Association of the time to first epinephrine administration and outcomes in out-of-hospital cardiac arrest: SOS-KANTO 2012 study

Objective

This study assessed the association between the timing of first epinephrine administration (EA) and the neurological outcomes following out-of-hospital cardiac arrests (OHCAs) with both initial shockable and non-shockable rhythms.

HIV cure: global overview of bNAbs’ patents and related scientific publications

Introduction: This article provides a global overview of patent deposits for broadly neutralizing antibodies (bNAbs), which have emerged as a key strategy for HIV cure and future HIV vaccines. Scientific and technological barriers to the discovery of an effective HIV vaccine in the last 40 years have raised concerns on the potential for relevant advances in this area. Nevertheless, recent breakthrough studies have identified novel immune pathways for new innovative HIV vaccine and HIV cure strategies.

Areas covered: In our patent study, we have identified in a global scale, in the last decade, a sharp increase in the number of bNAbs’ patent deposits related to HIV prevention and treatment strategies, reaching 90 bNAbs in 2017, protected by 184 different patent deposits. Refining our patent search to the different stages of bNAbs’ development has also allowed us to identify 12 of them already at clinical stage of research (VRC01, 10E8, 3BNC117, 10-1074, 2G12, 2F5, KD-247, 4E10, PG9, PGDM1400, PGT121, and VRC07). We describe these recent breakthroughs and discuss the prospects and limitations of these novel strategies.

Expert opinion: Our results indicate the intellectual property outcomes of a scientific revolution in this field, expressing innovative modifications in antibodies to increase their potency and half-life, which have resulted in extremely potent antibodies that could provide novel preventive and therapeutic HIV strategies.     

Anatomy of the ilium for bone marrow aspiration: map of sectors and implication for safe trocar placement

Purpose

The bony anatomy of the human ilium has been well described from a qualitative perspective; however, there are little quantitative data to help the surgeon to perform bone marrow aspiration from the iliac crest in the thickest part of the ilium. The minimum thickness of the spongiousus bone in an iliac wing (transverse thickness between the two tables) is an important factor in ensuring the safe placement of a trocar between the two tables of the iliac wing. For example, with an 8-gauge (3.26 mm) trocar, one can consider that if the transverse thickness of the spongiousus bone of the iliac wing is <3 mm, it will be difficult to insert the trocar safely between the two tables.

Methods

For this study, we measured spongiousus bone thickness on 48 iliac wings to map the ilium in six sectors, which were defined by drawing lines from equidistant points spaced along the rim of the iliac crest to the centre of the hip. These sectors can be transposed in the same manner to any patient. To evaluate the risks to reach vascular or neurologic structures, 410 trocars were introduced in the different sectors of 20 iliac bones of ten cadavers.

Results

A map was constructed indicating the thickness of the spongiousus bone in each sector. The thickness data was used to create a map that identifies the sites where bone marrow can be obtained with a trocar of 3-mm diameter according to the thickness of the spongiousus bone. Sectors 2, 3 and 6 appear to be more favourable for accommodating a 3-mm diameter trocar. Sectors 1, 4 and 5 comprise the areas with the thinnest parts of the iliac crest, with some areas being thinner than the trocar diameter. The sector system reliably predicted safe and unsafe areas for trocar placement. In cadavers, dissection demonstrated nine vascular or neurologic lesions created when trocars were introduced into sectors 1, 5 and 6.

Conclusion

Using the sector system, trocars can be directed away from neural and vascular structures and towards zones that are likely to contain larger bone marrow stock.     

Supercharging irradiated allografts with mesenchymal stem cells improves acetabular bone grafting in revision arthroplasty

Purpose

The procedure of bone allografting associated with a reinforcement device is widely used for acetabulum revision. However in absence of biologic fixation of the allograft, failure of the reconstruction may occur. We made the hypothesis that it would be possible to load these grafts with bone marrow derived mesenchymal stem cells (MSC) to rescue the osteogenic capacity of an allogenic dead bone and therefore enhance incorporation of allografts with the host bone and decrease the number of failures related to the allograft.

