Experiences and Needs of Families Caring for Children and Adolescents With Chronic Kidney Disease: A meta-Synthesis.

PROBLEM: Families struggle to care for children and adolescents with chronic kidney disease (CKD). They face extensive burden of care and altered family dynamics. ELIGIBILITY CRITERIA: A meta-synthesis review was conducted to explore the experiences and needs of families caring for children and adolescents with CKD using seven electronic databases (CINAHL, EMBASE, ProQuest Dissertations and Theses, PsycINFO, PubMed, Scopus, and Web of Science). The inclusion criteria are (1) qualitative English studies from January 2010 to December 2020 that (2) report personal experiences or needs of (3) family members caring for children and adolescents aged 19 years and below who have been diagnosed with CKD of any stage (4) across all settings. Quality appraisal was done using the Critical Appraisal Skill Program checklist. Data was synthesised using Sandelowski & Barroso's (2007) method. SAMPLE: 2,236 records were identified and 13 eligible studies were included. Family members involved mothers (n = 190), fathers (n = 83), siblings (n = 5), and grandparents (n = 2). RESULTS: Three themes emerged: (1) demands of caregiving, (2) support systems, and (3) defining and making sense of new reality. CONCLUSIONS: Family caregivers experience overwhelming demands of caregiving and unmet support needs to cope. Appropriate interventions are needed to alleviate their burden. IMPLICATIONS: Knowledge of learning and support needs of families caring for children with CKD may shape nursing education and practice to cultivate more effective communication for better psychosocial family support.

Severity of Airway Obstruction May Not Correlate With Weight Gain or Failure to Thrive in Infants With Robin Sequence: A Pilot Study.

OBJECTIVE: Patients with Robin sequence (RS) can present with varying degrees of upper airway obstruction, difficulty maintaining adequate weight gain, and failure to thrive (FTT). Although inductive reasoning would suggest that these issues should be interrelated, the relationships between these factors have not been formally studied. This investigation explores the correlation between polysomnographic (PSG) findings, weight gain, and FTT in patients with RS. DESIGN: A prospective database for baseline PSG parameters and serial weight measurements in infants with RS who were admitted for airway obstruction was reviewed. The association between PSG variables and calorie intake with FTT was assessed using univariate and multivariable logistic regression. Categorical analysis of the PSG variables against FTT was explored with a Poisson regression, and linear regression was performed to evaluate the correlation between PSG parameters and percentage of weight gain. RESULTS: Univariate and multivariate logistic regression in RS patients with (n = 13) and without (n = 20) FTT showed no significant association between apnea-hypopnea index (adjusted odds ratio [aOR]: 0.99, P-value = 0.403), O2 nadir (aOR: 0.98, P-value = 0.577), time of O2 saturation below 90% (aOR: 1.03, P-value = 0.574), maximum end tidal carbon dioxide (aOR: 1.0, P-value = 0.977), and average calorie intake (OR:1.02; P-value = 0.984). Furthermore, no significant associations were identified between these variables and weight gain. CONCLUSIONS: This pilot study questions the widely held and intuitively logical belief that poor weight gain and/or FTT should correlate with the severity of upper airway obstruction in patients with RS. Large prospective investigations should be initiated to better explore the authors' findings. Our results also underscore the importance of individualized treatment for these challenging patients.

Tumor heterogeneity is an active process maintained by a mutant EGFR-induced cytokine circuit in glioblastoma.

