 ± 95, older 352 ± 155; VA: young 95 ± 43, older 100 ± 30 ml/min) and relative (ICA: young 355 ± 125, older 323 ± 153; VA: young 115 ± 48, older 110 ± 32 ml/min) intensities, were not different between groups ( P > 0.670). The PCAvmean responses to visual stimulation (NVC) were blunted in older versus younger group at rest (16 ± 6% vs. 23 ± 7%, P < 0.026) and exercise; however, these responses were not changed from rest to exercise in either group. The ICA and VA CVRco2 were comparable in both groups and unaltered during exercise. Collectively, our findings suggest that 1) ICA and VA blood flow responses to dynamic exercise are similar in healthy young and older individuals, 2) NVC is blunted in healthy older individuals at rest and exercise but is not different between rest to exercise in either group, and 3) CVRco2 is similar during exercise in healthy young and older groups. NEW & NOTEWORTHY Internal carotid artery and vertebral artery blood flow responses to dynamic exercise are similar in healthy young and older individuals. Neurovascular coupling and cerebrovascular carbon dioxide reactivity, two key mechanisms mediating the cerebral blood flow responses to exercise, are generally unaffected by exercise in both healthy young and older individuals.

Cerebrovascular and ventilatory responses to acute normobaric hypoxia in girls and women.

Physiological responses to hypoxia in children are incompletely understood. We aimed to characterize cerebrovascular and ventilatory responses to normobaric hypoxia in girls and women. Ten healthy girls (9.9 ± 1.7 years; mean ± SD; Tanner stage 1 and 2) and their mothers (43.9 ± 3.5 years) participated. Internal carotid (ICA) and vertebral artery (VA) velocity, diameter and flow (Duplex ultrasound) was recorded pre- and post-1 h of hypoxic exposure (FIO2 = 0.126;~4000 m) in a normobaric chamber. Ventilation (V˙E) and respiratory drive (VT/TI) expressed as delta change from baseline (∆%), and end-tidal carbon-dioxide (PETCO2) were collected at baseline (BL) and 5, 30 and 60 min of hypoxia (5/30/60 HYP). Heart rate (HR) and oxygen saturation (SpO2) were also collected at these time-points. SpO2 declined similarly in girls (BL-97%; 60HYP-80%, P < 0.05) and women (BL-97%; 60HYP-83%, P < 0.05). Global cerebral blood flow (gCBF) increased in both girls (BL-687; 60HYP-912 mL·min-1, P < 0.05) and women (BL-472; 60HYP-651 mL·min-1, P < 0.01), though the ratio of ICA:VA (%) contribution to gCBF differed significantly (girls, 75:25%; women, 61:39%). The relative increase in V˙E peaked at 30HYP in both girls (27%, P < 0.05) and women (19%, P < 0.05), as did ∆%VT/TI (girls, 41%; women, 27%, P's < 0.05). Tidal volume (VT) increased in both girls and women at 5HYP, remaining elevated above baseline in girls at 30 and 60 HYP, but declined back toward baseline in women. Girls elicit similar increases in gCBF and ventilatory parameters in response to acute hypoxia as women, though the pattern and contributions mediating these responses appear developmentally divergent.

Extra- and intracranial blood flow regulation during the cold pressor test: influence of age.

