Clinical utility of comprehensive circulating tumor DNA genotyping compared with standard of care tissue testing in patients with newly diagnosed metastatic colorectal cancer.

BACKGROUND: Comprehensive biomarker testing is essential in selecting optimal treatment for patients with metastatic colorectal cancer (mCRC); however, incomplete genotyping is widespread, with most patients not receiving testing for all guideline-recommended biomarkers, in part due to reliance on burdensome sequential tissue-based single-biomarker tests with long waiting times or availability of only archival tissue samples. We aimed to demonstrate that liquid biopsy, associated with rapid turnaround time (TAT) and lower patient burden, effectively identifies guideline-recommended biomarkers in mCRC relative to standard of care (SOC) tissue testing. PATIENTS AND METHODS: Prospectively enrolled patients with previously untreated mCRC undergoing physician discretion SOC tissue genotyping submitted pretreatment blood samples for comprehensive circulating tumor DNA (ctDNA) analysis with Guardant360 and targeted RAS and BRAF analysis with OncoBEAM. RESULTS: Among 155 patients, physician discretion SOC tissue genotyping identified a guideline-recommended biomarker in 82 patients, versus 88 identified with comprehensive ctDNA (52.9% versus 56.8%, noninferiority demonstrated down to α = 0.005) and 69 identified with targeted PCR ctDNA analysis (52.9% versus 44.5%, noninferiority rejected at α = 0.05). Utilizing ctDNA in addition to tissue increased patient identification for a guideline-recommended biomarker by 19.5% by rescuing those without tissue results either due to tissue insufficiency, test failure, or false negatives. ctDNA median TAT was significantly faster than tissue testing when the complete process from sample acquisition to results was considered (median 10 versus 27 days, P < 0.0001), resulting in accelerated biomarker discovery, with 52.0% biomarker-positive patients identified by ctDNA versus 10.2% by SOC tissue 10 days after sample collection (P < 0.0001). CONCLUSIONS: Comprehensive ctDNA genotyping accurately identifies guideline-recommended biomarkers in patients with mCRC at a rate at least as high as SOC tissue genotyping, in a much shorter time. Based on these findings, the addition of ctDNA genotyping to clinical practice has significant potential to improve the care of patients with mCRC.

Acquired Resistance to Poly (ADP-ribose) Polymerase Inhibitor Olaparib in BRCA2-Associated Prostate Cancer Resulting From Biallelic BRCA2 Reversion Mutations Restores Both Germline and Somatic Loss-of-Function Mutations.

PARP1/2 inhibitors are effective against BRCA2-deficient tumors. The PARP inhibitor (PARPi) olaparib received FDA breakthrough designation for treatment of metastatic castration-resistant prostate cancers (CRPC) carrying mutations in BRCA1/2 or ATM genes. Emergent resistance to PARPi has been associated with tumor-specific BRCA2 mutations that revert the normal open reading frame rescuing homologous recombination. We describe a case of metastatic CRPC with germline BRCA2 mutation with acquired resistance to olaparib related to biallelic BRCA2 reversion mutations of both the germline and somatic loss of function alleles detected by circulating tumor DNA testing. We also summarize a retrospective analysis of 1,534 prostate cancer cases with ctDNA analysis showing a 1.6% incidence of germline BRCA2 mutations. Within the germline BRCA2-positive cases exposed to platinum chemotherapy or PARP inhibition, the prevalence of reversion mutations was 40%. This report documents the frequency of reversion mutations in a large cohort of prostate cancer patients carrying of BRCA mutations. It also shows the potential utility of ctDNA analyses for early detection of reversion mutation driving tumor resistance.

Immune responses to Schistosoma haematobium infection.

Urogenital schistosomiasis is one of the greatest single infectious sources of human morbidity and mortality known. Through a complex cycle of infection, migration and eventual maturation and mating, S. haematobium (the aetiological agent of urogenital schistosomiasis) deposits highly immunogenic eggs within the bladder and other pelvic organs, activating a wide range of immune programs that determine both infection outcome as well as downstream immunopathology. In this review, we discuss the experimental and observational bases for our current understanding of these immune programs, focusing specifically on how the balance of type 1 and type 2 responses governs subsequent immunopathology and clinical outcome.

