Reducing Sharps Injuries in the Operating Rooms of an Academic Tertiary Care Center.

BACKGROUND: Data on the prevalence and distribution of operating room (OR) sterile field sharps injuries sustained by attending surgeons, residents, scrub nurses, and surgical technologists are limited. The goal of this study is to understand current practices, injuries, and reporting behavior at an academic center, implement interventions, and assess their effect on sharps safety and reporting. METHODS: An electronic survey with questions pertaining to sharps handling practices, injuries, and reporting was e-mailed to 864 staff between July and September 2014. Adjusted analyses for risk of injury were performed. A follow-up survey was sent in January 2018, following the implementation of a shorter injury reporting form and a neutral zone. RESULTS: The overall response rate was 49.3%, with 363 completed surveys. Of respondents, 44.9% reported injuries occurring in the preceding three years. Physicians comprised 65.1% of injured staff and sustained 68.8% of the total injuries. Compared to attending surgeons, residents had a similar likelihood of injury (odds ratio 0.9, 95% confidence interval [CI] 0.37-2.2), whereas scrub nurses (odds ratio 0.3, 95% CI 0.17-0.54) and technologists (odds ratio 0.3, 95% CI 0.14-0.76) had a lower likelihood. Half of those injured reported to Occupational Health Services. Of those who did not report, 46.4% stated that time was a limiting factor. Following the interventions, the incidence of injuries among survey respondents remained unchanged. However, 54.0% of respondents stated that it was easier to report injuries. CONCLUSION: Attending surgeons and residents sustain the majority of OR sterile field sharps injuries and are the least likely to report them. Shorter reports made it easier to report the injuries.

Impact of staff turnover during cardiac surgical procedures.

OBJECTIVE: The impact of staff turnover during cardiac procedures is unknown. Accurate inventory of sharps (needles/blades) requires attention by surgical teams, and sharp count errors result in delays, can lead to retained foreign objects, and may signify communication breakdown. We hypothesized that increased team turnover raises the likelihood of sharp count errors and may negatively affect patient outcomes. METHODS: All cardiac operations performed at our institution from May 2011 to March 2016 were reviewed for sharp count errors from a prospectively maintained database. Univariate and multivariable analyses were performed. RESULTS: Among 7264 consecutive cardiac operations, sharp count errors occurred in 723 cases (10%). There were no retained sharps detected by x-ray in our series. Sharp count errors were lower on first start cases (7.7% vs 10.7%, P < .001). Cases with sharp count errors were longer than those without (7 vs 5.7 hours, P < .001). In multivariable analysis, factors associated with an increase in sharp count errors were non-first start cases (odds ratio [OR], 1.3; P = .006), weekend cases (OR, 1.6; P < .004), more than 2 scrub personnel (3 scrubs: OR, 1.3; P = .032; 4 scrubs: OR, 2; P < .001; 5 scrubs: OR, 2.4; P = .004), and more than 1 circulating nurse (2 nurses: OR, 1.9; P < .001; 3 nurses: OR, 2; P < .001; 4 nurses: OR, 2.4; P < .001; 5 nurses: OR, 3.1; P < .001). Sharp count errors were associated with higher rates of in-hospital mortality (OR, 1.9; P = .038). CONCLUSIONS: Sharp count errors are more prevalent with increased team turnover and during non-first start cases or weekends. Sharp count errors may be a surrogate marker for other errors and thus increased mortality. Reducing intraoperative team turnover or optimizing hand-offs may reduce sharp count errors.

Improved outcomes in cystic fibrosis using modified Re-Education of Airway Clearance Technique (REACT) programme.