We determined how the extra- and intracranial circulations respond to generalized sympathetic activation evoked by a cold pressor test (CPT) and whether this is affected by healthy aging. Ten young [23 ± 2 yr (means ± SD)] and nine older (66 ± 3 yr) individuals performed a 3-min CPT by immersing the left foot into 0.8 ± 0.3°C water. Common carotid artery (CCA) and internal carotid artery (ICA) diameter, velocity, and flow were simultaneously measured (duplex ultrasound) along with middle cerebral artery and posterior cerebral artery mean blood velocity (MCAvmean and PCAvmean) and cardiorespiratory variables. The increases in heart rate (~6 beats/min) and mean arterial blood pressure (~14 mmHg) were similar in young and older groups during the CPT (P < 0.01 vs. baseline). In the young group, the CPT elicited an ~5% increase in CCA diameter (P < 0.01 vs. baseline) and a tendency for an increase in CCA flow (~12%, P = 0.08); in contrast, both diameter and flow remained unchanged in the older group. Although ICA diameter was not changed during the CPT in either group, ICA flow increased (~8%, P = 0.02) during the first minute of the CPT in both groups. Whereas the CPT elicited an increase in MCAvmean and PCAvmean in the young group (by ~20 and ~10%, respectively, P < 0.01 vs. baseline), these intracranial velocities were unchanged in the older group. Collectively, during the CPT, these findings suggest a differential mechanism(s) of regulation between the ICA compared with the CCA in young individuals and a blunting of the CCA and intracranial responses in older individuals.NEW & NOTEWORTHY Sympathetic activation evoked by a cold pressor test elicits heterogeneous extra- and intracranial blood vessel responses in young individuals that may serve an important protective role. The extra- and intracranial responses to the cold pressor test are blunted in older individuals.

UBC-Nepal expedition: markedly lower cerebral blood flow in high-altitude Sherpa children compared with children residing at sea level.

Developmental cerebral hemodynamic adaptations to chronic high-altitude exposure, such as in the Sherpa population, are largely unknown. To examine hemodynamic adaptations in the developing human brain, we assessed common carotid (CCA), internal carotid (ICA), and vertebral artery (VA) flow and middle cerebral artery (MCA) velocity in 25 (9.6 ± 1.0 yr old, 129 ± 9 cm, 27 ± 8 kg, 14 girls) Sherpa children (3,800 m, Nepal) and 25 (9.9 ± 0.7 yr old, 143 ± 7 cm, 34 ± 6 kg, 14 girls) age-matched sea level children (344 m, Canada) during supine rest. Resting gas exchange, blood pressure, oxygen saturation and heart rate were assessed. Despite comparable age, height and weight were lower (both P < 0.01) in Sherpa compared with sea level children. Mean arterial pressure, heart rate, and ventilation were similar, whereas oxygen saturation (95 ± 2 vs. 99 ± 1%, P < 0.01) and end-tidal Pco2 (24 ± 3 vs. 36 ± 3 Torr, P < 0.01) were lower in Sherpa children. Global cerebral blood flow was ∼30% lower in Sherpa compared with sea level children. This was reflected in a lower ICA flow (283 ± 108 vs. 333 ± 56 ml/min, P = 0.05), VA flow (78 ± 26 vs. 118 ± 35 ml/min, P < 0.05), and MCA velocity (72 ± 14 vs. 88 ± 14 cm/s, P < 0.01). CCA flow was similar between Sherpa and sea level children (425 ± 92 vs. 441 ± 81 ml/min, P = 0.52). Scaling flow and oxygen uptake for differences in vessel diameter and body size, respectively, led to the same findings. A lower cerebral blood flow in Sherpa children may reflect specific cerebral hemodynamic adaptations to chronic hypoxia.NEW & NOTEWORTHY Cerebral blood flow is lower in Sherpa children compared with children residing at sea level; this may reflect a cerebral hemodynamic pattern, potentially due to adaptation to a hypoxic environment.

Anterior cerebral blood velocity and end-tidal CO2 responses to exercise differ in children and adults.

