MEDEX2015: Greater Sea-Level Fitness Is Associated with Lower Sense of Effort During Himalayan Trekking Without Worse Acute Mountain Sickness.

Rossetti, Gabriella M.K., Jamie H. Macdonald, Matthew Smith, Anna R. Jackson, Nigel Callender, Hannah K. Newcombe, Heather M. Storey, Sebastian Willis, Jojanneke van den Beukel, Jonathan Woodward, James Pollard, Benjamin Wood, Victoria Newton, Jana Virian, Owen Haswell, and Samuel J. Oliver. MEDEX2015: Greater sea-level fitness is associated with lower sense of effort during Himalayan trekking without worse acute mountain sickness. High Alt Med Biol. 18:152-162, 2017.-This study examined the complex relationships of fitness and hypoxic sensitivity with submaximal exercise responses and acute mountain sickness (AMS) at altitude. Determining these relationships is necessary before fitness or hypoxic sensitivity tests can be recommended to appraise individuals' readiness for altitude. Forty-four trekkers (26 men; 18 women; 20-67 years) completed a loaded walking test and a fitness questionnaire in normoxia to measure and estimate sea-level maximal aerobic capacity (maximum oxygen consumption [[Formula: see text]O2max]), respectively. Participants also completed a hypoxic exercise test to determine hypoxic sensitivity (cardiac, ventilatory, and arterial oxygen saturation responses to acute hypoxia, fraction of inspired oxygen [Fio2] = 0.112). One month later, all participants completed a 3-week trek to 5085 m with the same ascent profile. On ascent to 5085 m, ratings of perceived exertion (RPEascent), fatigue by Brunel Mood Scale, and AMS were recorded daily. At 5085 m, RPE during a fixed workload step test (RPEfixed) and step rate during perceptually regulated exercise (STEPRPE35) were recorded. Greater sea-level [Formula: see text]O2max was associated with, and predicted, lower sense of effort (RPEascent; r = -0.43; p < 0.001; RPEfixed; r = -0.69; p < 0.001) and higher step rate (STEPRPE35; r = 0.62; p < 0.01), but not worse AMS (r = 0.13; p = 0.4) or arterial oxygen desaturation (r = 0.07; p = 0.7). Lower RPEascent was also associated with better mood, including less fatigue (r = 0.57; p < 0.001). Hypoxic sensitivity was not associated with, and did not add to the prediction of submaximal exercise responses or AMS. In conclusion, participants with greater sea-level fitness reported less effort during simulated and actual trekking activities, had better mood (less fatigue), and chose a higher step rate during perceptually regulated exercise, but did not suffer from worse AMS or arterial oxygen desaturation. Simple sea-level fitness tests may be used to aid preparation for high-altitude travel.

Targeted gene addition in human CD34(+) hematopoietic cells for correction of X-linked chronic granulomatous disease.

Gene therapy with genetically modified human CD34(+) hematopoietic stem and progenitor cells (HSPCs) may be safer using targeted integration (TI) of transgenes into a genomic 'safe harbor' site rather than random viral integration. We demonstrate that temporally optimized delivery of zinc finger nuclease mRNA via electroporation and adeno-associated virus (AAV) 6 delivery of donor constructs in human HSPCs approaches clinically relevant levels of TI into the AAVS1 safe harbor locus. Up to 58% Venus(+) HSPCs with 6-16% human cell marking were observed following engraftment into mice. In HSPCs from patients with X-linked chronic granulomatous disease (X-CGD), caused by mutations in the gp91phox subunit of the NADPH oxidase, TI of a gp91phox transgene into AAVS1 resulted in ∼15% gp91phox expression and increased NADPH oxidase activity in ex vivo-derived neutrophils. In mice transplanted with corrected HSPCs, 4-11% of human cells in the bone marrow expressed gp91phox. This method for TI into AAVS1 may be broadly applicable to correction of other monogenic diseases.

The F.R.I.D.A.Y.S. checklist - Preparing our patients for a safe weekend.

There is a higher incidence of mortality and adverse events among inpatients in UK hospitals at the weekend compared to weekdays. The high volume of routine tasks handed over by the weekday doctors on Fridays may be a contributing factor. An audit was carried out on four acute wards on a Friday evening at University Hospital Lewisham (UHL). It demonstrated that most patients had at least one outstanding task that would need completing by the on-call team over the weekend. To address this problem a concise and memorable checklist was created to ensure that routine jobs are completed by the weekday team prior to the weekend. The checklist uses the acronym "F.R.I.D.A.Y.S." to prompt doctors to hand over weekend bloods, ensure drug charts are reviewed, document a plan for IV fluids, complete discharge summaries, monitor antibiotic levels, dose warfarin, and clearly document the ceiling of care. The F.R.I.D.A.Y.S. checklist was printed onto history paper and integrated into the patient notes on a Friday ward round. The efficacy of the checklist was evaluated by reviewing the number of outstanding jobs on the wards after 17:00 on a Friday in the categories listed. F-Phlebotomy R-Rewrite drug chart I-IV fluids D-Discharge summaries A-Antibiotic levels Y-Yellow book (warfarin) S-Resuscitation Status The number of outstanding jobs on a ward (A) that used F.R.I.D.A.Y.S. was 3 out of a total 132 jobs (2.3%) compared with 47 out of a total of 103 (45.6%) on a ward that did not use the checklist (B). When the F.R.I.D.A.Y.S. checklist is implemented there is an increase in the number of routine jobs that are carried out by the weekday team, and therefore a reduction in workload for the weekend on call team. Patient safety is improved as management decisions are made by a team that is familiar with the patient, and on call teams are able to prioritise emergencies. The cost saving of using the F.R.I.D.A.Y.S. checklist if implemented throughout UHL is estimated at £317,136 per annum.