BACKGROUND AND OBJECTIVES: Cystic fibrosis (CF) is known to reduce lung function as measured by per cent predicted for the forced expiratory volume in the first second (ppFEV1) over time. Our paediatric CF programme demonstrated significant gaps in benchmarked ppFEV1 predicted compared with the national median. Our objective was to assess whether the implementation of a modified Re-Education of Airway Clearance Techniques (REACT) programme could lead to an improvement in lung function as measured by ppFEV1. METHODS: This 2-year prospective quality improvement study at Lurie Children's CF Center for children aged >6 years used improvement methodology to implement a modified REACT programme. Outcome measures were assessed for our entire programme via the CF Foundation Patient Registry (CFFPR) and statistical process control. Comparisons were also made before and after REACT for outcome measures. RESULTS: By the end of implementation, monthly participation rate achieved 100%. Using CFFPR data and SPC, median ppFEV1 increased by 3.9%, whereas only body mass index (BMI) as a secondary outcome increased. Comparison of pre and post REACT showed improvements in average ppFEV1 (95% vs 96%, p<0.0001), FEF25%-75% (82% vs 83%, p=0.0590), rate of ppFEV1 decline (+2% vs -4%, p=0.0262) and BMI percentile (57% vs 60%, p<0.0001). CONCLUSIONS: Implementation of a modified REACT at Lurie Children's paediatric CF programme led to an increase in ppFEV1, FEF25%-75% and BMI percentile.

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures: a Cochrane systematic review.

BACKGROUND: Buffered intravenous fluid preparations contain substrates to maintain acid-base status. The objective of this systematic review was to compare the effects of buffered and non-buffered fluids administered during the perioperative period on clinical and biochemical outcomes. METHODS: We searched MEDLINE, EMBASE, CINAHL and the Cochrane Library until May 2017 and included all randomised controlled trials that evaluated buffered versus non-buffered fluids, whether crystalloid or colloid, administered to surgical patients. We assessed the selected studies for risk of bias and graded the level of evidence in accordance with Cochrane recommendations. RESULTS: We identified 19 publications of 18 randomised controlled trials, totalling 1096 participants. Mean difference (MD) in postoperative pH was 0.05 units lower immediately following surgery in the non-buffered group (12 studies of 720 participants; 95% confidence interval (CI) 0.04 to 0.07; I 2 = 61%). This difference did not persist on postoperative day 1. Serum chloride concentration was higher in the non-buffered group at the end of surgery (10 trials of 530 participants; MD 6.77 mmol/L, 95% CI 3.38 to 10.17). This effect persisted until postoperative day 1 (5 trials of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). Quality of this evidence was moderate. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Outcome data was variably reported at disparate time points and with heterogeneous patient groups. Consequently, the effect size and overall confidence interval was reduced, despite the relatively low inherent risk of bias. There was insufficient evidence on the effect of fluid composition on mortality and organ dysfunction. Confidence intervals of this outcome were wide and the quality of evidence was low (3 trials of 276 participants for mortality; odds ratio (OR) 1.85, 95% CI 0.37 to 9.33; I 2 = 0%). CONCLUSIONS: Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Buffered fluid may have biochemical benefits, including a significant reduction in postoperative hyperchloraemia and metabolic acidosis.

Perioperative administration of buffered versus non-buffered crystalloid intravenous fluid to improve outcomes following adult surgical procedures.

