Liver and pancreatic-targeted interleukin-22 as a therapeutic for metabolic dysfunction-associated steatohepatitis.

Metabolic dysfunction-associated steatohepatitis (MASH) is the most prevalent cause of liver disease worldwide, with a single approved therapeutic. Previous research has shown that interleukin-22 (IL-22) can suppress ß-cell stress, reduce local islet inflammation, restore appropriate insulin production, reverse hyperglycemia, and ameliorate insulin resistance in preclinical models of diabetes. In clinical trials long-acting forms of IL-22 have led to increased proliferation in the skin and intestine, where the IL-22RA1 receptor is highly expressed. To maximise beneficial effects whilst reducing the risk of epithelial proliferation and cancer, we designed short-acting IL-22-bispecific biologic drugs that successfully targeted the liver and pancreas. Here we show 10-fold lower doses of these bispecific biologics exceed the beneficial effects of native IL-22 in multiple preclinical models of MASH, without off-target effects. Treatment restores glycemic control, markedly reduces hepatic steatosis, inflammation, and fibrogenesis. These short-acting IL-22-bispecific targeted biologics are a promising new therapeutic approach for MASH.

Heat illness presentations to emergency departments in Western Sydney: surveillance for environmental, personal and behavioural risk factors.

OBJECTIVE: To pilot surveillance to describe environmental, personal and behavioural risk factors for people presenting to hospital emergency departments (EDs) with heat illness. METHODS: We conducted a retrospective case series and telephone interview study of people presenting to EDs across South Western Sydney, Western Sydney and Nepean Blue Mountains Local Health Districts with heat illness over the 2017/18 and 2018/19 summer periods (1 December to 28 February). We used the Public Health Rapid Emergency Disease Syndromic Surveillance (PHREDSS) 'heat problems' syndrome to identify people with heat illness and medical records to find contact details. We developed a detailed questionnaire instrument to guide the telephone interview. RESULTS: A total of 129 individuals presented with 'heat problems' (57 in 2017/18 and 72 in 2018/19). The median age was 44 years (range 1-89 years). Most attended hospitals via the NSW Ambulance Service (58%) or private car (40%). Of the total, 53% were classified as triage category 3 (potentially life-threatening), 27% as category 4 (potentially serious) and 16% as category 2 (imminently life-threatening). The main supplementary codes were heat exhaustion (35%), heat syncope (39%), and heat stroke (30%). The majority were discharged from the emergency department after completing treatment (73%), with 21% requiring admission. A total of 38 follow-up interviews were completed (29% response rate). Almost all individuals were exposed to heat outside their home environment: 11 (29%) were engaged in paid work, 5 (13%) in outdoor housework, and 10 (26%) in outdoor recreational activities. CONCLUSION: Our pilot surveillance study successfully collected home, local environment and behavioural risk factors on a small cohort presenting with 'heat problems' to EDs in Western Sydney during the summer months. Most were exposed to heat outdoors while engaged in work or recreation outside the home, and were preventable.

The Milieu Manager: A Nursing Staffing Strategy to Reduce Observer Use in the Acute Psychiatric Inpatient Setting.

BACKGROUND: Rising acuity levels in inpatient settings have led to growing reliance on observers and increased the cost of care. OBJECTIVES: Minimizing use of observers, maintaining quality and safety of care, and improving bed access, without increasing cost. DESIGN: Nursing staff on two inpatient psychiatric units at an academic medical center pilot-tested the use of a "milieu manager" to address rising patient acuity and growing reliance on observers. Nursing cost, occupancy, discharge volume, unit closures, observer expense, and incremental nursing costs were tracked. Staff satisfaction and reported patient behavioral/safety events were assessed. RESULTS: The pilot initiatives ran for 8 months. Unit/bed closures fell to zero on both units. Occupancy, patient days, and discharges increased. Incremental nursing cost was offset by reduction in observer expense and by revenue from increases in occupancy and patient days. Staff work satisfaction improved and measures of patient safety were unchanged. CONCLUSIONS: The intervention was effective in reducing observation expense and improved occupancy and patient days while maintaining patient safety, representing a cost-effective and safe approach for management of acuity on inpatient psychiatric units.

Nanocell targeting using engineered bispecific antibodies.