Human solid tumors frequently have pronounced heterogeneity of both neoplastic and normal cells on the histological, genetic, and gene expression levels. While current efforts are focused on understanding heterotypic interactions between tumor cells and surrounding normal cells, much less is known about the interactions between and among heterogeneous tumor cells within a neoplasm. In glioblastoma multiforme (GBM), epidermal growth factor receptor gene (EGFR) amplification and mutation (EGFRvIII/DeltaEGFR) are signature pathogenetic events that are invariably expressed in a heterogeneous manner. Strikingly, despite its greater biological activity than wild-type EGFR (wtEGFR), individual GBM tumors expressing both amplified receptors typically express wtEGFR in far greater abundance than the DeltaEGFR lesion. We hypothesized that the minor DeltaEGFR-expressing subpopulation enhances tumorigenicity of the entire tumor cell population, and thereby maintains heterogeneity of expression of the two receptor forms in different cells. Using mixtures of glioma cells as well as immortalized murine astrocytes, we demonstrate that a paracrine mechanism driven by DeltaEGFR is the primary means for recruiting wtEGFR-expressing cells into accelerated proliferation in vivo. We determined that human glioma tissues, glioma cell lines, glioma stem cells, and immortalized mouse Ink4a/Arf(-/-) astrocytes that express DeltaEGFR each also express IL-6 and/or leukemia inhibitory factor (LIF) cytokines. These cytokines activate gp130, which in turn activates wtEGFR in neighboring cells, leading to enhanced rates of tumor growth. Ablating IL-6, LIF, or gp130 uncouples this cellular cross-talk, and potently attenuates tumor growth enhancement. These findings support the view that a minor tumor cell population can potently drive accelerated growth of the entire tumor mass, and thereby actively maintain tumor cell heterogeneity within a tumor mass. Such interactions between genetically dissimilar cancer cells could provide novel points of therapeutic intervention.

A Comparison of 4 Analgesic Regimens for Acute Postoperative Pain Control in Breast Augmentation Patients.

PURPOSE: Patients undergoing breast augmentation are treated with multiple combinations of medications for pain control including ketorolac, liposomal bupivacaine, bupivacaine, and intravenous and oral narcotics. There is no current consensus on the optimal combination; therefore, all are used at the discretion of the surgeon. METHODS: This was a single-center, retrospective study. The total number of patients included was 132. Comparisons were made between 4 groups: bupivacaine only (B); bupivacaine and liposomal bupivacaine (BL); bupivacaine and liposomal bupivacaine plus intraoperative ketorolac (BLKi); and bupivacaine and liposomal bupivacaine plus postoperative ketorolac (BLKp). Average pain scores immediately postoperative and before discharge were recorded and correlated to percentage of patients who received narcotic in the post-anesthesia care unit (PACU). Additional end points noted were side effects including nausea and time spent in PACU postoperatively. RESULTS: Those receiving intraoperative ketorolac had the lowest pain on discharge (P < 0.0001) and the lowest percentage of patients receiving narcotics (P = 0.009) out of all 4 groups. There was no significant difference between the 4 groups in terms of time spent in PACU, pain immediately after the procedure, or amount of antiemetic given. No bleeding complications were noted for those who did or did not receive ketorolac. CONCLUSIONS: When given options for pain control in breast augmentation, intraoperative ketorolac should be considered, because its inclusion was significant in decreasing use of narcotics and pain upon discharge. Addition of other costly drugs such as liposomal bupivacaine may not provide additional benefit in the immediate postoperative setting for procedures with a short recovery period such as breast augmentation.

Exploring the meaning of hypoglycaemia to community-dwelling Singaporean Chinese adults living with type 2 diabetes mellitus.

This study aimed to explore how community-dwelling Singaporean Chinese adults diagnosed with type 2 diabetes mellitus experience hypoglycaemia. A qualitative interpretive research design was employed. Semi-structured interviews were conducted with six participants from a Singaporean diabetes specialist outpatient clinic, transcribed verbatim and analysed using qualitative manual thematic analysis. Eight major themes emerged: experiencing symptoms, knowing hypoglycaemia is manageable, using acute measures, using preventative strategies; applying knowledge, identifying causes of hypoglycaemia, forming relationships and working with health-care professionals. Participants underestimated the impact of hypoglycaemia mainly due to their experiencing mild and infrequent episodes, and knowledge deficits. Health-care professionals' roles were limited to information providers, and they were perceived as detached and impersonal. Theimplications are that health-care professionals need to provide more client-focused education, and improve the quality of their interpersonal relationships to ensure shared decision-making with their clients.