BACKGROUND: Perioperative fluid strategies influence clinical outcomes following major surgery. Many intravenous fluid preparations are based on simple solutions, such as normal saline, that feature an electrolyte composition that differs from that of physiological plasma. Buffered fluids have a theoretical advantage of containing a substrate that acts to maintain the body's acid-base status - typically a bicarbonate or a bicarbonate precursor such as maleate, gluconate, lactate, or acetate. Buffered fluids also provide additional electrolytes, including potassium, magnesium, and calcium, more closely matching the electrolyte balance of plasma. The putative benefits of buffered fluids have been compared with those of non-buffered fluids in the context of clinical studies conducted during the perioperative period. This review was published in 2012, and was updated in 2017. OBJECTIVES: To review effects of perioperative intravenous administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance, or both, on clinical outcomes in adults undergoing all types of surgery. SEARCH METHODS: We electronically searched the Clinicaltrials.gov major trials registry, the Cochrane Central Register of Controlled Trials (CENTRAL; 2016, Issue 6) in the Cochrane Library, MEDLINE (1966 to June 2016), Embase (1980 to June 2016), and the Cumulative Index to Nursing and Allied Health Literature (CINAHL; 1982 to June 2016). We handsearched conference abstracts and, when possible, contacted leaders in the field. We reran the search in May 2017. We added one potential new study of interest to the list of 'Studies awaiting classification' and will incorporate this trial into formal review findings when we prepare the review update. SELECTION CRITERIA: Only randomized controlled trials that compared buffered versus non-buffered intravenous fluids for surgical patients were eligible for inclusion. We excluded other forms of comparison such as crystalloids versus colloids and colloids versus different colloids. DATA COLLECTION AND ANALYSIS: Two review authors screened references for eligibility, extracted data, and assessed risks of bias. We resolved disagreements by discussion and consensus, in collaboration with a third review author. We contacted trial authors to request additional information when appropriate. We presented pooled estimates for dichotomous outcomes as odds ratios (ORs) and for continuous outcomes as mean differences (MDs), with 95% confidence intervals (CIs). We analysed data via Review Manager 5.3 using fixed-effect models, and when heterogeneity was high (I² > 40%), we used random-effects models. MAIN RESULTS: This review includes, in total, 19 publications of 18 randomized controlled trials with a total of 1096 participants. We incorporated five of those 19 studies (330 participants) after the June 2016 update. Outcome measures in the included studies were thematically similar, covering perioperative electrolyte status, renal function, and acid-base status; however, we found significant clinical and statistical heterogeneity among the included studies. We identified variable protocols for fluid administration and total volumes of fluid administered to patients intraoperatively. Trial authors variably reported outcome data at disparate time points and with heterogeneous patient groups. Consequently, many outcome measures are reported in small group sizes, reducing overall confidence in effect size, despite relatively low inherent bias in the included studies. Several studies reported orphan outcome measures. We did not include in the results of this review one large, ongoing study of saline versus Ringer's solution.We found insufficient evidence on effects of fluid therapies on mortality and postoperative organ dysfunction (defined as renal insufficiency leading to renal replacement therapy); confidence intervals were wide and included both clinically relevant benefit and harm: mortality (Peto OR 1.85, 95% CI 0.37 to 9.33; I² = 0%; 3 trials, 6 deaths, 276 participants; low-quality evidence); renal insufficiency (OR 0.82, 95% CI 0.34 to 1.98; I² = 0%; 4 trials, 22 events, 276 participants; low-quality evidence).We noted several metabolic differences, including a difference in postoperative pH measured at end of surgery of 0.05 units - lower in the non-buffered fluid group (12 studies with a total of 720 participants; 95% CI 0.04 to 0.07; I² = 61%). However, this difference was not maintained on postoperative day one. We rated the quality of evidence for this outcome as moderate. We observed a higher postoperative serum chloride level immediately after operation, with use of non-buffered fluids reported in 10 studies with a total of 530 participants (MD 6.77 mmol/L, 95% CI 3.38 to 10.17), and this difference persisted until day one postoperatively (five studies with a total of 258 participants; MD 8.48 mmol/L, 95% CI 1.08 to 15.88). We rated the quality of evidence for this outcome as moderate. AUTHORS' CONCLUSIONS: Current evidence is insufficient to show effects of perioperative administration of buffered versus non-buffered crystalloid fluids on mortality and organ system function in adult patients following surgery. Benefits of buffered fluid were measurable in biochemical terms, particularly a significant reduction in postoperative hyperchloraemia and metabolic acidosis. Small effect sizes for biochemical outcomes and lack of correlated clinical follow-up data mean that robust conclusions on major morbidity and mortality associated with buffered versus non-buffered perioperative fluid choices are still lacking. Larger studies are needed to assess these relevant clinical outcomes.

AARC Clinical Practice Guideline: Effectiveness of Pharmacologic Airway Clearance Therapies in Hospitalized Patients.

