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The emergence of the SARS-CoV-2 virus and new viral variations with higher transmission and mortality rates have highlighted the urgency to accelerate vaccination to mitigate the morbidity and mortality of the COVID-19 pandemic. For this purpose, this paper formulates a new multi-vaccine, multi-depot location-inventory-routing problem for vaccine distribution. The proposed model addresses a wide variety of vaccination concerns: prioritizing age groups, fair distribution, multi-dose injection, dynamic demand, etc. To solve large-size instances of the model, we employ a Benders decomposition algorithm with a number of acceleration techniques. To monitor the dynamic demand of vaccines, we propose a new adjusted susceptible-infectious-recovered (SIR) epidemiological model, where infected individuals are tested and quarantined. The solution to the optimal control problem dynamically allocates the vaccine demand to reach the endemic equilibrium point. Finally, to illustrate the applicability and performance of the proposed model and solution approach, the paper reports extensive numerical experiments on a real case study of the vaccination campaign in France. The computational results show that the proposed Benders decomposition algorithm is 12 times faster, and its solutions are, on average, 16% better in terms of quality than the Gurobi solver under a limited CPU time. In terms of vaccination strategies, our results suggest that delaying the recommended time interval between doses of injection by a factor of 1.5 reduces the unmet demand up to 50%. Furthermore, we observed that the mortality is a convex function of fairness and an appropriate level of fairness should be adapted through the vaccination., (© 2023 The Authors.)

Despite recent decreases in Black infant mortality, racial disparities persist, motivating continued research into factors related to these inequalities. While the inverse association between education and infant mortality has been documented across races, less is known about its geographic heterogeneity. Using vital statistics from the National Center for Health Statistics, this study considers Black-white disparities in infant mortality for births occurring between 2011 and 2015 across regions and metropolitan status of maternal residence. With logistic regressions, we investigate heterogeneity in maternal educational gradients of infant mortality by geographic residence both within and between races. Beyond confirming the well-known relationship between education and infant mortality, our findings document a slight metropolitan advantage for infants born to white mothers as well as lower returns to education for infants born to Black mothers residing in nonmetropolitan counties. We observe a metropolitan advantage for infants born to Black mothers with at least a bachelor's degree, but a metropolitan disadvantage for infants born to Black mothers with less than a high school degree. The South is driving this divergence, pointing to particular mechanisms limiting returns to education for Southern Black mothers in nonmetropolitan areas. This paper's geographic perspective emphasizes that racial infant health disparities are not uniform across the country and cannot be fully understood through individual and household characteristics., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Côté-Gendreau and Donnelly Moran.)

With the increasing presence of renewable energy sources in the electrical power grid, demand response via thermostatic appliances such as electric water heaters is a promising way to compensate for the significant variability in renewable power generation. We propose a multistage stochastic optimization model that computes the optimal day-ahead target profile of the mean thermal energy contained in a large population of heaters, given various possible wind power production and uncontrollable load scenarios. This optimal profile is calculated to make the variable net demand as even as possible., (© The Author(s) 2020.)

Volumetric-modulated arc therapy (VMAT) treatment planning is an efficient treatment technique with a high degree of flexibility in terms of dose rate, gantry speed, and aperture shapes during rotation around the patient. However, the dynamic nature of VMAT results in a large-scale nonconvex optimization problem. Determining the priority of the tissues and voxels to obtain clinically acceptable treatment plans poses additional challenges for VMAT optimization. The main purpose of this paper is to develop an automatic planning approach integrating dose-volume histogram (DVH) criteria in direct aperture optimization for VMAT, by adjusting the model parameters during the algorithm. The proposed algorithm is based on column generation, an optimization technique that sequentially generates the apertures and optimizes the corresponding intensities. We take the advantage of iterative procedure in this method to modify the weight vector of the penalty function based on the DVH criteria and decrease the use of trial-and-error in the search for clinically acceptable plans. We evaluate the efficiency of the algorithm and treatment quality using a clinical prostate case and a challenging head-and-neck case. In both cases, we generate 15 random initial weight vectors to assess the robustness of the algorithm. In the prostate case, our methodology obtained clinically acceptable plans in all instances with only a 10% increase in the computational time, while simple VMAT optimization found just three acceptable plans. To have an idea with respect to the existing software, we compared the obtained DVH to a commercial software. The quality of the diagrams of the proposed method, especially for the healthy tissues, is significantly better while the computational time is less. In the head-and-neck case, 93.3% of the clinically acceptable plans are obtained while no plan was acceptable in simple VMAT. In sum, the results demonstrate the ability of the proposed optimization algorithm to obtain clinically acceptable plans without human intervention and also its robustness to weight parameters. Moreover, our proposed weight adjustment procedure proves to reduce the symmetry in the solution space and the time required for the post-optimization phase.

