Investigation of Risks for Cerebral Embolism Associated With the Hemodynamics of Cardiopulmonary Bypass Cannula: A Numerical Model

Cerebral emboli originating in the ascending aorta are a major cause of noncardiac complications following cardiac surgery. The hemodynamics of the aortic cannula has been proven to play a significant role in emboli generation and distribution. The aim of the current study was to perform a thorough numerical investigation in order to examine the effect of the design and orientation of the cannula used during cardiopulmonary bypass on the risk to develop cerebral embolism. Hemodynamic analyses compared numerical models of 27 cases consisting of six different cannula orientations, four aortic anatomies, and three cannula designs. The cannula designs included a straight‐tip (ST) cannula, a moderately curved tip cannula (TIP₁), and a sharp‐angle curved cannula (TIP₂). Outcome measures included hemodynamic parameters such as emanating jet velocity, jet velocity drop, maximal shear stress, aortic wall reaction, emboli pathlines and distribution between upper and lower vessels, and stagnation regions. Based on these parameters, the risks for hemolysis, atheroembolism, and cerebral embolism were evaluated and compared. On one hand, the jet emerging from the ST cannula generated large wall‐shear stress at the aortic wall; this may have triggered the erosion and distribution of embolic atheromatous debris from the aortic arch. On the other hand, it diverted more emboli from the clamp region to the descending aorta and thus reduced the risk for cerebral embolism. The TIP₁ cannula demonstrated less shear stress on the aortic wall and diverted more emboli from the clamp region toward the upper vessels. The TIP₂ cannula exhibited a stronger emanating jet, higher shear stress inside the cannula, and highly disturbed flow, which was more stagnant near the clamp region. Current findings support the significant impact of the cannula design and orientation on emboli generation and distribution. Specifically, the straight tip cannula demonstrated a reduced risk of cerebral embolism, which may be pivotal in the clinical setting.     

A novel liposomal bupivacaine formulation to produce ultralong-acting analgesia

BACKGROUND: Currently available local anesthetics have relatively brief durations of action. An ultralong-acting local anesthetic would benefit patients with acute and chronic pain. The authors prepared and characterized a novel liposomal bupivacaine formulation using remote loading of bupivacaine along an ammonium sulfate gradient and assessed its efficacy in humans. METHODS: A large multivesicular liposomal bupivacaine formulation was prepared by subjecting small unilamellar vesicles to successive freeze-and-thaw cycles. Bupivacaine hydrochloride was then remotely loaded into the liposomes along an ammonium sulfate gradient ([(NH4)2SO4)]intraliposome/[(NH4)2SO4)]medium > 1000). The liposomes were then characterized for size distribution; drug-to-phospholipid ratio; in vitro release profile at 4 degree, 21 degree C, and 37 degree C; sterility; and pyrogenicity. Six subjects each received six intradermal injections in the lower back with 0.5 ml of 0.5, 1.0, and 2% liposomal bupivacaine; 0.5% standard bupivacaine; saline; and "empty" liposomes. Duration of analgesia was assessed using pinprick testing of the skin directly over the injection sites. Results were compared using the log-rank test. RESULTS: The mean large multivesicular vesicle size was 2439 +/- 544 nm, with a drug-to-phospholipid ratio of 1.8, fivefold greater than results previously reported. In vitro release was slowest at 4 degree C. The median duration of analgesia with 0.5% standard bupivacaine was 1 h. The median durations of analgesia after 0.5, 1.0, and 2.0% liposomal bupivacaine were 19, 38, and 48 h, respectively. Neither saline nor "empty" liposomes produced analgesia. CONCLUSIONS: This novel liposomal formulation had a favorable drug-to-phospholipid ratio and prolonged the duration of bupivacaine analgesia in a dose-dependent manner. If these results in healthy volunteers can be duplicated in the clinical setting, this formulation has the potential to significantly impact the management of pain.     

Respiratory trainer TDI-22

A small-size, transportable respiratory trainer designed for the treatment of bronchopulmonary diseases and made up of the air-mouthpiece, pellet and lateral regulating openings is described in the paper. The possibility of separate resistance regulation at inhale and expiration is its specificity.     

