Randomized, Controlled Trial of the FGF21 Analogue Pegozafermin in NASH.

BACKGROUND: Pegozafermin is a long-acting glycopegylated (pegylated with the use of site-specific glycosyltransferases) fibroblast growth factor 21 (FGF21) analogue in development for the treatment of nonalcoholic steatohepatitis (NASH) and severe hypertriglyceridemia. The efficacy and safety of pegozafermin in patients with biopsy-proven noncirrhotic NASH are not well established. METHODS: In this phase 2b, multicenter, double-blind, 24-week, randomized, placebo-controlled trial, we randomly assigned patients with biopsy-confirmed NASH and stage F2 or F3 (moderate or severe) fibrosis to receive subcutaneous pegozafermin at a dose of 15 mg or 30 mg weekly or 44 mg once every 2 weeks or placebo weekly or every 2 weeks. The two primary end points were an improvement in fibrosis (defined as reduction by ≥1 stage, on a scale from 0 to 4, with higher stages indicating greater severity), with no worsening of NASH, at 24 weeks and NASH resolution without worsening of fibrosis at 24 weeks. Safety was also assessed. RESULTS: Among the 222 patients who underwent randomization, 219 received pegozafermin or placebo. The percentage of patients who met the criteria for fibrosis improvement was 7% in the pooled placebo group, 22% in the 15-mg pegozafermin group (difference vs. placebo, 14 percentage points; 95% confidence interval [CI], -9 to 38), 26% in the 30-mg pegozafermin group (difference, 19 percentage points; 95% CI, 5 to 32; P = 0.009), and 27% in the 44-mg pegozafermin group (difference, 20 percentage points; 95% CI, 5 to 35; P = 0.008). The percentage of patients who met the criteria for NASH resolution was 2% in the placebo group, 37% in the 15-mg pegozafermin group (difference vs. placebo, 35 percentage points; 95% CI, 10 to 59), 23% in the 30-mg pegozafermin group (difference, 21 percentage points; 95% CI, 9 to 33), and 26% in the 44-mg pegozafermin group (difference, 24 percentage points; 95% CI, 10 to 37). The most common adverse events associated with pegozafermin therapy were nausea and diarrhea. CONCLUSIONS: In this phase 2b trial, treatment with pegozafermin led to improvements in fibrosis. These results support the advancement of pegozafermin into phase 3 development. (Funded by 89bio; ENLIVEN ClinicalTrials.gov number, NCT04929483.).

Shielding design for multiple-energy linear accelerators.

The introduction of medical linear accelerators (linacs) capable of producing three different x-ray energies has complicated the process of designing shielding for these units. The conventional approach for the previous generation of dual-energy linacs relied on the addition of some amount of supplementary shielding to that calculated for the higher-energy beam, where the amount of that supplement followed the historical "two-source" rule, also known as the "add one HVL rule," a practice derived from other two-source shielding considerations. The author describes an iterative approach that calculates shielding requirements accurately for any number of multiple beam energies assuming the workload at each energy can be specified at the outset. This method is particularly useful when considering the requirements for possible modifications to an existing vault when new equipment is to be installed as a replacement for a previous unit.

DNA-linker-induced surface assembly of ultra dense parallel single walled carbon nanotube arrays.

Ultrathin film preparations of single-walled carbon nanotube (SWNT) allow economical utilization of nanotube properties in electronics applications. Recent advances have enabled production of micrometer scale SWNT transistors and sensors but scaling these devices down to the nanoscale, and improving the coupling of SWNTs to other nanoscale components, may require techniques that can generate a greater degree of nanoscale geometric order than has thus far been achieved. Here, we introduce linker-induced surface assembly, a new technique that uses small structured DNA linkers to assemble solution dispersed nanotubes into parallel arrays on charged surfaces. Parts of our linkers act as spacers to precisely control the internanotube separation distance down to <3 nm and can serve as scaffolds to position components such as proteins between adjacent parallel nanotubes. The resulting arrays can then be stamped onto other substrates. Our results demonstrate a new paradigm for the self-assembly of anisotropic colloidal nanomaterials into ordered structures and provide a potentially simple, low cost, and scalable route for preparation of exquisitely structured parallel SWNT films with applications in high-performance nanoscale switches, sensors, and meta-materials.

