Model order reduction techniques to identify submarining risk in a simplified human body model.

This work investigates linear and non-linear parametric reduced order models (ROM) capable of replacing computationally expensive high-fidelity simulations of human body models (HBM) through a non-intrusive approach. Conventional crash simulation methods pose a computational barrier that restricts profound analyses such as uncertainty quantification, sensitivity analysis, or optimization studies. The non-intrusive framework couples dimensionality reduction techniques with machine learning-based surrogate models that yield a fast responding data-driven black-box model. A comparative study is made between linear and non-linear dimensionality reduction techniques. Both techniques report speed-ups of a few orders of magnitude with an accurate generalization of the design space. These accelerations make ROMs a valuable tool for engineers.

A Case of Post-COVID-19-Associated Paracentral Acute Middle Maculopathy and Giant Cell Arteritis-Like Vasculitis.

ABSTRACT: A 47-year-old man with a history of COVID-19 infection 2 months before presentation, presented with a scotoma of the paracentral visual field of the right eye. After thorough testing and evaluation, a diagnosis of paracentral acute middle maculopathy (PAMM) was established. Two months later, the patient developed temporal headache and jaw claudication. High-dose steroids were initiated, and workup for giant cell arteritis (GCA) was undertaken. The patient experienced resolution of the symptoms within 24 hours of steroid initiation. ESR, CRP, and temporal artery biopsy results were normal, although all were obtained more than 2 weeks after steroid initiation. To the best of our knowledge, our patient represents the first individual to date to potentially implicate COVID-19 in both small and large vessel vasculitis in the ophthalmic setting.

Meconium staining of amniotic fluid correlates with intestinal peel formation in gastroschisis.

Several studies in animal models demonstrate that peel formation in gastroschisis is due to the accumulation and activation of intestinal waste products (IWP) in the amniotic fluid. We reviewed our recent experience with gastroschisis and asked the following questions: First, does staining of the bowel and amniotic fluid with IWP correlate with intestinal peel formation? Second, what prenatal ultrasound findings indicate that peel formation is occurring in utero? Over two years, 16 neonates were treated for gastroschisis; twelve had been diagnosed by prenatal ultrasound and followed closely. Patients were grouped based on the presence of IWP in the amniotic fluid at the time of delivery (staining or no staining), and outcomes were reviewed. All neonates in the staining group (n=7) had a fibrinous peel present at the time of birth whereas a peel was absent in all neonates in the no-staining group (n=9). Matting of the bowel was seen by prenatal ultrasound in four patients in the staining group (0/8 in the no-staining group) and correlated with peel formation (Fisher's exact test p =0.007). Primary closure was done in 14 of the infants, and two required silo closure. In neonates with gastroschisis, staining of the amniotic fluid and bowel serosa with IWP correlated with intestinal peel formation. The ultrasound findings of matting correlated with both peel formation and staining with IWP. These results suggest that spillage of IWP into the amniotic fluid is one of the factors in peel formation in gastroschisis. Identification of matting of the bowel by prenatal ultrasound indicates formation of a peel.

Transcellular transport is not required for transmucosal bacterial passage across the intestinal membrane ex vivo.

The mechanisms underlying the process of bacterial translocation are poorly defined. Possible routes for transmucosal passage of bacteria include transcellular and paracellular channels. Bacterial engulfment is a prerequisite for transcellular transport. To determine whether transcellular transport is required for transmucosal bacterial passage, we examined the effect of various inhibitors of endocytosis, such as colchicine, cytochalasin B, and sodium fluoride on transmucosal passage of bacteria across an ileal mucosal membrane mounted in the Ussing chamber. Colchicine and sodium fluoride increased the rate of decline of the potential difference across the membranes. However, neither colchicine, cytochalasin B, nor sodium fluoride affected the incidence of transmucosal bacterial passage. Sodium fluoride, which depletes intracellular ATP, significantly decreased the number of bacteria that passed per membrane. Our data suggest that transcellular transport may not be required for spontaneous transmucosal passage of bacteria, and furthermore bacterial passage may be, at least in part, an energy-dependent process.

The efficacy of a low-dose, monodisperse parasympathicolytic aerosol compared with a standard aerosol from a metered-dose inhaler.

