Prevalence, Management, and Outcomes Related to Preoperative Medical Orders for Life Sustaining Treatment (MOLST) in an Adult Surgical Population: Preoperative MOLST and Code Status Discussions.

OBJECTIVE: To determine prevalence of documented preoperative code status discussions and postoperative outcomes (specifically mortality, readmission, and discharge disposition) of patients with completed MOLST forms before surgery. SUMMARY OF BACKGROUND DATA: A MOLST form documents patient care preference regarding treatment limitations. When considering surgery in these patients, preoperative discussion is necessary to ensure concordance of care. Little is known about prevalence of these discussions and postoperative outcomes. METHODS: A retrospective cohort study was conducted consisting of all patients having surgery during a 1-year period at a tertiary care academic center in Boston, Massachusetts. RESULTS: Among 21,787 surgical patients meeting inclusion criteria, 402 (1.8%) patients had preoperative MOLST. Within the MOLST, 224 (55.7%) patients had chosen to limit cardiopulmonary resuscitation and 214 (53.2%) had chosen to limit intubation and mechanical ventilation. Code status discussion was documented presurgery in 169 (42.0%) patients with MOLST. Surgery was elective or nonurgent for 362 (90%), and median length of stay (Q1, Q3) was 5.1 days (1.9, 9.9). The minority of patients with preoperative MOLST were discharged home [169 (42%), and 103 (25.6%) patients were readmitted within 30 days. Patients with preoperative MOLST had a 30-day mortality of 9.2% (37 patients) and cumulative 90-day mortality of 14.9% (60 patients). CONCLUSIONS: Fewer than half of surgical patients with preoperative MOLST have documented code status discussions before surgery. Given their high risk of postoperative mortality and the diversity of preferences found in MOLST, thoughtful discussion before surgery is critical to ensure concordant perioperative care.

Association of obesity with postoperative outcomes after proctectomy.

BACKGROUND: Prior efforts evaluating obesity as a risk factor for postoperative complications following proctectomy have been limited by sample size and uniform outcome classification. METHODS: The ACS NSQIP was queried for patients with non-metastatic rectal adenocarcinoma who underwent elective proctectomy. After stratification by BMI classification, multivariable modeling was used to identify the effect of BMI class on adjusted risk of 30-day outcomes controlling for patient, procedure, and tumor factors. RESULTS: Of 2241 patients identified, 33.4% had a normal BMI, 33.5% were overweight, 21.1% were obese, and 12.0% were morbidly obese. Increased risk of superficial surgical site infection (SSI) was observed in obese (OR 2.42, 95%CI:[1.36-4.29]) and morbidly obese (OR 3.29, 95%CI:[1.77-6.11]) patients when compared to normal BMI. Morbid obesity was associated with increased risk of any complication (OR 1.44, 95%CI:[1.05-1.96]). BMI class was not associated with risk adjusted odds of anastomotic leak. CONCLUSIONS: Morbid obesity is independently associated with an increased composite odds risk of short-term morbidity following elective proctectomy for cancer primarily due to increased risk of superficial SSI.

Serine proteases as luminal mediators of intestinal barrier dysfunction and symptom severity in IBS.

OBJECTIVE: The intestinal lumen contains several proteases. Our aim was to determine the role of faecal proteases in mediating barrier dysfunction and symptoms in IBS. DESIGN: 39 patients with IBS and 25 healthy volunteers completed questionnaires, assessments of in vivo permeability, ex vivo colonic barrier function in Ussing chambers, tight junction (TJ) proteins, ultrastructural morphology and 16 s sequencing of faecal microbiota rRNA. A casein-based assay was used to measure proteolytic activity (PA) in faecal supernatants (FSNs). Colonic barrier function was determined in mice (ex-germ free) humanised with microbial communities associated with different human PA states. RESULTS: Patients with IBS had higher faecal PA than healthy volunteers. 8/20 postinfection IBS (PI-IBS) and 3/19 constipation- predominant IBS had high PA (>95th percentile). High-PA patients had more and looser bowel movements, greater symptom severity and higher in vivo and ex vivo colonic permeability. High-PA FSNs increased paracellular permeability, decreased occludin and increased phosphorylated myosin light chain (pMLC) expression. Serine but not cysteine protease inhibitor significantly blocked high-PA FSN effects on barrier. The effects on barrier were diminished by pharmacological or siRNA inhibition of protease activated receptor-2 (PAR-2). Patients with high-PA IBS had lower occludin expression, wider TJs on biopsies and reduced microbial diversity than patients with low PA. Mice humanised with high-PA IBS microbiota had greater in vivo permeability than those with low-PA microbiota. CONCLUSION: A subset of patients with IBS, especially in PI-IBS, has substantially high faecal PA, greater symptoms, impaired barrier and reduced microbial diversity. Commensal microbiota affects luminal PA that can influence host barrier function.

Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand.

WNT1 mutations in humans are associated with a new form of osteogenesis imperfecta and with early-onset osteoporosis, suggesting a key role of WNT1 in bone mass regulation. However, the general mode of action and the therapeutic potential of Wnt1 in clinically relevant situations such as aging remain to be established. Here, we report the high prevalence of heterozygous WNT1 mutations in patients with early-onset osteoporosis. We show that inactivation of Wnt1 in osteoblasts causes severe osteoporosis and spontaneous bone fractures in mice. In contrast, conditional Wnt1 expression in osteoblasts promoted rapid bone mass increase in developing young, adult, and aged mice by rapidly increasing osteoblast numbers and function. Contrary to current mechanistic models, loss of Lrp5, the co-receptor thought to transmit extracellular WNT signals during bone mass regulation, did not reduce the bone-anabolic effect of Wnt1, providing direct evidence that Wnt1 function does not require the LRP5 co-receptor. The identification of Wnt1 as a regulator of bone formation and remodeling provides the basis for development of Wnt1-targeting drugs for the treatment of osteoporosis.

Considerations for sentinel lymph node biopsy in breast cancer patients with biopsy proven axillary disease prior to neoadjuvant treatment.

BACKGROUND: Axillary disease can be downstaged with neoadjuvant treatment for breast cancer. We attempted to identify factors to consider in determining whether to perform a sentinel lymph node biopsy in patients with biopsy proven axillary metastases (cN+) prior to neoadjuvant treatment. METHODS: A retrospective chart review was conducted on patients at a single tertiary care center who underwent neoadjuvant treatment followed by surgery between 9/2013 and 2/2017. RESULTS: 47% of patients with node positive disease prior to neoadjuvant treatment were downstaged to node negative (ypN0) disease. These patients were more likely to have triple negative or Her2 positive disease than those patients who remained node positive (ypN+) as these were more likely to have hormone receptor positive disease. These patients were also more likely to demonstrate complete clinical imaging response of the primary tumor and axilla on preoperative breast MRI. CONCLUSIONS: Tumor biology and clinical response noted on breast MRI can help guide the decision to perform sentinel lymph node biopsy in patients with axillary node positive disease prior to neoadjuvant treatment.

Reducing variation in feeding newborns with congenital heart disease.

OBJECTIVE: Enteral feeding is associated with decreased infection rates, decreased mechanical ventilation, decreased hospital length of stay, and improved wound healing. Enteral feeding difficulties are common in congenital heart disease. Our objective was to develop experience-based newborn feeding guidelines for the initiation and advancement of enteral feeding in the cardiothoracic intensive care unit. DESIGN: This is a retrospective analysis of a quality improvement project. SETTING: This quality improvement project was performed in a cardiothoracic intensive care unit. PATIENTS: Newborns admitted to the cardiothoracic intensive care unit for cardiac surgery from January 2011 to May 2015 were retrospectively reviewed. INTERVENTION: Newborn feeding guidelines for the initiation and advancement of enteral feeding were implemented in January 2012. OUTCOME MEASURES: Guideline compliance and clinical variables before and after guideline implementation were reviewed. RESULTS: Compliance with the guidelines increased from 83% in 2012 to 100% in the first two quarters of 2015. Preguidelines (January 2011-December 2011): 45 newborns underwent cardiac surgery; 8 deaths prior to discharge; 1 patient discharged from NICU, therefore, N = 36. Postguidelines (January 2012-May 2015): 131 newborns with 12 deaths, 12 admitted from home, 8 in the NICU, 3 on the floor preop, and 3 back transferred, therefore, N = 93. No difference in feeding preop (post 75% vs pre 69%; P = .5) or full po feeds at discharge (post 78% vs pre 89%; P = .2). Mesenteric ischemia was not statistically different postguidelines (post 6% vs pre 14%; P = .14). Length of hospital stay decreased postguidelines (post 27 + 17 d vs pre 34 + 42 d; P < .001). CONCLUSIONS: Implementation of experience-based newborn feeding guidelines for initiation and advancement of enteral feeding in the cardiothoracic intensive care unit was successful in reducing practice variation supported by increasing guideline compliance. Percentage of patient's full oral feeding at discharge did not change. Length of hospital stay was reduced although cannot be fully attributed to feeding guideline implementation.