Therapeutic RNAi targeting PCSK9 acutely lowers plasma cholesterol in rodents and LDL cholesterol in nonhuman primates.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates low density lipoprotein receptor (LDLR) protein levels and function. Loss of PCSK9 increases LDLR levels in liver and reduces plasma LDL cholesterol (LDLc), whereas excess PCSK9 activity decreases liver LDLR levels and increases plasma LDLc. Here, we have developed active, cross-species, small interfering RNAs (siRNAs) capable of targeting murine, rat, nonhuman primate (NHP), and human PCSK9. For in vivo studies, PCSK9 and control siRNAs were formulated in a lipidoid nanoparticle (LNP). Liver-specific siRNA silencing of PCSK9 in mice and rats reduced PCSK9 mRNA levels by 50-70%. The reduction in PCSK9 transcript was associated with up to a 60% reduction in plasma cholesterol concentrations. These effects were shown to be mediated by an RNAi mechanism, using 5'-RACE. In transgenic mice expressing human PCSK9, siRNAs silenced the human PCSK9 transcript by >70% and significantly reduced PCSK9 plasma protein levels. In NHP, a single dose of siRNA targeting PCSK9 resulted in a rapid, durable, and reversible lowering of plasma PCSK9, apolipoprotein B, and LDLc, without measurable effects on either HDL cholesterol (HDLc) or triglycerides (TGs). The effects of PCSK9 silencing lasted for 3 weeks after a single bolus i.v. administration. These results validate PCSK9 targeting with RNAi therapeutics as an approach to specifically lower LDLc, paving the way for the development of PCSK9-lowering agents as a future strategy for treatment of hypercholesterolemia.

siRNA knock-down of mutant torsinA restores processing through secretory pathway in DYT1 dystonia cells.

Most cases of the dominantly inherited movement disorder, early onset torsion dystonia (DYT1) are caused by a mutant form of torsinA lacking a glutamic acid residue in the C-terminal region (torsinADeltaE). TorsinA is an AAA+ protein located predominantly in the lumen of the endoplasmic reticulum (ER) and nuclear envelope apparently involved in membrane structure/movement and processing of proteins through the secretory pathway. A reporter protein Gaussia luciferase (Gluc) shows a reduced rate of secretion in primary fibroblasts from DYT1 patients expressing endogenous levels of torsinA and torsinADeltaE when compared with control fibroblasts expressing only torsinA. In this study, small interfering RNA (siRNA) oligonucleotides were identified, which downregulate the levels of torsinA or torsinADeltaE mRNA and protein by over 65% following transfection. Transfection of siRNA for torsinA message in control fibroblasts expressing Gluc reduced levels of luciferase secretion compared with the same cells non-transfected or transfected with a non-specific siRNA. Transfection of siRNA selectively inhibiting torsinADeltaE message in DYT fibroblasts increased luciferase secretion when compared with cells non-transfected or transfected with a non-specific siRNA. Further, transduction of DYT1 cells with a lentivirus vector expressing torsinA, but not torsinB, also increased secretion. These studies are consistent with a role for torsinA as an ER chaperone affecting processing of proteins through the secretory pathway and indicate that torsinADeltaE acts to inhibit this torsinA activity. The ability of allele-specific siRNA for torsinADeltaE to normalize secretory function in DYT1 patient cells supports its potential role as a therapeutic agent in early onset torsion dystonia.

A nurse-led, rheumatologist-assisted telemedicine intervention for dose escalation of urate-lowering therapy in gout.