OBJECTIVE: In previous experiments we showed that monodisperse bronchodilator aerosols with a median mass aerodynamic diameter of 2.8 microm induced stronger bronchodilatations than larger aerosols and that the dilatations were clinically relevant at low doses. To discover whether the bronchodilator effects of these low-dose monodisperse aerosols differed from those of standard dosages delivered by metered-dose inhalers, we carried out a comparative trial. METHODS: Ten stable outpatients with a mean forced expiratory volume in 1 s (FEV1) of 58.1% of the predicted value inhaled a placebo aerosol, 8 microg of a 2.8-microm monodisperse ipratropium bromide aerosol and 40 microg from a metered-dose inhaler plus spacer; lung-function measurements followed. Data were analysed with repeated measurements analysis of variance (ANOVA). RESULTS: Greater improvements than with placebo were evident for the forced vital capacity (FVC), the FEV1, the specific airway conductance (sGaw), the peak flow (PEF) and the maximum expiratory flow at 75% of the forced vital capacity (MEF75). In these cases, the low-dose 2.8-microm aerosol proved to be equivalent to the higher-dose metered-dose inhaler. CONCLUSION: By changing the polydisperse characteristic of inhaled aerosols to a monodisperse pattern, the dose of the drug administered can be reduced without loss of efficacy.

Palliative gastric transposition following pharyngolaryngoesophagectomy.

Extensive extirpative resection of advanced head and neck tumors followed by functional reconstruction is a formidable undertaking. Poor long-term survival and substantial morbidity and mortality have often conferred a nihilistic approach toward these patients. We reviewed our experience with transhiatal gastric transposition with pharyngogastric anastomosis for reconstruction of pharyngoesophageal defects to assess the value of undertaking such a formidable surgical intervention. A retrospective analysis (1990-1994) of 20 consecutive patients with advanced head and neck tumors who underwent pharyngolaryngoesophagectomy followed by transhiatal gastric transposition with pharyngogastric anastomosis was performed. Morbidity was 35 per cent; mortality was 10 per cent. Pharyngogastric leaks occurred in 10 per cent of patients. The median postoperative stay was 19 days. Ninety-four per cent of patients had good to excellent palliation. Follow-up averaged 14.3 months. Late stricture occurred in two patients that was easily amenable to dilatation. Tumor recurrence caused dysphagia in one patient; otherwise, all patients are swallowing well or have died without dysphagia. Gastric transposition without thoracotomy is a versatile and reliable method for reconstruction of large pharyngoesophageal defects and is associated with an acceptable morbidity and mortality, thus allowing good palliation in a patient population with an extremely poor prognosis and an otherwise poor quality of life.

Endoscopic preperitoneal herniorrhaphy in professional athletes with groin pain.

INTRODUCTION: Surgical exploration of the groin with subsequent herniorrhaphy has been recommended for obscure groin pain in athletes. The purpose of this study was to evaluate the efficacy of endoscopic preperitoneal herniorrhaphy and, if indicated, contralateral groin exploration in professional athletes with groin pain. PATIENTS AND METHODS: Eight professional athletes presented with groin pain and underwent endoscopic preperitoneal herniorrhaphy between February 1994 and May 1996. All athletes were male with a median age of 25.1 years (range: 22-30). Seven of the athletes complained of unilateral groin pain while one patient had bilateral pain. Seven had undergone previous conservative treatment without success. Despite multiple examinations, only two patients had been diagnosed with hernias prior to referral to the surgeon. Of the remaining six patients, all were found to have small inguinal hernias in the symptomatic groin. Seven of the patients were noted to have bilateral pathology. RESULTS: Operative time averaged 55.3 min. All patients were ambulatory without significant difficulty within the first 24 h, discontinued oral narcotic use within 72 h of surgery, and were back to recreational activities within 1 week. Aerobic conditioning was resumed within a maximum of 2 weeks. Full conditioning and/or return to full competition occurred within a 2- to 3-week period. At the time of 4 week follow-up, all athletes reported no more than minimal postexertional discomfort, with near total relief of early postoperative symptoms. No athletes noted any impairment in their ability to perform at peak levels. CONCLUSIONS: Groin pain in athletes is a difficult problem requiring a multidisciplinary approach to diagnosis and treatment planning. Endoscopic preperitoneal herniorrhaphy is an effective treatment for obscure groin pain when the pain is associated with an inguinal hernia and allows for a short recovery time back to full athletic activity.

