Incidence Morbidity and Mortality From Falls in Skilled Nursing Facilities: A Systematic Review and Meta-Analysis.

OBJECTIVES: The primary objective of this study was to systematically review and meta-analyze the incidence and consequential morbidity and mortality from falls in skilled nursing facilities. Our secondary objective is to synthesize current evidence on risk factors for injurious falls. DESIGN: Systematic review and meta-analysis. SETTING AND PARTICIPANTS: Older adults residing in skilled nursing facilities or similar settings. METHODS: We completed study screening, data extraction, and quality assessment in duplicate. Random effects models were used for meta-analysis of fall incidence rates and proportions of outcomes per fall. Sensitivity analysis and meta-regression were completed to assess differences based on study design, quality, and population characteristics. The Newcastle Ottawa Scale and Cochrane Risk of Bias tools were used to assess quality of observational and intervention-based studies, respectively. The GRADE tool was used to evaluate strength of evidence for fall risk factors. RESULTS: We identified 3103 unique references, of which 38 were included in systematic review and 37 in meta-analysis. Pooled incidence of falls was 121 per 100 person-years (95% CI 86-170). Outcomes of transfer to hospital, admission to hospital, overall injury, head injury, fracture, 30-day mortality, death in hospital, and disability were reported by included studies. Sensitivity analysis indicated no significant difference in fall rates between study designs. Meta-regression indicated no significant relationship between fall rate and age or sex; however, a weak positive correlation was identified with increasing prevalence of dementia. No fall risk factors were supported by high-quality evidence. CONCLUSION/IMPLICATIONS: Our study confirms that falls in skilled nursing facilities are common and cause significant morbidity, mortality and health system use. As populations in high-income countries age, falls will become increasingly prevalent. Future research should be directed at preventing injurious falls and determining when hospital care will benefit a faller.

Paravertebral blocks in immediate breast reconstruction following mastectomy.

BACKGROUND: Postoperative pain remains a major challenge following immediate breast reconstruction with 40% of patients experiencing acute pain and up to 60% developing chronic pain. Paravertebral blocks (PVB's) have emerged as a promising adjunct to standard analgesic protocols. The aim of this study was to assess the utility of PVB's in immediate breast reconstruction following mastectomy. METHODS: A retrospective review of patients undergoing immediate breast reconstruction following mastectomy was performed. The primary outcome was postoperative pain measured by total oral morphine equivalent usage and self reported pain scores and secondary outcomes were length of stay in the PACU, complications, and OR delay. RESULTS: Of 298 patients undergoing immediate breast reconstruction, 112(38%) underwent standard analgesic protocols and 186(62%) underwent PVB in addition to the standard protocol. PVB's were associated with reductions in average postoperative pain scores (2.8 vs 3.3, P = 0.002), total opiate consumption (52 units vs 63 units, P = 0.038) and time spent in the PACU 92 vs 142 minutes, P = 0.0228) compared to patients who had general anesthesia alone. The overall complication rate was 3.7% (7/186 patients), all which were minor complications such as headache, bloody tap, vasovagal episode and temporary weakness. The use of PVBs delayed the OR start time on average by 15 minutes (34 vs 49 minutes). CONCLUSIONS: The present study offers one of the largest retrospective cohort studies to date evaluating the utility of PVB's in immediate breast reconstruction following mastectomy. We demonstrate that, PVB's in immediate breast reconstruction are associated with reductions in postoperative pain, narcotic usage and length of stay in PACU, but are associated with delays to the start time of the case. Anesthesiologists, plastic surgeons and hospital administrators must continue to work together to ensure this important and necessary service is administered in an efficient and cost effective manner.

Improving breast diagnostic services with a Rapid Access Diagnostic and Support (RADS) program.

BACKGROUND: The diagnostic phase of care is an anxiety-provoking and stressful experience for the potential breast cancer patient. A multidisciplinary team of breast cancer specialists embarked on a new initiative to pilot a Rapid Diagnosis and Support (RADS) Clinic to coordinate the diagnostic workup and nursing support for patients with a high probability of breast cancer. METHODS: Consecutive patients with an initial diagnostic imaging classified as BI-RADS 5 were invited to participate in this 1-year prospective study. Coordination of diagnostic imaging workup and nursing support were provided by a nurse navigator. Wait times were evaluated at several intervals of care. Satisfaction surveys were given to study participants and compared to scores from patients who did not go through RADS clinic. RESULTS: A total of 211 patients participated in the RADS clinic. Biopsy wait times improved from a mean of 7 to 3 days (p < 0.001), pathology from 3.9 to 3.3 days (p < 0.001), surgical consultation from 16.1 to 5.9 days (p < 0.001), and operative wait times from 31.5 to 24.1 days (p = 0.042). There was a 95.3 % satisfaction rate with the RADS clinic with significantly improvement in patients' sense of an understanding of the treatment plan (p = 0.031), timeliness of tests (p = 0.045), and timeliness of results (p = 0.0419). CONCLUSIONS: The RADS clinic significantly improved diagnostic wait times and satisfaction scores for patients with a high probability of diagnosis of breast cancer and can serve as an innovative service delivery model for other breast care centers.