Method

We identified 60 patients who had undergone acetabular component revision for aseptic failure of cemented implants associated with massive periacetabular osteolysis and Paprosky type 3A or 3B classification (without pelvic discontinuity) between 1996 and 2001. The study group of 30 patients received MSCs in the allograft and at the host graft junction. The average total number of MSCs received by each patient was 195,000 cells (range 86,000–254,000 cells). The control group of 30 patients had no MSCs in the allograft. Patients were matched for the size of periacetabular osteolysis (Paprosky type 3A or 3B). We compared the evolution of the allografts and evaluated cup migration and revision of the hips as end points at a minimum of 12 years or until failure.

Result

Better radiographic graft union rates and less allograft resorption were observed with allografts loaded with stem cells. Allograft resorption was significantly decreased in the group with allograft loaded with MSCs (1.2 cm² —range 0–2.3 cm²—of resorption on radiographs in the group with MSCs; versus 6 cm², range 2.1–8.5 cm² in the group without MSCs). The rate of mechanical failure was highest (p?=?0.01) among the 30 patients with allograft without stem cells (9/30; 30 %) compared with no failures for patients with allograft loaded with stem cells. Revision of the cup was necessary in nine patients in the control group. No revision was performed in the 30 patients of the study group with MSCs.

Conclusion

For acetabular defect reconstruction, loading the allograft with MSCs has resulted in a lower rate of failure as compared with allograft without MSCs.     

Understanding bone safety zones during bone marrow aspiration from the iliac crest: the sector rule

Purpose

Should the trocar suddenly lose contact with bone during bone marrow aspiration, it may result in visceral injury. The anatomy of the ilium and the structures adjacent to the iliac bone were studied to determine the danger of breach by a trocar introduced into the iliac crest.

Methods

The authors followed two series of patients, one series to do measurements of distance and angles of the structures at risk to the iliac bone and the other to evaluate the risk of a trocar being directed outside the iliac wing during bone marrow aspiration. The authors also examined 24 pelvices by computed tomography (CT) scans of mature adults (48 iliac crests). Lines dividing the iliac wing into six equal sectors were used to form sectors (e.g. sector 1 anterior, sector 6 posterior). Vascular or neurological structures were considered at risk if they were accessible to the tip of a 10-cm trocar introduced into the iliac crest with a possible deviation of 20° from the plane of the iliac wing on the three-dimensional reconstruction. The authors tracked bone marrow aspiration of six different surgeons and calculated among 120 patients (480 entry points) the number of times the needle lost contact with bone in each sector of aspiration.

Results

The sector system reliably predicted safe and unsafe areas for trocar placement. Among the 480 entry points in the 120 patients, 94 breaches were observed and higher risks were observed in the thinner sectors. The risk was also higher in obese patients and the risk decreased with more experienced surgeons. The trocar could reach the external iliac artery on pelvic CT scans in the four most anterior sectors with a higher frequency in women. Posterior sectors were at risk for sciatic nerve and gluteal vessel damage when the trocar was pushed deeper than 6 cm into the posterior iliac crest. In cadavers, the dissection demonstrated nine vascular or neurological lesions.

Conclusions

Using the sector system, trocars can be directed away from neural and vascular structures and toward zones that are likely to contain larger bone marrow stock.     