Design of field-cycled magnetic resonance systems for small animal imaging.

This paper presents a design study for a field-cycled magnetic resonance imaging (MRI) system directed at small animal imaging applications. A field-cycled MRI system is different from a conventional MRI system in that it uses two separate and dynamically controllable magnetic fields. A strong magnetic field is used to polarize the object, and a relatively weak magnetic field is used during signal acquisition. The potential benefits of field-cycled MRI are described. The theoretical dependences of field-cycled MRI performance on system design are introduced and investigated. Electromagnetic, mechanical and thermal performances of the system were considered in this design study. A system design for imaging 10 cm diameter objects is presented as an example, capable of producing high-duty-cycle polarizing magnetic fields of 0.5 T and readout magnetic fields corresponding to a proton Larmor frequency of 5 MHz. The specifications of the final design are presented along with its expected electromagnetic and thermal performance.

The effect of short-term temperature changes on superelastic nickel-titanium archwires activated in orthodontic bending.

The bending stiffness of superelastic nickel-titanium archwires is influenced by alterations in mouth temperature. The activation and deactivation phases of a load-deflection loop of superelastic wires have different stress-magnitudes. This investigation compared the effect of short-term cooling or heating on the bending force exerted by nickel-titanium archwires. Two rectangular superelastic and one conventional nickel titanium wire were tested in bending at 37 degrees C. The specimens were tested during the activation phase and during the deactivation phase. The wires were kept at constant strain and the bending force was measured continually while the activated specimens were subjected to cold (10 degrees C) or hot (80 degrees C) water. The test situation simulates a patient's archwire that is subjected to cold or hot drinks or food during a meal. The conventional nickel-titanium wire was marginally affected by brief cooling or heating, regardless of activation phase. In contrast, the superelastic wires were strongly affected by short-term application of cold or hot water. When tested in activation phase, the effect of heating was transient whereas the wires continued to exert sub-baseline bending forces after short-term application of cold water. When tested in deactivation phase, the effect of cooling was transient whereas the wires exerted supra-baseline bending forces after a short-term application of hot water. The effect of short-term temperature changes on the bending stiffness of superelastic nickel titanium archwires is dependent upon the bending phase. Cooling induced transient effects on a wire in its deactivation phase, but prolonged effects when the wire was tested in the activation phase. In contrast, the effect of short-term heating was transient when the wire was tested in the activation phase, but prolonged when the wire was tested in the deactivation phase.

Short-term temperature changes influence the force exerted by superelastic nickel-titanium archwires activated in orthodontic bending.

BACKGROUND: Alterations in mouth temperature may lead to changes in the force exerted by an activated superelastic wire. It has been assumed that variations in archwire stiffness associated with short-term cooling or heating are transient. This investigation studied the effect of short-term cooling or heating on the bending force exerted by nickel-titanium archwire. MATERIAL AND METHODS: Six rectangular superelastic wires and one conventional nickel-titanium wire were tested in bending at 37 degrees C. The test specimens were deflected 0.5 mm, and the bending force was measured continually. The activated specimens were subjected to cold (10 degrees C) or hot (80 degrees C) water under constant deflection, simulating an inserted archwire that is subjected to cold or hot drinks or food during a meal. RESULTS: The conventional nickel-titanium wire was marginally affected by brief cooling or heating. In contrast, some of the superelastic wires were strongly affected by short-time application of cold or hot water. Whereas the effect of brief heating disappeared quickly, some wires continued to exert sub-baseline bending forces (up to 32% less) after short-time application of cold water and showed little or no tendencies toward increase even after 30 minutes of postexposure restitution (up to 43% less). CONCLUSIONS: Short-term exposures to hot liquid increased the bending force exerted for a given deflection transiently. The effect of short-term exposures to cold liquid was not always transient; the bending force remained sub-baseline for a number of the thermosensitive wires tested for a prolonged time.

The effect of temperature on the elastic responses to longitudinal torsion of rectangular nickel titanium archwires.