Pain sensitivity in prematurely born adolescents

BACKGROUND: Several studies reported that preterm infants were found to be hypersensitive to pain. However, longitudinal and quantitative assessments of subsequent pain thresholds in adolescence are scarce. OBJECTIVE: To assess the tenderness threshold in adolescents born prematurely compared with matched children born at full term. DESIGN: Case-control study. SETTING: Children in the community recruited from the files of the neonatal intensive care unit. PARTICIPANTS: Sixty adolescents (aged 12-18 years) born prematurely and 60 adolescents born at full term. MAIN OUTCOME MEASURES: Tenderness thresholds were assessed by tender-point count and by dolorimeter. RESULTS: The preterm-born children had significantly more tender points (6.0 +/- 5.2 vs 3.3 +/- 3.3; P =.001) and lower tender thresholds (4.2 +/- 1.5 vs 4.8 +/- 1.6 kg; P =.04), measured by a dolorimeter, than children born at full term. In both groups, girls had significantly more tender points and lower tender thresholds. Despite their increased tenderness, most of the preterm children did not report pain or other related symptoms. CONCLUSIONS: The fact that preterm-born children and adolescents display higher somatic pain sensitivity may be of relevance to physicians taking care of these children, since they may be prone to developing pain syndromes in the future. Further follow-up studies are needed to confirm this hypothesis.     

The efficacy of intraoperative internal intercostal nerve block during video-assisted thoracic surgery on postoperative pain

Background. Video-assisted thoracic surgery (VATS) is widely used for many thoracic surgical procedures. Postoperative pain is less after VATS than after conventional thoracic surgery, but is still significant. The objective of this study was to assess the efficacy of thoracoscopic, internal intercostal nerve block in alleviating immediate postoperative pain.

Methods. Thirty-two patients underwent VATS bilateral sympathectomy for the treatment of hyperhidrosis. The patients were randomly divided into two groups with similar demographic and preoperative physiologic parameters. Group A (n = 16) was submitted to thoracoscopic, internal intercostal nerve blocks performed at T2, T3, and T4 intercostal levels using 3 cc of 0.5% bupivacain in each intercostal space. The injections were performed bilaterally, immediately after the sympathectomy, through the same port. Group B (n = 16) underwent bilateral thoracic sympathectomy without the block. During the immediate postoperative period, heart rate, blood pressure, respiratory rate, pain score, and analgesic requirements were monitored every 30 minutes.

Results. No morbidity was recorded in association with the thoracoscopic, internal intercostal nerve block. The mean heart rates (77 ± 6 vs 89 ± 12 beats per minute, p < 0.001), respiratory rates (15 ± 2 vs 18 ± 3 respirations per minute, p < 0.01), pain score (1.9 ± 0.6 vs 2.7 ± 0.5, p < 0.01), and postoperative analgesic requirements (20 ± 18 vs 50 ± 21 mg pethidine HCL, p < 0.001) were significantly lower in group A. There was no significant difference in blood pressures.

Conclusions. Thoracoscopic, internal intercostal nerve block with bupivacain 0.5% during VATS is safe and effectively reduced the immediate postoperative pain and analgesic requirements.     

De novo mutation rates at the single-mutation resolution in a human HBB gene region associated with adaptation and genetic disease

Although it is known that the mutation rate varies across the genome, previous estimates were based on averaging across various numbers of positions. Here, we describe a method to measure the origination rates of target mutations at target base positions and apply it to a 6-bp region in the human hemoglobin subunit beta (HBB) gene and to the identical, paralogous hemoglobin subunit delta (HBD) region in sperm cells from both African and European donors. The HBB region of interest (ROI) includes the site of the hemoglobin S (HbS) mutation, which protects against malaria, is common in Africa, and has served as a classic example of adaptation by random mutation and natural selection. We found a significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than in Europeans in the HBB region studied. Finally, the rate of the 20A→T mutation, called the “HbS mutation” when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations; no instances were observed elsewhere. Further studies will be needed to examine mutation rates at the single-mutation resolution across these and other loci and organisms and to uncover the molecular mechanisms responsible.