The efficacy of epidural anesthesia for endoscopic preperitoneal herniorrhaphy: a prospective study.

Laparoscopic herniorrhaphy has been criticized because of the need for general anesthesia. The endoscopic preperitoneal approach allows the use of epidural anesthesia, obviating the potential complications and side effects seen with general anesthesia. The purpose of this study was to determine the efficacy of epidural anesthesia for preperitoneal herniorrhaphy. Fifty-two patients underwent repair of a total of 80 hernias over a 6-month period. Thirty-six patients underwent their repairs with the use of epidural anesthesia with the goal of a T-4 sensory level. A tension-free prosthetic repair was performed in all patients. Seventeen patients had unilateral repairs and nineteen had bilateral repairs under epidural, while seven patients had unilateral repairs and nine patients had bilateral repairs under general anesthesia. There were no significant differences in patient demographics. All herniorrhaphies were electively performed on an outpatient basis by a single surgeon (A.L.S.) in a teaching setting. There were no significant differences for unilateral and bilateral repairs when type of anesthesia was compared. There was only one conversion from epidural to general anesthesia, secondary to poor sensory blockade first noticed during creation of the preperitoneal space (97% success rate). Seven patients receiving epidural anesthesia experienced pneumoperitoneum during the procedure. This did not effect the ability to perform the hernia repair successfully. There were no complications related to the epidural anesthetic. Endoscopic preperitoneal herniorrhaphy can be performed effectively under epidural anesthesia, obviating the need for general anesthesia.

Optimal particle size for beta 2 agonist and anticholinergic aerosols in patients with severe airflow obstruction.

BACKGROUND: The optimal particle size of a beta 2 agonist or anticholinergic aerosol in patients with severe airflow obstruction is unknown. METHODS: Seven stable patients with a mean forced expiratory volume in one second (FEV1) of 37.9% of the predicted value inhaled three types of monodisperse salbutamol and ipratropium bromide aerosols with particle sizes of 1.5 microns, 2.8 microns, and 5 microns, respectively, and a placebo aerosol. The volunteers inhaled 20 micrograms salbutamol and 8 micrograms ipratropium bromide, after which lung function changes were determined and analysed with repeated measurements analysis of variance (ANOVA). RESULTS: Greater improvements in FEV1, specific airway conductance (sGaw) and maximum expiratory flow at 75%/50% of the forced vital capacity (MEF75/50) were induced by the 2.8 microns aerosol than by the other particle sizes. CONCLUSIONS: In patients with severe airflow obstruction the particle size of choice for a beta 2 agonist or anticholinergic aerosol should be approximately 3 microns.

Gasless laparoscopic esophagomyotomy.

A case of gasless laparoscopic esophagogastric myotomy for achalasia is presented. The technical aspects of the technique as well as the benefits of this approach are reviewed.

Trocar site herniation following laparoscopic cholecystectomy and the significance of an incidental preexisting umbilical hernia.

With the expansion of both laparoendoscopic surgery and the number of those performing it, the surgeon must remain cognizant of the uncommon complication of herniation through a previous trocar site. Herniation through laparoscopic trocar defects most often occurs as a Richter's hernia, hence its presentation can be insidious and can lead to significant morbidity. A retrospective chart review of 1300 consecutive laparoscopic cholecystectomies over 5 years was performed. An incidence of 0.77 per cent for trocar site herniations was found. All of the trocar site hernias occurred through large (> or = 10 mm) defects at the umbilical site. Ninety per cent of those patients with trocar site herniations had an umbilical hernia or midline incisional hernia found incidentally upon entrance into the peritoneal cavity. All of the herniations occurred despite primary fascial closure of the trocar sites. One trocar site hernia resulted in a small bowel obstruction secondary to an incarcerated Richter's hernia. This required a small bowel resection. Consequently, we now close trocar fascial defects in patients with preexisting hernias in a formal fashion. We recommend that trocar ports be removed under direct vision and that large fascial defects (> or = 10mm) be primarily closed. Furthermore, we recommend in those patients with incidentally found umbilical hernias that both the fascial edge and complete extent of the hernia defect be defined and then closed as a formal herniorrhaphy with interrupted nonabsorbable suture and a synthetic patch if necessary.