Parathyroid hormone induces expression and proteolytic processing of Rankl in primary murine osteoblasts.

Rankl, the major pro-osteoclastogenic cytokine, is synthesized as a transmembrane protein that can be cleaved by specific endopeptidases to release a soluble form (sRankl). We have previously reported that interleukin-33 (IL-33) induces expression of Tnfsf11, the Rankl-encoding gene, in primary osteoblasts, but we failed to detect sRankl in the medium. Since we also found that PTH treatment caused sRankl release in a similar experimental setting, we directly compared the influence of the two molecules. Here we show that treatment of primary murine osteoblasts with PTH causes sRankl release into the medium, whereas IL-33 only induces Tnfsf11 expression. This difference was not explainable by alternative splicing or by PTH-specific induction of endopeptidases previously shown to facilitate Rankl processing. Since sRankl release after PTH administration was blocked in the presence a broad-spectrum matrix metalloprotease inhibitor, we applied genome-wide expression analyses to identify transcriptional targets of PTH in osteoblasts. We thereby confirmed some of the effects of PTH established in other systems, but additionally identified few PTH-induced genes encoding metalloproteases. By comparing expression of these genes following administration of IL-33, PTH and various other Tnfsf11-inducing molecules, we observed that PTH was the only molecule simultaneously inducing sRankl release and Adamts1 expression. The functional relevance of the putative influence of PTH on Rankl processing was further confirmed in vivo, as we found that daily injection of PTH into wildtype mice did not only increase bone formation, but also osteoclastogenesis and sRankl concentrations in the serum. Taken together, our findings demonstrate that transcriptional effects on Tnfsf11 expression do not generally trigger sRankl release and that PTH has a unique activity to promote the proteolytic processing of Rankl.

Osteoblast-specific Notch2 inactivation causes increased trabecular bone mass at specific sites of the appendicular skeleton.

Notch signaling is a key pathway controlling various cell fate decisions during embryogenesis and adult life. It is activated by binding of specific ligands to four different Notch receptors that are subsequently cleaved by presenilins to release an intracellular domain that enters the nucleus and activates specific transcription factors. While the skeletal analysis of various mouse models with activated or inactivated Notch signaling has demonstrated a general impact of this pathway on bone remodeling, the more recent identification of NOTCH2 mutations in individuals with Hajdu-Cheney syndrome (HCS) has highlighted its human relevance. Since HCS is primarily characterized by skeletal defects, these latter findings led us to analyze the specific role of Notch2 in skeletal remodeling. After observing Notch2 expression in osteoblasts and osteoclasts, we utilized Runx2-Cre and Lyz2-Cre mice to inactivate Notch2 in cells of the osteoblast or osteoclast lineage, respectively. Whereas Notch2(fl/fl)/Lyz2-Cre mice did not display significant alterations of skeletal growth, bone mass or remodeling, Notch2(fl/fl)/Runx2-Cre mice progressively developed skeletal abnormalities in long bones. More specifically, these mice displayed a striking increase of trabecular bone mass in the proximal femur and the distal tibia at 6 and 12months of age. Whereas undecalcified sectioning of the respective regions did not reveal impaired osteocyte differentiation as a potential trigger for the observed phenotype, ex vivo experiments with bone marrow cells identified an increased osteogenic capacity of Notch2(fl/fl)/Runx2-Cre cultures. Collectively, our findings demonstrate that Notch2 physiologically regulates bone remodeling by inhibiting trabecular bone formation in the appendicular skeleton. Understanding the underlying mechanisms may help to improve diagnosis and therapy of HCS.