It is widely known that mutation rates vary across the genome at multiple scales (Hodgkinson and Eyre-Walker 2011; Rahbari et al. 2016; Carlson et al. 2018) and are affected by multiple factors, from the mutation type (Gojobori et al. 1982; Bulmer 1986), to the local genetic context (Gojobori et al. 1982; Bulmer 1986; Blake et al. 1992; Hwang and Green 2004; Rahbari et al. 2016; Carlson et al. 2018), to the general location in the genome (Wolfe et al. 1989; Matassi et al. 1999; Lercher et al. 2001; Ellegren et al. 2003). Although this knowledge is highly advanced now compared with what was known a mere decade ago (Campbell et al. 2012; Michaelson et al. 2012; Francioli et al. 2015; Rahbari et al. 2016; Carlson et al. 2018), it could be enhanced further. In particular, rate measurements to date all have been based on averages of various kinds, such as an average across the genome (Nachman and Crowell 2000; Rahbari et al. 2016), or across the instances of any particular motif (Hwang and Green 2004; Carlson et al. 2018), or in certain cases, across the entire stretch of a gene (Haldane 1949; Vogel and Motulsky 1997; Kondrashov 2003). In contrast, technological limitations have precluded measuring mutation rates at particular base positions and of particular mutations at such positions. However, such high-resolution knowledge of the mutation rate variation would bear on multiple open questions in genetics and evolution—from the relative importance of mutation rate variation to the site frequency spectrum (SFS) (Harpak et al. 2016; Lek et al. 2016; Mathieson and Reich 2017), to its importance for adaptive evolution and parallelism (Inoue et al. 2001; Crow et al. 2009; Dumas et al. 2012; Losos 2017; Kratochwil et al. 2019; Kratochwil and Meyer 2019; Lind 2019; Xie et al. 2019), to its contribution to recurrent genetic disease and cancer (Lupski 1998; McClellan and King 2010; Veltman and Brunner 2012; Shendure and Akey 2015).The most precise way of measuring mutation rates, free of biases attributable to past natural selection or random genetic drift events, is offered by de novo mutations—mutations that appeared for the first time in their carrier (Goldmann et al. 2016; Rahbari et al. 2016). These mutations are usually detected by studies comparing the genomes of children to those of their parents, also known as “trio studies” (Roach et al. 2010; Conrad et al. 2011). However, because each individual carries only a small number (e.g., several dozen in humans) of de novo mutations scattered across the genome, the chance of encountering any particular target mutation of interest is miniscule, rendering it impractical to measure rates of target mutations using such studies.To overcome this barrier, we have developed a method that enables identifying and counting, with high accuracy, ultrarare genetic variants of choice in extremely narrow regions of interest (ROIs) within large populations of cells, such as a single target mutant in 100 million genomes. Because this method has both an error rate lower than the human mutation rate and sufficient yield for the purpose, it enables measuring the frequencies of target mutations of choice in human sperm samples by counting their de novo instances at a single-digit resolution. For variants that are not expected to affect sperm fertility and viability (as in the case below), this frequency is the evolutionarily relevant mutation rate in males. Note that aside from this evolutionary application, ultra-accurate methods of mutation-detection are sought after for early detection of cancer, noninvasive prenatal testing, early identification of virus within host, and more (Salk et al. 2018).As a first target for this method, we chose two sites: a 6-bp region spanning three codons within the human hemoglobin subunit beta (HBB) gene that is of great importance for adaptation and hematologic disease, and the identical, paralogous region within the hemoglobin subunit delta (HBD) gene. The former region includes, among others, the site of the hemoglobin S (HbS) mutation. The most iconic balanced polymorphism mutation (Pauling et al. 1949; Allison 1954; Ingram 1957; Cavalli-Sforza and Feldman 2003; Feng et al. 2004; Hartl and Clark 2007), the HbS mutation is an A to T transversion (GAG→GTG, Glu→Val) in codon 6 of HBB causing sickle-cell anemia in homozygotes (Pauling et al. 1949) and providing substantial protection against severe malaria in heterozygotes (Allison 1954; Flint et al. 1998; Kwiatkowski 2005; Piel et al. 2010). Malaria, in turn, has been a leading cause of human morbidity and mortality, often causing more than a million deaths per year in the recent past, with Africa bearing the brunt of the disease burden (Carter and Mendis 2002), and thus has been possibly the strongest known agent of selection in humans in recent history (Kwiatkowski 2005). Besides the HbS mutation, many other mutations, both point mutations and indels, are also known at this site, many of which are involved in hematologic illness (Hardison et al. 2002; Hardison and Miller 2002). In contrast to HBB, mutations in HBD have a more limited effect and are not thought to confer resistance to malaria, because the HBD’s lower expression levels make it account for <3% of the circulating red blood cell hemoglobin in adults (Steinberg and Adams 1991). Although the population prevalence of the HBB mutations, whether beneficial or detrimental, is normally attributed to natural selection, so far it has not been possible to examine to what degree, if at all, mutational phenomena may also be relevant to their prevalence. To address this gap, we sought to characterize the rates of mutations, including the HbS mutation, in the HBB and HBD ROIs in sperm samples of both African and European donors.