Aerosolized medications are used as airway clearance therapy to treat a variety of airway diseases. These guidelines were developed from a systematic review with the purpose of determining whether the use of these medications to promote airway clearance improves oxygenation and respiratory mechanics, reduces ventilator time and ICU stay, and/or resolves atelectasis/consolidation compared with usual care. Recombinant human dornase alfa should not be used in hospitalized adult and pediatric patients without cystic fibrosis. The routine use of bronchodilators to aid in secretion clearance is not recommended. The routine use of aerosolized N-acetylcysteine to improve airway clearance is not recommended. Aerosolized agents to change mucus biophysical properties or promote airway clearance are not recommended for adult or pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough. Mucolytics are not recommended to treat atelectasis in postoperative adult or pediatric patients, and the routine administration of bronchodilators to postoperative patients is not recommended. There is no high-level evidence related to the use of bronchodilators, mucolytics, mucokinetics, and novel therapy to promote airway clearance in these populations.

Device Cleaning and Infection Control in Aerosol Therapy.

Aerosol delivery equipment used to administer inhaled medications includes the nebulizer, positive expiratory pressure devices added to the nebulizer, and valved holding chambers (spacers). These devices are semi-critical medical devices, and as such, infection prevention and control (IPC) guidelines recommend that they be cleaned, disinfected, rinsed with sterile water, and air-dried. There is confusion surrounding the care of aerosol devices because of inconsistencies in the various published IPC guidelines, lack of a standard of practice among institutions and respiratory therapists (RTs), and manufacturer's instructions for use of these devices are not always compatible with guidelines or practice. Challenges lie in awareness of IPC guidelines and establishing a standard for the care of aerosol delivery devices among all stakeholders/manufacturers, governments, vendors, and users. The latest IPC guideline from the Cystic Fibrosis Foundation, reviewed and endorsed by the Society for Healthcare Epidemiology of America and the Association for Professionals in Infection Control, has a recommendation for disposable nebulizers and a recommendation for reusable nebulizers. Reusable nebulizers should be cleaned, disinfected, rinsed with sterile water (if using a cold disinfectant), and air-dried between uses. The mouthpiece/mask of disposable nebulizers should be wiped with an alcohol pad, the residual volume should be rinsed out with sterile water after use, and the nebulizer should be replaced every 24 h. The RT plays a significant and responsible role in providing and teaching aerosol therapy to patients. The RT and all stakeholders need to work together to provide a standard of care for the safe use of aerosol delivery devices.

Safety culture and care: a program to prevent surgical errors.

Surgical errors are under scrutiny in health care as part of ensuring a culture of safety in which patients receive quality care. Hospitals use safety measures to compare their performance against industry benchmarks. To understand patient safety issues, health care providers must have processes in place to analyze and evaluate the quality of the care they provide. At one facility, efforts made to improve its quality and safety led to the development of a robust safety program with resources devoted to enhancing the culture of safety in the Perioperative Services department. Improvement initiatives included changing processes for safety reporting and performance improvement plans, adding resources and nurse roles, and creating communication strategies around adverse safety events and how to improve care. One key outcome included a 54% increase in the percentage of personnel who indicated in a survey that they would speak up if they saw something negatively affecting patient care.

Improved patient safety through reduced airway infection rates in a paediatric cystic fibrosis programme after a quality improvement effort to enhance infection prevention and control measures.

OBJECTIVE: To reduce the risk of pathogen transmission between patients with cystic fibrosis (CF) and decrease the rate of acquisition of new CF pathogens in our patients. DESIGN: Using the Model for Improvement, we developed a new process for infection prevention and control in our outpatient CF clinics. SETTING: Paediatric CF programme at Ann & Robert H. Lurie Children's Hospital of Chicago; approximately 180 paediatric patients aged birth to 21 years. PARTICIPANTS: All paediatric patients enrolled in the Cystic Fibrosis Foundation Patient Data Registry at this institution. INTERVENTIONS: Implemented contact precautions with all patients, regardless of respiratory tract culture results. MEASUREMENT: Respiratory tract culture rates of specific pathogens by quarter were compared prior to and after implementation. RESULTS: Our percentage of patients with a positive respiratory tract culture for Pseudomonas aeruginosa dropped from 30% to 21% (p<0.0001) and for methicillin-resistant Staphylococcus aureus (MRSA) dropped from 10.8% to 8.7% (p=0.008). CONCLUSIONS: Use of contact precautions by all care providers, for all patients, regardless of respiratory tract culture results resulted in decreased P aeruginosa and MRSA infection rates.