AIMS: Urate-lowering therapy (ULT) is effective in gout, but suboptimal management with wide variability in dose escalation remains widespread. We protocolized dose escalation of ULT to improve gout management. The aim was to reduce time to achieve target serum urate (SU) <360 µmol/L. METHODS: Process improvement tools were used to identify underlying causes of prolonged time to target SU. We designed a nurse-led telemedicine intervention for dose escalation of ULT. Patients with gout with SU ≥360 µmol/L meeting indications for ULT at a single institution were recruited. Exclusion criteria were estimated glomerular filtration rate <30 mL/min, pregnancy, cognitive impairment and poor mobility. A nurse-led telemedicine clinic was set up to perform patient education, monitoring of adverse events and drug escalation. We partnered with primary healthcare centers for routine blood tests. RESULTS: From July 2016 to December 2017, 127 patients were recruited. Median time to target SU was 19.0 weeks (interquartile range [IQR] 11.0-31.0). Median dose of allopurinol was 300 mg/d (IQR 200-400) in normal renal function and lower in renal impairment. Median telemedicine calls required to achieve target SU was 2 (IQR 1-3). No patient was hospitalized for gout flares. Two patients had adverse drug reactions, one required cessation of allopurinol for rash with eosinophilia, the other had self-resolving ulcers and allopurinol was continued. Lower baseline SU and number of gout flares were associated with attainment of target SU. CONCLUSION: A nurse-led telemedicine for gout care is effective and safe. Our results affirm the utility of telemedicine in increasing access to care and lower healthcare utilization.

Is Epinephrine Safe for Infant Digit Excision? A Retrospective Review of 402 Polydactyly Excisions in Patients Younger than 6 Months.

BACKGROUND: Conventional dogma suggests that the use of local anesthetic with epinephrine is contraindicated in the digits because of fear of ischemia and necrosis. Although several reports have refuted this notion, the precept is still propagated in many clinical forums. For many years, the authors have used lidocaine with epinephrine to perform removal of postaxial polydactyly in infants and have observed few complications and no cases of digital ischemia or necrosis. This investigation details the authors' outcomes with this anesthetic modality in neonates and supports the growing body of literature documenting the safety of using lidocaine with epinephrine in the digits. METHODS: A retrospective review of all infants younger than 6 months who underwent preaxial and postaxial polydactyly excision and removal of their sequelae of the hand or foot under local anesthesia, from 2011 to 2017, was completed. All demographic characteristics, frequency of complications, and descriptive statistics of the sample clinical group were documented. RESULTS: In the 215 patients who met inclusion criteria, a total of 402 procedures were performed. Mean follow-up was 19.9 months for 140 patients, or 264 procedures (65.7 percent). The total complication rate was 2.6 percent. There were two cases of minor bleeding, one wound dehiscence, and four surgical-site infections. CONCLUSIONS: In 402 procedures of surgical excision of polydactyly in infants, there were few short-term complications, none of which were necrosis or any vascular complication related to the use of epinephrine. The authors believe that, with the use of a low-dose epinephrine injection (1:200,000), the risk for digital infarction is low in this population. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Left Ventricular Assist Device Salvage with Omental Flap.

A large number of people are affected with heart failure annually and require left ventricular assist device placement as a bridge to heart transplant or as destination therapy. When these devices become infected, it is a challenge to eradicate the infection. Failure ultimately results in a significant morbidity and mortality. Source control along with debridement and antibiotics can eradicate the infection of the patient, but many times there is a large defect that needs soft-tissue coverage. Many options for soft-tissue coverage have been suggested, but omentum may be an excellent choice due to its vascularity, bulk, and immunological properties. In this case report, the omental flap is employed for salvage of the left ventricular assist device with excellent results.

Prevalence of Tobacco Smoking and Accuracy of Self-Reporting in Pregnant Women at a Public Hospital for Women and Children.