Bile leak following laparoscopic cholecystectomy.

The incidence and significance of bile leak after open cholecystectomy have been studied. The purpose of this study was to determine the incidence and significance of postoperative bile leak associated with both emergent and elective laparoscopic cholecystectomies. One thousand four hundred patients undergoing laparoscopic cholecystectomy from July 1990 to January 1995 were retrospectively reviewed. Twenty-seven percent of laparoscopic cholecystectomies were performed urgently for acute cholecystitis. Diisopropyl-iminodiacetic acid (DISIDA) scan was used to determine the presence of a bile leak or obstruction. Also, a subgroup of 63 patients from March to May of 1992 was studied in a nonblinded prospective fashion to determine the rate of asymptomatic bile leak. The incidence of bile leak in the subgroup of 63 patients was 4.7% (n = 3). All of these bile leaks were asymptomatic and of no clinical significance. The incidence of bile leak in the remaining 1337 was 0.14% (n = 2). These bile leaks were discovered by DISIDA scan following a workup of atypical abdominal pain following laparoscopic cholecystectomy. Both of these patients underwent ERCP with papillotomy. There were no ductal injuries in the entire series. Symptomatic bile leaks following laparoscopic cholecystectomy are rare. Asymptomatic bile leaks occur infrequently and are of no clinical significance.

Rapamycin-FKBP inhibits cell cycle regulators of proliferation in vascular smooth muscle cells.

Multiple growth factors can stimulate quiescent vascular smooth muscle cells to exit from G0 and reenter the cell cycle. The macrolide antibiotic rapamycin, bound to its cytosolic receptor FKBP, is an immunosuppressant and a potent inhibitor of cellular proliferation. In the present study, the antiproliferative effects of rapamycin on human and rat vascular smooth muscle cells were examined and compared with the effects of a related immunosuppressant, FK520. In vascular smooth muscle cells, rapamycin, at concentrations as low as 1 ng/mL, inhibited DNA synthesis and cell growth. FK520, an analogue of the immunosuppressant FK506, is structurally related to rapamycin and binds to FKBP but did not inhibit vascular smooth muscle cell growth. Molar excesses of FK520 blocked the antiproliferative effects of rapamycin, indicating that the effects of rapamycin required binding to FKBP. Rapamycin-FKBP inhibited retinoblastoma protein phosphorylation at the G1/S transition. This inhibition of retinoblastoma protein phosphorylation was associated with a decrease in p33cdk2 kinase activity. These observations suggest that rapamycin, but not FK520, inhibits vascular smooth muscle cell proliferation by reducing cell-cycle kinase activity.

Differential regulation of two types of intracellular calcium release channels during end-stage heart failure.

The molecular basis of human heart failure is unknown. Alterations in calcium homeostasis have been observed in failing human heart muscles. Intracellular calcium-release channels regulate the calcium flux required for muscle contraction. Two forms of intracellular calcium-release channels are expressed in the heart: the ryanodine receptor (RyR) and the inositol 1,4,5-trisphosphate receptor (IP3R). In the present study we showed that these two cardiac intracellular calcium release channels were regulated in opposite directions in failing human hearts. In the left ventricle, RyR mRNA levels were decreased by 31% (P < 0.025) whereas IP3R mRNA levels were increased by 123% (P < 0.005). In situ hybridization localized both RyR and IP3R mRNAs to human cardiac myocytes. The relative amounts of IP3 binding sites increased approximately 40% compared with ryanodine binding sites in the failing heart. RyR down-regulation could contribute to impaired contractility; IP3R up regulation may be a compensatory response providing an alternative pathway for mobilizing intracellular calcium release, possibly contributing to the increased diastolic tone associated with heart failure and the hypertrophic response of failing myocardium.