Little is known about the response of the cerebrovasculature to acute exercise in children and how these responses might differ with adults. Therefore, we compared changes in middle cerebral artery blood velocity (MCAVmean), end-tidal Pco2 ([Formula: see text]), blood pressure, and minute ventilation (V̇e) in response to incremental exercise between children and adults. Thirteen children [age: 9 ± 1 (SD) yr] and thirteen sex-matched adults (age: 25 ± 4 yr) completed a maximal exercise test, during which MCAVmean, [Formula: see text], and V̇e were measured continuously. These variables were measured at rest, at exercise intensities specific to individual ventilatory thresholds, and at maximum. Although MCAVmean was higher at rest in children compared with adults, there were smaller increases in children (1-12%) compared with adults (12-25%) at all exercise intensities. There were alterations in [Formula: see text] with exercise intensity in an age-dependent manner [F(2.5,54.5) = 7.983, P < 0.001; η2 = 0.266], remaining stable in children with increasing exercise intensity (37-39 mmHg; P > 0.05) until hyperventilation-induced reductions following the respiratory compensation point. In adults, [Formula: see text] increased with exercise intensity (36-45 mmHg, P < 0.05) until the ventilatory threshold. From the ventilatory threshold to maximum, adults showed a greater hyperventilation-induced hypocapnia than children. These findings show that the relative increase in MCAVmean during exercise was attenuated in children compared with adults. There was also a weaker relationship between MCAVmean and [Formula: see text] during exercise in children, suggesting that cerebral perfusion may be regulated by different mechanisms during exercise in the child.NEW & NOTEWORTHY These findings provide the first direct evidence that exercise increases cerebral blood flow in children to a lesser extent than in adults. Changes in end-tidal CO2 parallel changes in cerebral perfusion in adults but not in children, suggesting age-dependent regulatory mechanisms of cerebral blood flow during exercise.

Gankyrin activates mTORC1 signaling by accelerating TSC2 degradation in colorectal cancer.

Gankyrin is overexpressed in some malignancies. However its roles in colorectal carcinogenesis and underlying mechanisms remain largely unexplored. Here we report that gankyrin promotes the initiation and development of colorectal carcinogenesis by activating mTORC1 signaling through TSC/Rheb dependent mechanism. We further show that Gankyrin overexpression accelerated TSC2 degradation, while knockdown in a panel of colorectal cancer (CRC) cell lines, cell line derived xenografts and CRC patient derived xenograft (PDX) tumors delayed TSC2 degradation, restored the TSC2 protein level, and inhibited mTORC1 signaling and CRC growth. Our findings reveal a unique mechanism by which gankyrin promotes colorectal carcinogenesis and show that gankyrin is a potential therapeutic target to improve the clinical management of CRC.

Rab1A is an mTORC1 activator and a colorectal oncogene.

Amino acid (AA) is a potent mitogen that controls growth and metabolism. Here we describe the identification of Rab1 as a conserved regulator of AA signaling to mTORC1. AA stimulates Rab1A GTP binding and interaction with mTORC1 and Rheb-mTORC1 interaction in the Golgi. Rab1A overexpression promotes mTORC1 signaling and oncogenic growth in an AA- and mTORC1-dependent manner. Conversely, Rab1A knockdown selectively attenuates oncogenic growth of Rab1-overexpressing cancer cells. Moreover, Rab1A is overexpressed in colorectal cancer (CRC), which is correlated with elevated mTORC1 signaling, tumor invasion, progression, and poor prognosis. Our results demonstrate that Rab1 is an mTORC1 activator and an oncogene and that hyperactive AA signaling through Rab1A overexpression drives oncogenesis and renders cancer cells prone to mTORC1-targeted therapy.

Attending and resident physician perceptions of an EMR-generated rounding report for adult inpatient services.

BACKGROUND: With limited work hours, efficient rounding and effective hand-offs have become essential. We created a completely electronic medical record (EMR)-generated rounding report for use during pre-rounding, team rounds, and sign-out/hand-offs. We hypothesized that this would reduce workloads. METHODS: We used a pre- and post-implementation survey of the residents and faculty members of the Departments of Family and Community Medicine and Internal Medicine. RESULTS: After 5 months of use, residents and attending physicians reported a daily time savings of 44 minutes. Seventy-six percent of users also agreed that the rounding report improved patient safety. Rounding report users were more satisfied with the rounding process, spent less time updating other lists or documents, and less time pre-rounding. In addition, there were trends toward spending more time with patients, adherence to work-hour rules, increased accuracy of information during sign-out, improved satisfaction, confidence while cross-covering, and decreased clinically relevant errors. CONCLUSIONS: Utilization of well-designed, EMR-generated reports for the use of patient transfer, sign-out, and rounding should become more commonplace considering the improved efficiency, satisfaction, and potential for improved patient care.