INTRODUCTION: Denial of smoking status by pregnant women presents a missed opportunity for referral to smoking cessation programmes that are shown to be effective in helping them quit smoking. MATERIALS AND METHODS: A cross-sectional epidemiological survey was conducted to detect the true prevalence of active smoking pregnant patients and the accuracy of self-reporting, investigate the sociodemographic risk factors and test the knowledge of pregnant patients on adverse effects of smoking. This involved 972 antenatal patients of a maternity hospital where participants completed a sociodemographic data survey and answered a knowledge questionnaire. Urine cotinine testing was carried out after informed consent. RESULTS: The prevalence of active smokers was 5.2% (n = 50) with 3% (n = 29) being light smokers and 2.2% (n = 21) being heavy smokers. This was significantly higher than self-reported active smoking status of 3.7% (n = 36; P = 0.02). The Malay race, being aged less than 20 years and not having tertiary level qualifications independently increased the likelihood of being an active smoker. Knowledge of the adverse effects of smoking was generally good with a mean total score of 8.18 out of 10 but there were differences amongst the non-smokers, passive smokers, light smokers and active smokers (P = 0.012). CONCLUSION: While the prevalence of active smoking among pregnant women is low in Singapore compared to other countries, this study substantiated the unreliability of self-reporting of smoking status in the pregnant population which could complicate referral to smoking cessation programmes. The lower awareness of the harms of smoking during pregnancy among smokers highlights a potential area for improvement.

Three-dimensional spatial configuration of tumour cells confers resistance to chemotherapy independent of drug delivery.

Anticancer drug discovery has been hampered by the lack of reliable preclinical models, which routinely use cells grown in two-dimensional (2D) culture systems. However, many of the characteristics of cells in 2D culture do not translate into the findings in animal xenografts. Three-dimensional (3D) growth may be responsible for some of these changes, and models using cells grown in 3D may form a more representative step in tumouricidal validation prior to animal implantation and human testing. For the 3D model, we cultured 143.98.2, SaOS2 or U2OS osteosarcoma cells seeded in porous Bombyx mori silk sponges. We conducted real-time PCR on cells grown in 2D culture and 3D scaffolds for the proliferation markers cyclin B1 and E2F1 and the actin regulator RhoA, and found a significant decrease in expression levels for the 3D tumour models (p = 0.02, < 0.001 and 0.008 for cyclin B1, E2F1 and RhoA for 143.98.2; p = 0.02, 0.002 and 0.02 for cyclin B1, E2F1 and RhoA for U2OS, respectively). In contrast, p21 was upregulated when SaOS2 and U2OS were cultured in the 3D scaffolds (p < 0.001) and there was no increase in DNA quantity during the culture period. We correspondingly observed G1 arrest when cell cycle analysis was conducted. Cytotoxicity results for cells treated with serial dilutions of doxorubicin and cisplatin showed that cells in 3D scaffolds were less sensitive to drug treatment than in 2D culture, and the difference was more pronounced for cell cycle specific agents. Copyright © 2013 John Wiley & Sons, Ltd.

Decidualised fallopian tube endometriotic implant causing spontaneous haemoperitoneum in a twin pregnancy.

Spontaneous haemoperitoneum in pregnancy (SHiP) is a rare but serious condition associated with an adverse pregnancy outcome. We present a case of previable twin pregnancy presenting with SHiP secondary to endometriosis, necessitating an emergency laparotomy and hysterotomy as a life-saving measure to achieve haemostasis. At laparotomy there was massive haemoperitoneum with active bleeding from the left fallopian tube and a left salpingectomy was performed. Histological examination showed haemorrhagic foci of endometriosis on the fallopian tube exhibiting florid stromal decidual change. We wish to raise awareness of this uncommon but potentially life-threatening condition requiring early recognition and prompt recourse to surgical intervention to minimise the morbidity and mortality.

The dominant role of IL-8 as an angiogenic driver in a three-dimensional physiological tumor construct for drug testing.