The human type 1 inositol 1,4,5-trisphosphate receptor from T lymphocytes. Structure, localization, and tyrosine phosphorylation.

Inositol 1,4,5-trisphosphate receptors (IP3R) are intracellular calcium release channels involved in diverse signaling pathways. An IP3R is thought to play a role in mobilizing calcium required for activation of T lymphocytes. The IP3R is a tetrameric structure comprised of four approximately 300-kDa subunits encoded by a approximately 10-kilobase mRNA. In the present study we determined the structure of the human type 1 IP3R expressed in T lymphocytes (Jurkats). The IP3R in human T cells had a predicted molecular mass of 308 kDa and was most similar to the non-neuronal form of the rodent type 1 IP3R. Two putative tyrosine phosphorylation sites were identified, one near the amino terminus and one near the putative channel pore at the carboxyl terminus. During T cell activation the IP3R was tyrosine phosphorylated. A site-specific anti-IP3R antibody was used to localize the carboxyl terminus of the IP3R to the cytoplasm in T cells.

The effect of endotoxin on intestinal mucosal permeability to bacteria in vitro.

OBJECTIVE: To examine the role of the intestinal mucosa in bacterial translocation, in vitro bacterial passage across ileal mucosal segments mounted in Ussing chambers were studied in control and endotoxin (lipopolysaccharide)-treated rats. DESIGN: Experimental study. MATERIALS AND METHODS: Three groups of rats were studied. The experimental group received an intraperitoneal injection of lipopolysaccharide, while controls received an equivalent volume of saline solution; a third group received no treatment. Twenty-four hours later, all groups underwent laparotomy and organ culture to assess bacterial translocation. At the same time, a segment of mucosa from the terminal ileum of each animal was mounted in a Ussing chamber, and the transmucosal passage of labeled Escherichia coli from the luminal to serosal surface was assessed by results of serial cultures. RESULTS: In vivo bacterial translocation occurred in 100% of the lipopolysaccharide-treated animals, significantly higher than the incidence seen in controls (25%; P < .05). In vitro passage of labeled E coli across ileal mucosa in the Ussing chamber occurred in 78% of lipopolysaccharide-treated animals, while in controls transmucosal passage was seen in only 14% (P < .05). Histologic examination of mucosa from both groups using light and transmission electron microscopy demonstrated no structural differences between groups. CONCLUSIONS: Increased permeability to bacteria at the mucosal level contributes to the bacterial translocation seen in endotoxemia.

Quantitative and morphologic analysis of bacterial translocation in neonates.

OBJECTIVE: To elucidate the mechanisms of bacterial translocation in animals fed a conventional formula by correlating transmucosal bacterial passage in vitro with the structural characteristics of the neonatal intestinal mucosa. DESIGN: Newborn rabbits were randomized to receive a conventional formula or breast milk. Bacterial translocation to the mesenteric lymph nodes, liver, and spleen was quantitated after 7 days, and transmucosal passage of bacteria was measured in vitro using the Ussing chamber. The mucosal membranes were examined by light, transmission electron, and confocal laser scanning microscopy. RESULTS: Bacterial passage was rarely seen in the breast milk-fed animals in contrast to the formula-fed animals. Unlike the normal-appearing membranes from breast milk-fed animals, the epithelial cells of formula-fed animals were vacuolated but healthy, with normal polarization and microvillus border by confocal laser scanning microscopy. Villi of formula-fed animals were less densely packed than those of the breast milk-fed animals. Bacterial adhesion, internalization, and transmucosal passage were seen only in membranes from formula-fed animals. Transmission electron microscopy demonstrated bacteria incorporating into the epithelial surface through an active phagocytic process, with rearrangement of the actin cytoskeleton. Once internalized, these bacteria were seen within the cytoplasmic vacuoles and subsequently in the submucosa. No bacteria passed between epithelial cells. CONCLUSION: Morphological changes in the intestinal mucosa of formula-fed newborn rabbits may increase permeability to bacteria.

Breast milk protects the neonate from bacterial translocation.