Hybrid-fuel bacterial flagellar motors in Escherichia coli

The bacterial flagellar motor rotates driven by an electrochemical ion gradient across the cytoplasmic membrane, either H⁺ or Na⁺ ions. The motor consists of a rotor ∼50 nm in diameter surrounded by multiple torque-generating ion-conducting stator units. Stator units exchange spontaneously between the motor and a pool in the cytoplasmic membrane on a timescale of minutes, and their stability in the motor is dependent upon the ion gradient. We report a genetically engineered hybrid-fuel flagellar motor in Escherichia coli that contains both H⁺- and Na⁺-driven stator components and runs on both types of ion gradient. We controlled the number of each type of stator unit in the motor by protein expression levels and Na⁺ concentration ([Na⁺]), using speed changes of single motors driving 1-μm polystyrene beads to determine stator unit numbers. De-energized motors changed from locked to freely rotating on a timescale similar to that of spontaneous stator unit exchange. Hybrid motor speed is simply the sum of speeds attributable to individual stator units of each type. With Na⁺ and H⁺ stator components expressed at high and medium levels, respectively, Na⁺ stator units dominate at high [Na⁺] and are replaced by H⁺ units when Na⁺ is removed. Thus, competition between stator units for spaces in a motor and sensitivity of each type to its own ion gradient combine to allow hybrid motors to adapt to the prevailing ion gradient. We speculate that a similar process may occur in species that naturally express both H⁺ and Na⁺ stator components sharing a common rotor.Molecular motors are tiny machines that perform a wide range of functions in living cells. Typically each motor generates mechanical work using a specific chemical or electrochemical energy source. Linear motors such as kinesin on microtubules or myosin on actin filaments and rotary motors such as F₁-ATPase, the soluble part of ATP-synthase, run on ATP, whereas the rotary bacterial flagellar motor embedded in the bacterial cell envelope is driven by the flux of ions across the cytoplasmic membrane (1–4). Coupling ions are known to be either protons (H⁺) or sodium ions (Na⁺) (5, 6).The bacterial flagellar motor consists of a rotor ∼50 nm in diameter surrounded by multiple stator units (7–10). Each unit contains two types of membrane proteins forming ion channels: MotA and MotB in H⁺ motors in neutrophiles (e.g., Escherichia coli and Salmonella) and PomA and PomB in Na⁺ motors in alkalophiles and Vibrio species (e.g., Vibrio alginolyticus) (1, 11). Multiple units interact with the rotor to generate torque independently in a working motor (9, 10, 12, 13). The structure and function of H⁺ and Na⁺ motors are very similar, to the extent that several functional chimeric motors have been made containing different mixtures of H⁺- and Na⁺-motor components (11). One such motor that runs on Na⁺ in E. coli combines the rotor of the H⁺-driven E. coli motor with the chimeric stator unit PomA/PotB, containing PomA from V. alginolyticus and a fusion protein between MotB from E. coli and PomB from V. alginolyticus (14).In most flagellated bacteria, motors are driven by ion-specific rotor–stator combinations. However, some species (e.g., Bacillus subtilis and Shewanella oneidensis) combine a single set of rotor genes with multiple sets of stator genes encoding both H⁺ and Na⁺ stator proteins, and it has been speculated that these stator components may interact with the rotor simultaneously, allowing a single motor to use both H⁺ and Na⁺. An appealing hypothesis that the mixture of stator components is controlled dynamically depending on the environment has arisen from the observation that the localization of both stator components depends upon Na⁺ (15). However, despite some experimental effort there is as yet no direct evidence of both H⁺ and Na⁺ stator units interacting with the same rotor (16).The rotation of single flagellar motors can be monitored in real time by light microscopy of polystyrene beads (diameter ∼1 μm) attached to truncated flagellar filaments (17). Under these conditions, the E. coli motor torque and speed are proportional to the number of stator units in both H⁺-driven MotA/MotB and Na⁺-driven PomA/PotB (17–19) motors. The maximum number of units that can work simultaneously in a single motor has been shown to be at least 11 by “resurrection” experiments, in which newly produced functional units lead to restoration of motor rotation in discrete speed increments in an E. coli strain lacking functional stator proteins (19). Stator units are not fixed permanently in a motor: Each dissociates from the motor with a typical rate of ∼2 min⁻¹, exchanging between the motor and a pool of diffusing units in the cytoplasmic membrane (20). Removal of the relevant ion gradient inactivates both H⁺ and Na⁺ stator units, most likely leading to dissociation from the motor into the membrane pool (2, 21, 22).Here we demonstrate a hybrid-fuel motor containing both H⁺-driven MotA/MotB and Na⁺-driven PomA/PotB stator components, sharing a common rotor in E. coli. We control the expression level of each stator type by induced expression from plasmids, and the affinity of Na⁺-driven stator units for the motor by external [Na⁺]. Units of each type compete for spaces around the rotor, and the motor torque is simply the sum of the independent contributions, with no evidence of direct interaction between units. Thus, we demonstrate the possibility of modularity in the E. coli flagellar motor, with ion selectivity determined by the choice of stator modules interacting with a common rotor. Our artificial hybrid motor demonstrates that species with multiple types of stator gene and a single set of rotor genes could contain natural hybrid motors that work on a similar principle (15, 16, 23).