The induction of angiogenesis and the promotion of tumor growth and invasiveness are processes critical to metastasis, and are dependent on reciprocal interactions between tumor cells and their microenvironment. The formation of a clinically relevant tumor requires support from the surrounding stroma, and it is hypothesized that three-dimensional (3D) tumor coculture models offer a microenvironment that more closely resembles the physiological tumor microenvironment. In this study, we investigated the effects of tissue-engineered 3D architecture and tumor-stroma interaction on the angiogenic factor secretion profiles of U2OS osteosarcoma cells by coculturing the tumor cells with immortalized fibroblasts or human umbilical vein endothelial cells (HUVECs). We also carried out Transwell migration assays for U2OS cells grown in monoculture or fibroblast coculture systems to study the physiological effect of upregulated angiogenic factors on endothelial cell migration. Anti-IL-8 and anti-vascular endothelial growth factor (VEGF)-A therapies were tested out on these models to investigate the role of 3D culture and the coculture of tumor cells with immortalized fibroblasts on the efficacy of antiangiogenic treatments. The coculture of U2OS cells with immortalized fibroblasts led to the upregulation of IL-8 and VEGF-A, especially in 3D culture. Conversely, coculture with endothelial cells resulted in the downregulation of VEGF-A for cells seeded in 3D scaffolds. The migration of HUVECs through the Transwell polycarbonate inserts increased for the 3D and immortalized fibroblast coculture models, and the targeted inhibition of IL-8 greatly reduced HUVEC migration despite the presence of VEGF-A. A similar effect was not observed when anti-VEGF-A neutralizing antibody was used instead, suggesting that IL-8 plays a more critical role in endothelial cell migration than VEGF-A, with significant implications on the clinical utility of antiangiogenic therapy targeting VEGF-A.

Pretreatment neutrophil/lymphocyte ratio is superior to platelet/lymphocyte ratio as a predictor of long-term mortality in breast cancer patients.

The aim of our study was to assess the predictive value of platelet/lymphocyte ratio (PLR) and neutrophil/lymphocyte ratio (NLR) in terms of survival in breast cancer patients. This is an observational study of 437 breast cancer patients treated between January 2004 and December 2006. Survival status was obtained from our cancer registry and Social Security Death Index. Survival analysis, stratified by NLR and PLR quartiles, was used to evaluate their prognostic values. Patients in the highest 4th PLR and NLR quartiles had higher 5-year mortality rate (30.4 and 40.3 %) compared to those in the lower three PLR and NLR quartiles (12.1 and 8.2 %), p < 0.0001. Multivariate hazard ratios of 4th PLR and NLR quartiles compared to first PLR and NLR quartiles were 3.68 (1.74-7.77, p = 0.001) and 3.67 (1.52-8.86, p = 0.004). Higher PLR only showed a trend of higher mortality in patients with normal lymphocyte count, whereas NLR continued to be statistically significant predictor of 5-year mortality in all lymphocyte count subsets. Pretreatment NLR is an independent predictor of long-term mortality in breast cancer patients, whereas pretreatment PLR was not superior to absolute lymphocyte count alone in predicting long-term mortality.

Experience of hypoglycaemia and strategies used for its management by community-dwelling adults with diabetes mellitus: a systematic review.

AIM: To synthesise the evidence on how community-dwelling adults with type 1 and type 2 diabetes mellitus experience hypoglycaemia and the strategies they use to control it. METHODS: Using a three-step search strategy, all published and unpublished qualitative studies in English from January 2000 to August 2010 were retrieved. Participants diagnosed with type 1 or type 2 diabetes mellitus, experienced in self-managing their hypoglycaemia, and who lived independently in the community and attended primary care or outpatient clinics were included. An initial limited search was conducted in MEDLINE and CINAHL to identify keywords and index terms, which were then used in a second search across the CINAHL, PUBMED, SCOPUS, PsycINFO, PsycARTICLES, Web of Science, JSTOR, EMBASE and MEDNAR databases. Additionally, the reference lists of all retrieved papers were hand-searched for additional studies. Retrieved studies were assessed for methodological validity using the standardised Joanna Briggs Institute-Qualitative Assessment and Review Instrument (JBI-QARI). Data, in terms of research findings, were extracted from included studies using the standardised JBI-QARI data extraction tool. Five studies (six papers) were included in the review. RESULTS: The 20 findings from the six papers were grouped into three categories, which were then synthesised into one overall finding - that is 'People with diabetes mellitus can self-manage their diabetes and thus prevent hypoglycaemic episodes more effectively when health professionals provide psychological, physiological and spiritual support, and an individually targeted education programme'. CONCLUSIONS: Within the constraints of this review, it appears that the patient-identified priority is to maintain normality in blood glucose self-management. There is also evidence that some people lack the knowledge to identify and self-manage hypoglycaemia. IMPLICATIONS FOR PRACTICE: To enable community-dwelling adults with diabetes mellitus to self-manage hypoglycaemia, healthcare professionals should provide individualised information and emotional support and regularly discuss and assess the person's level of knowledge, awareness of hypoglycaemia and their ability to self-manage.