AARC clinical practice guideline: effectiveness of nonpharmacologic airway clearance therapies in hospitalized patients.

Airway clearance therapy (ACT) is used in a variety of settings for a variety of ailments. These guidelines were developed from a systematic review with the purpose of determining whether the use of nonpharmacologic ACT improves oxygenation, reduces length of time on the ventilator, reduces stay in the ICU, resolves atelectasis/consolidation, and/or improves respiratory mechanics, versus usual care in 3 populations. For hospitalized, adult and pediatric patients without cystic fibrosis, 1) chest physiotherapy (CPT) is not recommended for the routine treatment of uncomplicated pneumonia; 2) ACT is not recommended for routine use in patients with COPD; 3) ACT may be considered in patients with COPD with symptomatic secretion retention, guided by patient preference, toleration, and effectiveness of therapy; 4) ACT is not recommended if the patient is able to mobilize secretions with cough, but instruction in effective cough technique may be useful. For adult and pediatric patients with neuromuscular disease, respiratory muscle weakness, or impaired cough, 1) cough assist techniques should be used in patients with neuromuscular disease, particularly when peak cough flow is < 270 L/min; CPT, positive expiratory pressure, intrapulmonary percussive ventilation, and high-frequency chest wall compression cannot be recommended, due to insufficient evidence. For postoperative adult and pediatric patients, 1) incentive spirometry is not recommended for routine, prophylactic use in postoperative patients, 2) early mobility and ambulation is recommended to reduce postoperative complications and promote airway clearance, 3) ACT is not recommended for routine postoperative care. The lack of available high-level evidence related to ACT should prompt the design and completion of properly designed studies to determine the appropriate role for these therapies.

Patterns of weight change and progression to overweight and obesity differ in men and women: implications for research and interventions.

OBJECTIVE: To evaluate long-term patterns of weight change and progression to overweight and obesity during adulthood. DESIGN: Prospective study. Changes in mean BMI, waist circumference (WC) and weight were assessed over a mean 26-year follow-up (1971­1975 to 1998­2001). Mean BMI (95% CI) and mean WC (95% CI) of men and women in BMI and age groups were computed. Mean weight change in BMI and age categories was compared using analysis of covariance. SETTING: Framingham Heart Study Offspring/Spouse Nutrition Study. SUBJECTS: Men and women (n 2394) aged 20­63 years. RESULTS: During follow-up, increases in BMI (men: 2?2 kg/m2; women: 3?7 kg/m2) and WC (men: 5?7 cm; women: 15?1 cm) were larger in women than men. BMI gains were greatest in younger adults (20­39 years) and smallest in obese older adults (50­69 years). The prevalence of obesity doubled in men (to 33?2%) and tripled in women (to 26?6 %). Among normal-weight individuals, abdominal obesity developed in women only. The prevalence of abdominal obesity increased 1?8-fold in men (to 53?0%) and 2?4-fold in women (to 71?2 %). Weight gain was greatest in the youngest adults (20­29 years), particularly women. Gains continued into the fifth decade among men and then declined in the sixth decade; in women gains continued into the sixth decade. CONCLUSIONS: Patterns of weight change and progression to obesity during adulthood differ in men and women. Preventive intervention strategies for overweight and obesity need to consider age- and sex-specific patterns of changes in anthropometric measures.

Perioperative buffered versus non-buffered fluid administration for surgery in adults.