There are many design formats for bispecific antibodies (BsAbs), and the best design choice is highly dependent on the final application. Our aim was to engineer BsAbs to target a novel nanocell (EnGeneIC Delivery Vehicle or EDV(TM)nanocell) to the epidermal growth factor receptor (EGFR). EDV(TM)nanocells are coated with lipopolysaccharide (LPS), and BsAb designs incorporated single chain Fv (scFv) fragments derived from an anti-LPS antibody (1H10) and an anti-EGFR antibody, ABX-EGF. We engineered various BsAb formats with monovalent or bivalent binding arms and linked scFv fragments via either glycine-serine (G4S) or Fc-linkers. Binding analyses utilizing ELISA, surface plasmon resonance, bio-layer interferometry, flow cytometry and fluorescence microscopy showed that binding to LPS and to either soluble recombinant EGFR or MDA-MB-468 cells expressing EGFR, was conserved for all construct designs. However, the Fc-linked BsAbs led to nanocell clumping upon binding to EDV(TM)nanocells. Clumping was eliminated when additional disulfide bonds were incorporated into the scFv components of the BsAbs, but this resulted in lower BsAb expression. The G4S-linked tandem scFv BsAb format was the optimal design with respect to EDV binding and expression yield. Doxorubicin-loaded EDV(TM)nanocells actively targeted with tandem scFv BsAb in vivo to MDA-MB-468-derived tumors in mouse xenograft models enhanced tumor regression by 40% compared to passively targeted EDV(TM)nanocells. BsAbs therefore provide a functional means to deliver EDV(TM)nanocells to target cells.

Characteristics of patients with histories of multiple seclusion and restraint events during a single psychiatric hospitalization.

BACKGROUND: This descriptive, retrospective study examined patient and event characteristics associated with multiple seclusion and restraint (SR). OBJECTIVE: The goal was to identify patient characteristics of multiple seclusion and restraint users to improve patient care and decrease the need for seclusion or restraint. DESIGN: Medical charts were reviewed for 63 patients hospitalized at the Henry Phipps Psychiatric Service at the Johns Hopkins Hospital between January 2006 and December 2008 who had been secluded or restrained multiple times during a single hospitalization. Patient characteristics and events associated with multiple SR use were examined. Characteristics were then compared with those who had a single (n = 110) and no SR events (n = 3,585) during hospitalization in those study years. RESULTS: Compared with patients with no SR events, those with multiple SR events were more likely to be male, have histories of aggression before and during previous hospitalizations, and have longer lengths of stay. Patients with any SR event were more likely to have cognitive impairment and have been admitted involuntarily. CONCLUSIONS: Results highlight the need for practice changes targeting subgroups of patients at elevated risk for multiple SR use.

Purification of recombinant protein by cold-coacervation of fusion constructs incorporating resilin-inspired polypeptides.

Polypeptides containing between 4 and 32 repeats of a resilin-inspired sequence AQTPSSYGAP, derived from the mosquito Anopheles gambiae, have been used as tags on recombinant fusion proteins. These repeating polypeptides were inspired by the repeating structures that are found in resilins and sequence-related proteins from various insects. Unexpectedly, an aqueous solution of a recombinant resilin protein displays an upper critical solution temperature (cold-coacervation) when held on ice, leading to a separation into a protein rich phase, typically exceeding 200 mg/mL, and a protein-poor phase. We show that purification of recombinant proteins by cold-coacervation can be performed when engineered as a fusion partner to a resilin-inspired repeat sequence. In this study, we demonstrate the process by the recombinant expression and purification of enhanced Green fluorescent protein (EGFP) in E. coli. This facile purification system can produce high purity, concentrated protein solutions without the need for affinity chromatography or other time-consuming or expensive purification steps, and that it can be used with other bulk purification steps such as low concentration ammonium sulfate precipitation. Protein purification by cold-coacervation also minimizes the exposure of the target protein to enhanced proteolysis at higher temperature.

Crisis prevention management: a program to reduce the use of seclusion and restraint in an inpatient mental health setting.

The use of seclusion and restraint in the treatment of mentally ill patients is a highly controversial and potentially dangerous practice. A group of direct care psychiatric nurses in a large urban teaching hospital created an evidenced-based performance improvement program that resulted in a decrease in the use of seclusion and restraint. No additional funds were required to develop this program. The public health prevention model was the framework utilized. Early results show a 75% reduction in the use of seclusion and restraint with no increase in patient or staff injuries since its implementation.

The unit-based CNS: a hand in everything.

Unit-based clinical nurse specialists influence the entire organizational system within a tertiary care setting at Johns Hopkins Hospital, Baltimore, Md.