Clinical and experimental evidence suggests that breast milk enhances the neonatal gut barrier. Using bacterial translocation (BT) as a measure of gut barrier function, a series of experiments was designed to explore the relationship between the neonatal gut barrier and breast milk as well as the factors associated with the feeding of breast milk. Full-term newborn rabbits were assigned to one of four groups: formula-fed (group I), fed with colostrum plus formula (group II), breast-fed with breast milk (group III), and fed with colostrum plus stored breast milk (group IV). At 7 days of age, body weights were obtained, the rabbits were killed, and the mesenteric lymph nodes (MLN), liver, and spleen were quantitatively cultured for translocating bacteria. The cecum was cultured for aerobic and anaerobic enteric organisms. Distal ileal tissues were examined by light and transmission electron microscopy and compared among groups. The viability of cells in the stored, frozen breast milk was assessed by Trypan blue staining. Group I rabbits had significantly lower mean body weights compared with the other groups. The animals breast-fed breast milk had no BT to the MLN or liver and had a 9% incidence of BT to the spleen. There was no difference between BT in groups III and IV. The stored breast milk contained no viable cells. The incidence of BT to all three areas was significantly lower than in groups I and II. The animals fed with formula alone had the highest incidence of BT to the MLN (88%), liver (60%), and spleen (32%). BT in this group was significantly higher compared with groups III and IV.(ABSTRACT TRUNCATED AT 250 WORDS)

Quantitative thallium-201 myocardial exercise scintigraphy in normal subjects and patients with normal coronary arteries.

Quantitative thallium-201 myocardial exercise scintigraphy was tested in two patient populations representing alternative standards for cardiac normality: group I comprised 18 male uncatheterized patients with a low likelihood of coronary artery disease (CAD); group II contained 41 patients with normal coronary arteriograms. Group I patients were younger, they achieved a higher rate-pressure product than group II patients; all had normal findings by physical examination and electrocardiography at rest and exercise. Group II patients comprised 21 females, 11 patients showed abnormal electrocardiography at rest, and five patients showed ischemic ST depression during exercise. Twelve patients had signs of minimal CAD. Twelve patients revealed abnormal visual and quantitative thallium findings, three of these patients had minimal CAD. Profiles of uptake and washout of thallium-201 were derived from both patient groups, and compared with normal limits developed by Maddahi et al. Furthermore, low likelihood and angiographically normal patients may differ substantially, and both sets of normal patients should be considered when establishing criteria for abnormality in exercise thallium imaging. When commercial software containing normal limits for quantitative analysis of exercise thallium-201 imaging is used in clinical practice, it is mandatory to compare these with normal limits of uptake and washout of thallium-201, derived from the less heterogeneous group of low-likelihood subjects, which should be used in selecting a normal population to define normality.

Myocardial neutrophil accumulation during reperfusion after reversible or irreversible ischemic injury.

Recent studies suggest that polymorphonuclear leukocytes (PMNs) may cause additional myocyte injury during reperfusion of ischemic myocardium. The present study was done to investigate whether PMNs accumulate in myocardium during early reperfusion after reversible or irreversible ischemic injury. Open-chest anesthetized dogs underwent circumflex coronary occlusions for 12 min (n = 5), 40 min (n = 8), or 90 min (n = 8), followed by 1 h of reperfusion. Autologous PMNs were radiolabeled with 111In and reinjected to quantitate myocardial PMN influx during reflow. 125I-labeled albumin was injected simultaneously to correct for 111In associated with plasma proteins in myocardial tissue. The number of PMNs was determined in the inner, middle, and outer one-third of nonischemic and ischemic-reperfused myocardium. In the 12-min group, 40% fewer PMNs were present in the reperfused than in the nonischemic control tissue. In contrast, in both the 40- and 90-min groups, PMN accumulation was two- to sixfold greater in the ischemic-reperfused than nonischemic myocardium, with a transmural gradient of PMN influx increasing from the outer to inner layers. Collateral blood flow, measured with radioactive microspheres, was not significantly different among the three groups. The failure of PMNs to accumulate during reperfusion after 12 min of ischemia does not support the hypothesis that PMNs contribute to postischemic dysfunction of reversibly injured myocytes. Whether PMNs caused cell death during early reperfusion after longer ischemic episodes remains unknown; however, the rapidity of PMN accumulation in the zones of predicted infarction is consistent with this possibility.