BACKGROUND: Perioperative fluid therapy influences clinical outcomes following major surgery. Fluid preparations may be based on a simple non-buffered salt solution, such as normal saline, or may be modified with bicarbonate or bicarbonate precursor buffers, such as maleate, gluconate, lactate or acetate, to better reflect the human physiological state. These latter fluids have theoretical advantages over normal saline in preventing hyperchloraemic acidosis. A number of clinical studies have now compared fluid preparations with and without a buffer to achieve a balanced electrolyte solution for perioperative fluid resuscitation. OBJECTIVES: To review the safety and efficacy of perioperative administration of buffered versus non-buffered fluids for plasma volume expansion or maintenance in adult patients undergoing surgery. SEARCH METHODS: We electronically searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2011, Issue 4), MEDLINE (1966 to May 2011), EMBASE (1980 to May 2011), and CINAHL (1982 to May 2011). We handsearched conference abstracts and where possible, contacted leaders in the field. SELECTION CRITERIA: We only included randomized trials of buffered versus non-buffered intravenous fluids for perioperative fluid resuscitation. The trials with other forms of comparisons such as crystalloids versus colloids and colloids versus different colloids were excluded. We also excluded trials using hypertonic fluids and dextrose-based fluids. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed the methodological quality of clinical trials. We resolved any disagreements by discussion. We contacted the trial authors to provide additional information where appropriate. We presented pooled estimates of the dichotomous outcomes as odds ratios (OR) and on continuous outcomes as mean differences, with 95% confidence intervals (CI). We analysed data on Review Manager 5.1 using fixed-effect models, and when heterogeneity was high (I² > 40%) random-effect models were used. MAIN RESULTS: We identified 14 publications reporting 13 trials or comparisons with a total of 706 participants. For many of the outcomes reported, there was significant clinical and statistical heterogeneity. The primary outcome of mortality at any time was reported in only three studies with a total of 267 patients. The mortality rate was 2.9% for the buffered fluids group and 1.5% for the non-buffered fluids group but this difference was not statistically significant. The Peto OR was 1.85 (95% CI 0.37 to 9.33, P = 0.45, I(2)= 0%). Organ dysfunction was only presented for renal impairment. There was no difference in renal insufficiency leading to renal replacement therapy between the buffered and non-buffered groups (OR 0.61, 95% CI 0.23 to 1.63, P = 0.32, I(2) = 0%). Markers of organ system failure as assessed by urine output, creatinine and its variables (for renal function), PaC0(2) (respiratory function) and postoperative nausea and vomiting (gastro-intestinal function) showed a statistically significant difference only in PaC0(2) levels. The mean difference was 1.18 with lower PaC0(2) levels in the non-buffered fluid group (95% CI 0.09 to 2.28, P = 0.03, I(2) = 0%) compared to the buffered fluid group.There was no difference in intraoperative blood loss nor the volumes of intraoperative red cell or fresh frozen plasma transfused between groups. There was an increase in platelet transfusion in the non-buffered group which was statistically significant after analysing the transformed data (log transformation because the data were highly skewed).A number of metabolic differences were noted. There was a difference in postoperative pH of 0.06 units, lower in the non-buffered fluid group (95% CI 0.04 to 0.08, P < 0.00001, I(2) = 74%). However, this difference was not maintained on postoperative day one. The non-buffered fluid group also had significantly greater base deficit, serum sodium and chloride levels.There was no difference demonstrated in length of hospital stay and no data were reported on cost or quality of life. AUTHORS' CONCLUSIONS: The administration of buffered fluids to adult patients during surgery is equally safe and effective as the administration of non-buffered saline-based fluids. The use of buffered fluids is associated with less metabolic derangement, in particular hyperchloraemia and metabolic acidosis. Larger studies are needed to assess robust outcomes such as mortality.

Progressive neuronal inclusion formation and axonal degeneration in CHMP2B mutant transgenic mice.