An unrecognized occupancy change in the vicinity of a medical linear accelerator.

It seems obvious that if a significant increase in occupancy occurs in the immediate vicinity of any radiation room a reexamination of the adequacy of the shielding should be performed. We discuss a facility where a new building was constructed in close proximity to an existing medical linear accelerator and no consideration was given to the consequences of that construction as it might impact the doses received by occupants of the new structure. For more than 10 years some areas in that building may have received exposures greater than the allowed regulatory limit. The situation reported here should serve as a cautionary tale for those who have the responsibility for providing radiation protection at any site where new construction or increases in occupancy might require a reanalysis of the previously designed radiation shielding.

Emergency room crowding: a marker of hospital health.

Emergency room (ER) crowding has become a widespread problem in hospitals across the United States. Two main reasons can be cited. First, emergency medicine is the only specialty in the "House of Medicine" that has a federal mandate to provide care to any patients requesting treatment. Second, primary care providers are in short supply, forcing sick people to seek medical care in ERs. Once seen as an "ER problem," crowding has become more appropriately recognized as a "hospital problem," related to factors beyond the doors of the ER. This realization has led many regulating agencies to launch corrective attempts, some of which have actually been effective. Now, the lack of ER crowding is considered a measure of the success of a hospital or system. This review considers the complex causative factors that contribute to ER crowding and explores corrective measures that may prove helpful in alleviating this paralyzing condition.

Evaluating screening age for colonoscopy: a quality assurance assessment.

OBJECTIVE: To evaluate colonoscopies in patients aged 40 to 49 and 50 to 59 years from multiple endoscopy surgery centers serving a wide geographical area. METHODS: An observational prospective multicenter quality assurance review was conducted in 49 Ambulatory Surgery Centers in 17 states with 315 gastroenterologists. Care of patients and routine of gastroenterologists continued as standard practice with patients attending for purposes of screening, surveillance, and symptoms. RESULTS: There were 1688 and 5090 consecutive qualified patients aged 40 to 49 and 50 to 59 years, respectively, receiving colonoscopies in a designated 4 week period. There was no significant difference (P=0.55) in the screening category between ages 40 to 49 (n=420) and 50 to 59 years (n=2705) in incidence of colon polyps although the older age group had more than 6 times the number of patients than the younger age group. Age group of 40 to 49-year-old males (21.5%) are at similar risk to 40 to 49-year-old females (21.1%) in development of carcinoma and adenoma polyps combined. Age group of 50 to 59-year-old males (31.3%) appear at greater risk (P<0.0001) than age 50 to 59-year-old females (18.4%) in development of carcinoma and adenoma polyps combined in the screening category. For surveillance and symptom categories significant differences (P<0.05) occurred between both age groups 40 to 49 and 50 to 59 years for males but not females in development of carcinoma and adenoma polyps combined. CONCLUSIONS: The equal risk of colon polyps in screening colonoscopies for age 40 to 49 and 50 to 59 years suggest reexamination of current recommendations for 50 years as the beginning age for screening colonoscopy. Further studies are needed to examine sex differences and cost effectiveness of screening colonoscopies beginning at age 40 years and to explore these factors as well in surveillance and symptom categories.

Withdrawal times and associated factors in colonoscopy: a quality assurance multicenter assessment.