Optimization of the in vitro cardiac safety of hydroxamate-based histone deacetylase inhibitors.

Histone deacetylase (HDAC) inhibitors have shown promise in treating various forms of cancer. However, many HDAC inhibitors from diverse structural classes have been associated with QT prolongation in humans. Inhibition of the human ether a-go-go related gene (hERG) channel has been associated with QT prolongation and fatal arrhythmias. To determine if the observed cardiac effects of HDAC inhibitors in humans is due to hERG blockade, a highly potent HDAC inhibitor devoid of hERG activity was required. Starting with dacinostat (LAQ824), a highly potent HDAC inhibitor, we explored the SAR to determine the pharmacophores required for HDAC and hERG inhibition. We disclose here the results of these efforts where a high degree of pharmacophore homology between these two targets was discovered. This similarity prevented traditional strategies for mitigating hERG binding/modulation from being successful and novel approaches for reducing hERG inhibition were required. Using a hERG homology model, two compounds, 11r and 25i, were discovered to be highly efficacious with weak affinity for the hERG and other ion channels.

A Smac mimetic rescue screen reveals roles for inhibitor of apoptosis proteins in tumor necrosis factor-alpha signaling.

Smac mimetic compounds targeting the inhibitor of apoptosis proteins (IAP) baculoviral IAP repeat-3 domain are presumed to reduce the threshold for apoptotic cell death by alleviating caspase-9 repression. We explored this tenet in an unbiased manner by searching for small interfering RNAs that are able to confer resistance to the Smac mimetic compound LBW242. Among the screening hits were multiple components of the tumor necrosis factor alpha (TNFalpha) signaling pathway as well as X-linked inhibitor of apoptosis (XIAP) itself. Here, we show that in a subset of highly sensitive tumor cell lines, activity of LBW242 is dependent on TNFalpha signaling. Mechanistic studies indicate that in this context, XIAP is a positive modulator of TNFalpha induction whereas cellular inhibitor of apoptosis protein 1 negatively regulates TNFalpha-mediated apoptosis.

Inhibitors of Raf kinase activity block growth of thyroid cancer cells with RET/PTC or BRAF mutations in vitro and in vivo.

PURPOSE: Papillary thyroid carcinomas are associated with nonoverlapping activating mutations of RET, NTRK, RAS and BRAF, which altogether are present in approximately 70% of cases. We postulated that compounds that inhibit a distal effector in the mitogen-activated protein kinase (MAPK) pathway would inhibit growth and tumorigenicity of human thyroid cancer cell lines with mutations of RET or BRAF. EXPERIMENTAL DESIGN AND RESULTS: We first examined the effects of AAL-881 and LBT-613, two inhibitors of RAF kinase activity, on RAF-MAPK/extracellular signal-regulated kinase (ERK) kinase (MEK)-ERK activation in thyroid PCCL3 cells after conditional induction of expression of H-RAS(G12V) or BRAF(V600E). Both compounds blocked RAS and RAF-dependent MEK and ERK phosphorylation. They also potently blocked MEK phosphorylation in human thyroid cancer cell lines with either RET/PTC1 (TPC1) or BRAF(V600E) (NPA, ARO, and FRO) mutations. Inhibition of ERK phosphorylation was transient in TPC1 and ARO cells, with recovery of ERK phosphorylation associated with concomitant down-regulation of the MAPK phosphatases MKP-3 and DUSP5. Both compounds inhibited growth of all cell lines, with LBT-613 being approximately 10-fold more potent than AAL-881. TPC1 cells were more sensitive to growth inhibition (IC50 0.1-0.25 and approximately 0.05 micromol/L for AAL-881 and LBT-613, respectively) than BRAF + lines (IC50 2.5-5 and 0.1-0.5 micromol/L, respectively). Growth inhibition was associated with G1 arrest, and induction of cell death. Growth of ARO and NPA tumor xenografts was inhibited by LBT-613 or AAL-881. MEK and ERK phosphorylation was inhibited by both compounds in ARO but not in NPA cell xenografts. CONCLUSIONS: Compounds that inhibit kinase activity are effective growth inhibitors for poorly differentiated thyroid cancer cell lines with either RET or RAF mutations, and hold promise for treatment of most forms of papillary thyroid carcinoma.