Mutations in the charged multivesicular body protein 2B (CHMP2B) gene cause frontotemporal lobar degeneration. The mutations lead to C-terminal truncation of the CHMP2B protein. We generated Chmp2b knockout mice and transgenic mice expressing either wild-type or C-terminally truncated mutant CHMP2B. The transgenic CHMP2B mutant mice have decreased survival and show progressive neurodegenerative changes including gliosis and increasing accumulation of p62- and ubiquitin-positive inclusions. The inclusions are negative for the TAR DNA binding protein 43 and fused in sarcoma proteins, mimicking the inclusions observed in patients with CHMP2B mutation. Mice transgenic for mutant CHMP2B also develop an early and progressive axonopathy characterized by numerous amyloid precursor protein-positive axonal swellings, implicating altered axonal function in disease pathogenesis. These findings were not observed in Chmp2b knockout mice or in transgenic mice expressing wild-type CHMP2B, indicating that CHMP2B mutations induce degenerative changes through a gain of function mechanism. These data describe the first mouse model of dementia caused by CHMP2B mutation and provide new insights into the mechanisms of CHMP2B-induced neurodegeneration.

PrP antibodies do not trigger mouse hippocampal neuron apoptosis.

Intraperitoneal administration of ICSM18 and 35, monoclonal antibodies against prion protein (PrP), has been shown to significantly delay the onset of prion disease in mice, and humanized versions are candidate therapeutics for prion and Alzheimer's diseases. However, a previous report of severe and widespread apoptosis after intracerebral injection of anti-PrP monoclonal antibodies raised concerns about such therapy and led to an influential model of prion neurotoxicity via cross-linking of cell surface PrP by disease-related PrP aggregates. In extensive studies including ICSM18 and 35, fully humanized ICSM18, and the previously reported proapoptotic antibodies, we found no evidence of apoptosis, thereby questioning this model of prion neurotoxicity.

Inherited prion disease with 4-octapeptide repeat insertion: disease requires the interaction of multiple genetic risk factors.

Genetic factors are implicated in the aetiology of sporadic late-onset neurodegenerative diseases. Whether these genetic variants are predominantly common or rare, and how multiple genetic factors interact with each other to cause disease is poorly understood. Inherited prion diseases are highly heterogeneous and may be clinically mistaken for sporadic Creutzfeldt-Jakob disease because of a negative family history. Here we report our investigation of patients from the UK with four extra octapeptide repeats, which suggest that the risk of clinical disease is increased by a combination of the mutation and a susceptibility haplotype on the wild-type chromosome. The predominant clinical syndrome is a progressive cortical dementia with pyramidal signs, myoclonus and cerebellar abnormalities that closely resemble sporadic Creutzfeldt-Jakob disease. Autopsy shows perpendicular deposits of prion protein in the molecular layer of the cerebellum. Identity testing, PRNP microsatellite haplotyping and genealogical work confirm no cryptic close family relationships and suggests multiple progenitor disease haplotypes. All patients were homozygous for methionine at polymorphic codon 129. In addition, at a single nucleotide polymorphism upstream of PRNP thought to confer susceptibility to sporadic Creutzfeldt-Jakob disease (rs1029273), all patients were homozygous for the risk allele (combined P=5.9×10(-5)). The haplotype identified may also be a risk factor in other partially penetrant inherited prion diseases although it does not modify age of onset. Blood expression of PRNP in healthy individuals was modestly higher in carriers of the risk haplotype. These findings may provide a precedent for understanding apparently sporadic neurodegenerative diseases caused by rare high-risk mutations.

Effect of fixation on brain and lymphoreticular vCJD prions and bioassay of key positive specimens from a retrospective vCJD prevalence study.