OBJECTIVE: To evaluate the use and impact of the recommended withdrawal time of at least 6 minutes from the cecum in colonoscopy in multiple gastroenterology endoscopy ambulatory surgery centers serving a wide geographical area. METHODS: An observational prospective multicenter quality assurance review was conducted in 49 ambulatory surgery centers in 17 states with 315 gastroenterologists. There was no intervention with this quality assessment program as care of patients and the routine of gastroenterologists continued as standard practice. Multivariable analysis was applied to the database to examine factors affecting withdrawal time and polyp detection. RESULTS: There were 15,955 consecutive qualified patients receiving colonoscopies in a designated 4-week period. Gastroenterologists with average withdrawal times of 6 minutes or more in patients with no polyps were 1.8 times more likely to detect 1 or more polyps and had a significantly higher rate (P<0.0001) of polyp detection in patients with findings of polyps compared to gastroenterologists with average withdrawal times of less than 6 minutes in patients with no polyps. For patients with no pathology, the mean time of withdrawal was 6.98 (SD=4.34) minutes and for patients with pathology mean time of withdrawal was 11.27 (SD=6.71) minutes. Strongest predictors of withdrawal time of 6 minutes or more were presence of carcinoma (3.7 times more likely than those with no pathology), adenoma (2.0 times more likely than those with no pathology), and number of polyps visualized (1.7 times more likely for each polyp). CONCLUSIONS: This quality assurance assessment from standard colonoscopy practices of 315 gastroenterologists in 49 endoscopic ambulatory surgery centers serving a wide geographical area provides support for the merits of a colonoscopy withdrawal time from the cecum of 6 minutes or more to improve the detection of polyps.

Self-assembly of carbon nanotubes into two-dimensional geometries using DNA origami templates.

A central challenge in nanotechnology is the parallel fabrication of complex geometries for nanodevices. Here we report a general method for arranging single-walled carbon nanotubes in two dimensions using DNA origami-a technique in which a long single strand of DNA is folded into a predetermined shape. We synthesize rectangular origami templates ( approximately 75 nm x 95 nm) that display two lines of single-stranded DNA 'hooks' in a cross pattern with approximately 6 nm resolution. The perpendicular lines of hooks serve as sequence-specific binding sites for two types of nanotubes, each functionalized non-covalently with a distinct DNA linker molecule. The hook-binding domain of each linker is protected to ensure efficient hybridization. When origami templates and DNA-functionalized nanotubes are mixed, strand displacement-mediated deprotection and binding aligns the nanotubes into cross-junctions. Of several cross-junctions synthesized by this method, one demonstrated stable field-effect transistor-like behaviour. In such organizations of electronic components, DNA origami serves as a programmable nanobreadboard; thus, DNA origami may allow the rapid prototyping of complex nanotube-based structures.

An information-bearing seed for nucleating algorithmic self-assembly.

Self-assembly creates natural mineral, chemical, and biological structures of great complexity. Often, the same starting materials have the potential to form an infinite variety of distinct structures; information in a seed molecule can determine which form is grown as well as where and when. These phenomena can be exploited to program the growth of complex supramolecular structures, as demonstrated by the algorithmic self-assembly of DNA tiles. However, the lack of effective seeds has limited the reliability and yield of algorithmic crystals. Here, we present a programmable DNA origami seed that can display up to 32 distinct binding sites and demonstrate the use of seeds to nucleate three types of algorithmic crystals. In the simplest case, the starting materials are a set of tiles that can form crystalline ribbons of any width; the seed directs assembly of a chosen width with >90% yield. Increased structural diversity is obtained by using tiles that copy a binary string from layer to layer; the seed specifies the initial string and triggers growth under near-optimal conditions where the bit copying error rate is <0.2%. Increased structural complexity is achieved by using tiles that generate a binary counting pattern; the seed specifies the initial value for the counter. Self-assembly proceeds in a one-pot annealing reaction involving up to 300 DNA strands containing >17 kb of sequence information. In sum, this work demonstrates how DNA origami seeds enable the easy, high-yield, low-error-rate growth of algorithmic crystals as a route toward programmable bottom-up fabrication.

Radiation protection at an aviation museum.

The U.S. Nuclear Regulatory Commission (U.S. NRC) will soon publish a proposed amendment to its rules that will classify the naturally occurring isotope Ra as "byproduct material" subject to its regulatory control. One of the uses of radium in the first half of the twentieth century was as a source of energy that would make certain consumer products "glow in the dark." In addition to wristwatches and other timepieces, this form of self-luminescence was widely used on aircraft instruments. There have been a number of facilities where large numbers of such instruments were stored and leakage of this isotope occurred. Subsequent decontamination of these areas, including expensive disposal of the radioactive waste, was required. We were asked to evaluate the potential hazards of aircraft and aircraft instruments at a museum in New York City, specifically the decommissioned aircraft carrier USS Intrepid. We present the results of our investigation and discuss the implications as they relate to the proposed new U.S. NRC regulations and compatibility issues with State regulations.