Limiting PGY 1 residents to 16 hours of duty: review and report of a workshop.

BACKGROUND: In 2003, the Accreditation Council for Graduate Medical Education (ACGME) instituted limits on duty hours. Residents were restricted to working 80 hours/week and limited to 24 hours of continuous patient care. Effective July 2011, an additional restriction will be instituted for PGY 1 residents limiting continuous duty to 16 hours maximum. OBJECTIVE: Prospective evaluation of the impact of the upcoming work shift limitations for PGY 1 residents. DESIGN/SETTING/PARTICIPANTS: Review of literature and discussions among program directors, program coordinators, and residents on the effects of prior limitations of duty hours, as a point of reference, to manage the changes of duty hours for PGY 1 residents during a workshop at the Association of Program Directors in Surgery Annual Meeting. RESULTS: Work-hour restrictions necessitate a change from the traditional 24-hour on-duty call schedule for PGY 1 residents. The benefits to patients of being treated by less tired doctors working in shifts may be offset by communication failures from poor handoffs, rendering the system prone to adverse events/near misses. With additional work-hour restrictions, it is imperative to anticipate problems and deal with them effectively. Continued reevaluation of the handoff system and efforts made to decrease the number of preventable adverse events that typically occur during periods of cross coverage should be undertaken. Labor costs to carry out these new restrictions are predictably high but can be made budget neutral if improvement in patient care leads to reduction in the costs of corrective actions. CONCLUSIONS: Residency programs have adapted to the 2003 work-hour restrictions without apparent ill effect. We must study the effects of the July 2011 requirements prospectively as the traditional frontline physicians (PGY 1 residents) will no longer be available for 24-hour duty shifts.

Interstitial fluid pressure as an alternate regulator of angiogenesis independent of hypoxia driven HIF-1α in solid tumors.

We previously showed that interstitial fluid pressure (IFP) may be an alternate regulator of angiogenesis in solid tumors. Given the accepted link between hypoxia-induced factor and angiogenesis this study investigated the effect of IFP on hypoxia-inducible factor (HIF-1α) and vascular endothelial growth factor (VEGF) in human osteosarcoma xenografts in SCID mice and in different hypoxic environments. Tumors were grown either at heterotopic (flank) or orthotopic (medullary canal of the proximal tibia) sites in the host animal. Microfluidic probes determined pH, O(2)-saturation, IFP, and peripheral blood flow perfusion continuously. We assessed tumor growth in the orthotopic site (n = 15) by softex radiographs weekly, 3D microCT, histological evaluation, and for molecular responses. An increased cytoplasmic immunohistostaining of cells for HIF-1α (p = 0.03) and VEGF-A (p = 0.004) on the outer periphery was noted compared to the tumor center, with VEGFR2 uniformly stained throughout. This paralleled a raised state of interstitial hypertension (p = 0.007) in the tumor center relative to the peripheral surface but was inconsistent with a state of hypoxia (p = 0.03) in the tumor center. In vitro culture of human osteosarcoma cell lines (HOS, U2OS) and a human osteoblast control at 0- and 20-mmHg of hydrostatic pressure revealed suppression of HIF-1α (p = 0.02) and VEGF-A (p = 0.02) gene expression when IFP was raised, while the effect on VEGFR1 was equivocal. This study proposes an alternative regulatory angiogenic pathway via the influence of IFP on cancer cell function. The identification of a mechanistic cellular link to the physical parameter becomes an important tool to evaluate cancer cell growth within solid tumors.