To investigate responses to longitudinal torsion and the effect of temperature on the torsional stiffness of superelastic nickel titanium archwires, eight batches of rectangular wires were tested at 18, 27, 37, and 40 degrees C ambient temperature. The wires were twisted 25 degrees and studied in deactivation. The resulting torque-twist diagrams show that only half the wires had discernible deactivation plateaus at body temperature. The plateaus were generally narrow (1 to 3 degrees) and started at 20 to 23 degrees of torsional twist. The clinical significance of these deactivation plateaus is debatable. Only one wire had a well-defined plateau that was fairly wide (6 degrees) and started at a lower level of twist (17 degrees). The wires without plateaus when deactivated from 25 degrees of twist were retested at body temperature. All exhibited deactivation plateaus subsequent to activating twists of 45 and 60 degrees, and the plateaus became more distinct as the degree of prior activation increased. This indicates that the stress imparted on the alloys by 25 degrees of activating twist is insufficient to induce martensitic transformation at body temperature. As prescriptions advocate bracket pretorque of less than 25 degrees for a maxillary central incisor, the clinical relevance of alloys requiring large activations before they demonstrate deactivation plateaus is questionable. Half the wires tested were markedly influenced by ambient temperature changes; the other half were relatively insensitive to temperature. Responsiveness to thermal stimuli seemed closely related to superelastic tendency.

The effect of short-term temperature changes on the mechanical properties of rectangular nickel titanium archwires tested in torsion.

Due to their exceptional temperature sensitivity, superelastic nickel titanium wires may be affected by temperature changes associated with ingestion of cold or hot food. It has been assumed that the alterations in archwire stiffness associated with short-term cooling or heating are transient. This investigation studied the effect of these temperature changes on the torsional stiffness of nickel titanium alloys. Eight rectangular superelastic wires were activated to 20 degrees, in longitudinal torsion at body temperature and subjected to cold (10 degrees C) or hot (80 degrees C) water with the strain held constant. The torsional stiffness of some wires was strongly affected. The effect of hot water disappeared quickly, but the wires remained at a level of reduced torsional stiffness (up to 85% less than baseline) after short applications of cold water. The most thermodynamic archwires showed incremental reductions in torsional stiffness when cold water was repeatedly applied. Furthermore, the torsional stiffness remained low (up to 50% less than baseline) and showed no tendency to increase even after 2 hours of post-exposure restitution. It is conceivable that some wires may provide inadequate forces for tooth movement after ingestion of cold liquids.

A formula for the displacement of an arch wire when subjected to a second-order couple.

A new formula, expressing the local angular displacement of an orthodontic beam when subjected to a second-order couple applied at midspan, has been developed and analyzed. The computed displacements were compared with the results of ex vivo testing. There was good agreement between the results from the theoretical evaluation and the bench testing. Second-order activation of an orthodontic beam can be described in four sequential phases. The initial displacement is influenced by the second-order clearance between bracket-slot and wire as well as the relationship between the bracket-slot width and interbracket distance. During phase II there is a nonlinear relationship between applied couple and rotational displacement. Within phases three and four displacement is linearly related to the interbracket distance, provided the relationship between the bracket-slot width and interbracket distance remains constant. For a given tooth size, the second-order beam stiffness is exponentially related to bracket width. The experiments also show that even small deflections of thin stainless steel wires can lead to second-order couples of large magnitudes when using a clinically relevant interbracket distance. Consequently, it is important that the orthodontist evaluates his or her choice of bracket width and arch wire stiffness in each clinical case in order to avoid supra-physiologic force levels.

The effect of cross-sectional dimensional variations of square and rectangular chrome-cobalt archwires on torsion.