Anonymous screening of lymphoreticular tissues removed during routine surgery has been applied to estimate the UK population prevalence of asymptomatic vCJD prion infection. The retrospective study of Hilton et al (J Pathol 2004; 203: 733-739) found accumulation of abnormal prion protein in three formalin-fixed appendix specimens. This led to an estimated UK prevalence of vCJD infection of ∼1 in 4000, which remains the key evidence supporting current risk reduction measures to reduce iatrogenic transmission of vCJD prions in the UK. Confirmatory testing of these positives has been hampered by the inability to perform immunoblotting of formalin-fixed tissue. Animal transmission studies offer the potential for 'gold standard' confirmatory testing but are limited by both transmission barrier effects and known effects of fixation on scrapie prion titre in experimental models. Here we report the effects of fixation on brain and lymphoreticular human vCJD prions and comparative bioassay of two of the three prevalence study formalin-fixed, paraffin-embedded (FFPE) appendix specimens using transgenic mice expressing human prion protein (PrP). While transgenic mice expressing human PrP 129M readily reported vCJD prion infection after inoculation with frozen vCJD brain or appendix, and also FFPE vCJD brain, no infectivity was detected in FFPE vCJD spleen. No prion transmission was observed from either of the FFPE appendix specimens. The absence of detectable infectivity in fixed, known positive vCJD lymphoreticular tissue precludes interpreting negative transmissions from vCJD prevalence study appendix specimens. In this context, the Hilton et al study should continue to inform risk assessment pending the outcome of larger-scale studies on discarded surgical tissues and autopsy samples.

Chronic wasting disease prions are not transmissible to transgenic mice overexpressing human prion protein.

Chronic wasting disease (CWD) is a prion disease that affects free-ranging and captive cervids, including mule deer, white-tailed deer, Rocky Mountain elk and moose. CWD-infected cervids have been reported in 14 USA states, two Canadian provinces and in South Korea. The possibility of a zoonotic transmission of CWD prions via diet is of particular concern in North America where hunting of cervids is a popular sport. To investigate the potential public health risks posed by CWD prions, we have investigated whether intracerebral inoculation of brain and spinal cord from CWD-infected mule deer transmits prion infection to transgenic mice overexpressing human prion protein with methionine or valine at polymorphic residue 129. These transgenic mice have been utilized in extensive transmission studies of human and animal prion disease and are susceptible to BSE and vCJD prions, allowing comparison with CWD. Here, we show that these mice proved entirely resistant to infection with mule deer CWD prions arguing that the transmission barrier associated with this prion strain/host combination is greater than that observed with classical BSE prions. However, it is possible that CWD may be caused by multiple prion strains. Further studies will be required to evaluate the transmission properties of distinct cervid prion strains as they are characterized.

Diet quality, physical activity, smoking status, and weight fluctuation are associated with weight change in women and men.

The effect of diet quality on weight change, relative to other body weight determinants, is insufficiently understood. Furthermore, research on long-term weight change in U.S. adults is limited. We evaluated prospectively patterns and predictors of weight change in Framingham Offspring/Spouse (FOS) women and men (n = 1515) aged > or =30 y with BMI > or = 18.5 kg/m2 and without cardiovascular disease, diabetes, and cancer at baseline over a 16-y period. Diet quality was assessed using the validated Framingham Nutritional Risk Score. In women, older age (P < 0.0001) and physical activity (P < 0.05) were associated with lower weight gain. Diet quality interacted with former smoking status (P-interaction = 0.02); former smokers with lower diet quality gained an additional 5.2 kg compared with those with higher diet quality (multivariable-adjusted P-trend = 0.06). Among men, older age (P < 0.0001) and current smoking (P < 0.01) were associated with lower weight gain, and weight fluctuation (P < 0.01) and former smoking status (P < 0.0001) were associated with greater weight gain. Age was the strongest predictor of weight change in both women (partial R(2) = 11%) and men (partial R(2) = 8.6%). Normal- and overweight women gained more than obese women (P < 0.05) and younger adults gained more weight than older adults (P < 0.0001). Patterns and predictors of weight change differ by sex. Age in both sexes and physical activity among women as well as weight fluctuation and smoking status in men were stronger predictors of weight change than diet quality among FOS adults. Women who stopped smoking over follow-up and had poor diet quality gained the most weight. Preventive interventions need to be sex-specific and consider lifestyle factors.