Approach to ophthalmologic emergencies.

This article presents evaluation and treatment approaches to ophthalmologic conditions that are likely to be encountered in a primary care office. These conditions can be organized by diagnostic category, symptoms, and location of complaint. By using one ora combination of these categories, the practitioner can provide appropriate, timely, and effective ophthalmologic evaluation and treatment. Acute conditions are categorized according to urgency of intervention.

Two computational primitives for algorithmic self-assembly: copying and counting.

Copying and counting are useful primitive operations for computation and construction. We have made DNA crystals that copy and crystals that count as they grow. For counting, 16 oligonucleotides assemble into four DNA Wang tiles that subsequently crystallize on a polymeric nucleating scaffold strand, arranging themselves in a binary counting pattern that could serve as a template for a molecular electronic demultiplexing circuit. Although the yield of counting crystals is low, and per-tile error rates in such crystals is roughly 10%, this work demonstrates the potential of algorithmic self-assembly to create complex nanoscale patterns of technological interest. A subset of the tiles for counting form information-bearing DNA tubes that copy bit strings from layer to layer along their length.

Minimizing entrance door thickness for direct-entry radiotherapy rooms.

When medical linear accelerator rooms are constructed without entrance mazes, the entrance doors can be as thick as 50 cm, weigh 10,000 kg, and cost 50-60 thousand dollars. We describe a method of room design in which the therapy unit is positioned 180 degrees from the usual orientation. A short stub wall that attenuates the leakage component of the secondary radiation protects the door. Using this approach, the door can be reduced to approximately half the usual thickness with a significant impact on cost. For these motor-driven doors, there are also long-term benefits related to maintenance of the operating hardware.

Three-helix bundle DNA tiles self-assemble into 2D lattice or 1D templates for silver nanowires.

We present a DNA nanostructure, the three-helix bundle (3HB), which consists of three double helical DNA domains connected by six immobile crossover junctions such that the helix axes are not coplanar. The 3HB motif presents a triangular cross-section with one helix lying in the groove formed by the other two. By differential programming of sticky-ends, 3HB tiles can be arrayed in two distinct lattice conformations: one-dimensional filaments and two-dimensional lattices. Filaments and lattices have been visualized by high-resolution, tapping mode atomic force microscopy (AFM) under buffer. Their dimensions are shown to be in excellent agreement with designed structures. We also demonstrate an electroless chemical deposition for fabricating metallic nanowires templated on self-assembled filaments. The metallized nanowires have diameters down to 20 nm and display Ohmic current-voltage characteristic.

In-flight radiation exposure during pregnancy.

During high-altitude flight, the cosmic radiation dose rate in an airliner is greater than it is at ground level. For a casual traveler, the impact on pregnancy from cosmic radiation exposure during flight is trivial. Pregnant frequent flyers, pilots, and flight attendants can, however, receive exposures that exceed current recommended values if they do not appropriately modify their work schedules. In addition to the galactic cosmic-ray background that is the source of this radiation, severe disturbances on the sun may cause eruptions that significantly raise radiation levels at airliner altitudes for brief periods, possibly having an impact even on casual travelers. This article will help obstetrician-gynecologists provide advice to their pregnant patients about in-flight radiation risks. That advice should be influenced by an understanding of recommended radiation exposure limits and a perspective on how those limits relate to the potential for real harm. Resources provided by the U.S. Federal Aviation Administration and others to help pregnant women and their physicians make informed decisions about the acceptability of this type of exposure are described.

North American snake envenomation: diagnosis, treatment, and management.

A bite from a venomous snake is a medical emergency involving not only the affected site but also multiple organ systems. Rapid transport of a snakebite victim to a medical facility is paramount. Management decisions must be based on close clinical monitoring of the potentially erratic envenomation syndrome. Because of the many variables inherent in the management of snakebite victims, consultation with a physician specialist is recommended.