The purpose of this investigation was to study the control of cross-sectional dimensions and edge bevel by various manufacturers in the production of chrome-cobalt archwires and this effect on transmitting torque through an .018 inc slot bracket system. Twenty-seven different square and rectangular chrome-cobalt wires commonly used in the edgewise technique supplied by five different manufacturers were studied with respect to dimensions, edge bevel, and mechanical properties in torsion. The mechanical study simulated application of torque to an individual tooth. Standard brackets with .018 inch slot heights were used. The results show that variation in cross-sectional dimension and edge bevel leads to variable torsional play (third-order clearance). As an example, .016 x .016 wires have a mean torsional play of as much as 26.8 degrees, with a range of 21.0 to 32.3 degrees. When using .016 x .016 wires, one must apply from 34.8 to 48.6 degrees of twist to get 20 N-mm of torsional moment. This variation is primarily due to the rather wide range in torsional play. As a result, the prediction by which a predetermined torsional moment can be delivered becomes uncertain. The results also show that because the working range in torsion of chrome-cobalt wires is somewhat limited due to high torsional stiffness, precise delivery of torsional moment based on the condition present in the oral cavity is difficult. The torsional stiffness varies between manufacturers within the various dimensional groups as a result of differences in cross-sectional geometry and material properties.

On the variability of cross-sectional dimensions and torsional properties of rectangular nickel-titanium arch wires.

Twenty-five rectangular superelastic or conventional work-hardened nickel-titanium alloy wires, commonly used in the 0.018-inch edgewise technique, supplied by seven different manufacturers, along with one braided nickel-titanium and two beta-titanium wires, were studied with respect to wire dimensions, edge bevel, and mechanical properties in longitudinal torsion at 37 degrees C. The wires were twisted 25 degrees and studied in deactivation, simulating application of torque to an individual tooth. Standard Siamese brackets. with stated slot heights of 0.018 inches and measured slot heights of 0.0187 inches, were used. Most wires were within +/-0.0005 inches of the stated dimensions, but had more edge bevel than previously reported for stainless steel and chrome-cobalt alloy wires. Variations in wire dimensions and edge bevel led to variable torsional (third-order) clearance. The torsional stiffness varied among manufacturers within the various wire sizes, this being the result of differences in actual cross-sectional geometry and material properties. None of the tested wires exhibited superelastic properties under the current conditions, and only one wire had a superelastic tendency.

On bracket slot height: a methodologic study.

Effective bracket slot height is estimated by using a formula that describes the relationship between bracket slot height, wire dimensions, wire edge bevel, and torsional play (third-order clearance). With a torque measuring instrument, the torsional play was estimated for 10 different brackets (0.018-inch stated slot) of the same manufacturer and type. One arch wire with known dimensions and edge bevel was used for all the measurements. With known torsional play, wire dimensions and edge bevel, the bracket slot height could be calculated. This was performed five times for each bracket and the method error for estimation of torsional play for a single measurement was 0.04 degrees, corresponding to 0.36 mm in slot height. The brackets tested had a mean slot height of 0.476 +/- 0.003 mm, with a range of 0.470 to 0.481 mm (0.0187 +/- 0.0001 inches, range 0.0185 to 0.0189). The variation in bracket slot height was much greater than the method error. The method used to measure bracket slot height seems to have a high degree of accuracy and is easier to implement than conventional methods.

The effect of second-order couple on the application of torque.

Complex combinations of linear forces, moments, and couples are developed by the arch wire during orthodontic treatment. For instance, application of torque to a canine during distal driving may create force interactions if the tooth tips distally toward the extraction site. This investigation studied the effect of second-order couples and bracket angulations on the application of torque to a single tooth. By using a test apparatus to simulate application of torque to a single tooth, 0.016 x 0.022 inch stainless steel wires were tested in longitudinal torsion simultaneous to fixed amounts of second-order couples or fixed degrees of second-order bracket angulation. Application of a second-order couple through a bracket to a longitudinally twisted arch wire produces a third-order couple, since the bracket slot walls exert forces on the wire, tending to detwist it. This third-order couple will usually be small as the distance between the two couple members is short. Nevertheless, it may have a restraining effect on the third-order wire-bracket interaction. The results show that application of second-order couples or bracket angulations lead to an increase in exerted torque for angles of twist below 22 degrees. Because of torsional play, a wire twisted 18 degrees in a 0.018-inch bracket slot did not exert any torque unless it was subjected to a second-order couple. Thus, in an in vivo situation where forces interact, the actual torsional play may be substantially less than predicted from theoretical models only regarding third-order mechanics. The restraining effect of second-order couples tapered when the torque created by longitudinal twisting became much larger than the torque exerted by the second-order couple. Second-order couples of biologically acceptable magnitudes had little effect on the level of torque after the third-order clearance had been eliminated.

The effect of friction on the bending stiffness of orthodontic beams: a theoretical and in vitro study.

The purpose of this study was to investigate the effect of friction on the bending stiffness of orthodontic beams. A theoretical and experimental model have been established where tensile and compressive forces are applied to an arch wire to simulate the effect of additional friction during activation and deactivation, respectively. The results show that tensile force increases wire stiffness, and that compressive force increases flexibility. Thus more force will be needed during activation and more force will be lost during deactivation. The amount of force lost increases nearly linearly with increasing friction. During activation, the percentage increase in force due to friction for a given deflection is about equal to the loss of force due to friction during deactivation. Friction affects thin flexible wires more than heavy wires. Careful ligation is recommended in the leveling phase to reduce the negative side effects of friction.

On mechanical properties of square and rectangular stainless steel wires tested in torsion.

Forty different sizes and types of square and rectangular stainless steel wires, supplied by five different manufacturers, were tested in torsion. The study simulated the situation occurring when torque is applied to an individual tooth. We used standard brackets with 0.018-inch slot heights, with an interbracket distance of 4 mm. The results show that variation in cross-sectional dimension and edge bevel leads to variable torsional play (third-order clearance). As an example 0.016 x 0.022-inch wires have a mean torsional play of as much as 18.5 degrees, with a range of 16.6 degrees to 20.4 degrees. We have shown that when 0.016 x 0.022-inch wires are used, one must apply from 24.6 degrees to 29.2 degrees of twist to get 20 Nmm of torsional moment. This variation is mostly due to a rather wide range in torsional play. As a result, the prediction by which a predetermined torsional moment can be delivered becomes uncertain. The results show that because the working range in torsion of stainless steel wires is somewhat limited, precise delivery of torsional moment, based on the condition present in the oral cavity, is difficult. Torsional stiffness varies considerable within the various dimensional groups, this being the result of variation in cross-sectional geometry and material properties.

The effects of loops on the torsional stiffnesses of rectangular wires: an in vitro study.

Various loop designs have been investigated with respect to the increased torsional flexibility given to the wire by their inclusion. The torsional flexibility of the wire was shown to be enlarged from 26% to 63%, depending on loop design. Both variation in wire cross-section and loop geometry will influence torsional stiffness. Wires with small cross-sectional dimensions will show greater flexibility in torsion. Even small deviations from the stated cross-sectional dimensions can influence the change in torsional stiffness caused by a specific loop design. Inclusion of a reverse-closing loop led to the greatest increase in flexibility, while a Bull loop changed torsional stiffness the least. When vertical flexibility is needed along with reduced torsional stiffness, the T-loop is the loop of choice.

[Alcohol consumption among adolescents in 3 municipalities. A survey of local variations in alcohol consumption]. / Alkoholkonsumet blant ungdom i tre kommuner. Kartlegging av lokale variasjoner i alkoholforbruk.

Drinking habits among 663 adolescents 14, 15, 17 and 18 years of age in three local communities were investigated by means of a questionnaire. Half had tasted alcohol already at the age of 14 years. The total amount consumed per person per year averaged 3.5 litres pure alcohol. Geographical variations in consumption were more than six-fold. At the age of 17 years, boys began to consume more than girls. In both sexes, home distilled spirits was the most common beverage obtained or provided illegally. The main reason for drinking alcohol seems to be to get drunk.

[Development of drinking habit among adolescents. Factors connected with alcohol consumption]. / Utvikling av alkoholvaner blant ungdom. Faktorer som har sammenheng med alkoholkonsumet.

Factors related to drinking habits among 663 adolescents 14, 15, 17 and 18 years old were investigated in three municipalities by means of a questionnaire. In a multiple regression analysis, variation in alcohol consumption was examined using several independent variables describing access to alcohol, behavioural factors, environmental influences, attitudes and demographic background. The most important factors predicting high alcohol consumption were early drinking debut, being away from home at night without the parents' knowledge, having friends who drink a lot and early high consumption of unhealthy foods such as soft drinks, peanuts and chips. All these factors were again related to upbringing and home environment.