In this paper, we propose a novel heuristic algorithm for the volumetric-modulated arc therapy treatment planning problem, optimizing the trade-off between delivery time and treatment quality. We present a new mixed integer programming model in which the multi-leaf collimator leaf positions, gantry speed, and dose rate are determined simultaneously. Our heuristic is based on column generation; the aperture configuration is modeled in the columns and the dose distribution and time restriction in the rows. To reduce the number of voxels and increase the efficiency of the master model, we aggregate similar voxels using a clustering technique. The efficiency of the algorithm and the treatment quality are evaluated on a benchmark clinical prostate cancer case. The computational results show that a high-quality treatment is achievable using a four-thread CPU. Finally, we analyze the effects of the various parameters and two leaf-motion strategies.

Infectious diseases are still among the leading causes of death worldwide due to their persistence, emergence, and reemergence. As the recent Ebola virus disease and MERS-CoV outbreaks demonstrate, the modern epidemics and large-scale infectious outbreaks emerge and spread quickly. Air transportation is a major vehicle for the rapid spread and dissemination of communicable diseases, and there have been a number of reported outbreaks of serious airborne diseases aboard commercial flights including tuberculosis, severe acute respiratory syndrome, influenza, smallpox, and measles, to name a few. In 2014 alone, over 3.3 billion passengers (a number equivalent to 42% of the world population) and 50 million metric tons of cargo traveled by air from 41,000 airports and 50,000 routes worldwide, and significant growth is anticipated, with passenger numbers expected to reach 5.9 billion by 2030. Given the increasing numbers of travelers, the risk of infectious disease transmission during air travel is a significant concern, and this chapter focuses on the current knowledge about transmission of infectious diseases in the context of both transmissions within the aircraft passenger cabin and commercial aircraft serving as vehicles of worldwide infection spread.

Almost 2 billion people travel aboard commercial airlines every year. Health-care providers and travellers need to be aware of the potential health risks associated with air travel. Environmental and physiological changes that occur during routine commercial flights lead to mild hypoxia and gas expansion, which can exacerbate chronic medical conditions or incite acute in-flight medical events. The association between venous thromboembolism and long-haul flights, cosmic-radiation exposure, jet lag, and cabin-air quality are growing health-care issues associated with air travel. In-flight medical events are increasingly frequent because a growing number of individuals with pre-existing medical conditions travel by air. Resources including basic and advanced medical kits, automated external defibrillators, and telemedical ground support are available onboard to assist flight crew and volunteering physicians in the management of in-flight medical emergencies.

Statement of the Problem: When conducting a treatment intervention study, it is assumed that a level of reliability can be obtained from the measurement tool such that the outcome can be reasonably assessed., Purpose of Study: Investigate the reliability of laboratory polysomnography, the gold standard for assessment of treatment outcomes for obstructive sleep apnea, at a 1-month interval., Materials and Methods: In a clinical trial of 118 patients recruited to assess the effects of a pharmaceutical treatment intervention, a subset of 20 patients designated as placebo controls completed two polysomnography studies, one at baseline and one at least one month later., Results: The correlation between the overall Apnea/Hypopnea indices from the two polysomnography (PSG) studies was poor (r = 0.44) and the results were biased, with a mean increase of seven events per hour on night 2. Twenty-five percent of the subjects had an increase greater than 20 events/hour on night 2 and only 45% of participants had a night-to-night difference of < or =5 events/hour. The correlation between overall apnea indexes for nights 1 and 2 (r = 0.61) was improved, compared to the overall apnea/hypopnea indexes. The correlation in sleep efficiency across the two nights was relatively week (r = 0.52) but significant. The correlations between nights 1 and 2 for the percentage of time supine (r = 0.70) and the supine apnea-hypopnea index (AHI) (r = 0.69) were similar and highly significant. The correlation for the non-supine AHI was only 0.25, Conclusions: In this study, the reliability of a single-night PSG in measuring treatment outcome was compromised as a result of the large night-to-night variability of subjects' obstructive sleep apnea (OSA). Studies employing the AHI as an outcome need to be adequately powered with respect to the inherent night-to-night variability in the measurement. When assessing treatment intervention outcomes, there may be benefit from the acquisition and averaging of multiple nights of data in order to mitigate the inherent night-to-night variability of OSA and improve the accuracy of the outcome assessment.

Fibromyalgia syndrome is a systemic disorder of widespread pain which is thought to result from abnormal pain processing within the central nervous system. There are no currently approved treatments for this indication. Antidepressants appear, however, to be effective, especially those with an action on noradrenergic neurotransmission. The objective of the present study was to test the efficacy of the dual action noradrenaline and serotonin reuptake inhibitor antidepressant, milnacipran, in the treatment of fibromyalgia. The 125 patients, who were enrolled in a double-blind, placebo-controlled, flexible dose escalation trial, were randomized to receive placebo or milnacipran for 4 weeks of dose escalation (up to 200 mg/day), followed by 8 weeks at a constant dose. The study evaluated the efficacy and safety of milnacipran for the treatment of pain and associated symptoms such as fatigue, depressed mood and sleep. 75% of milnacipran-treated patients reported overall improvement, compared with 38% in the placebo group (p < 0.01). Furthermore, 37% of twice daily milnacipran-treated patients reported at least 50% reduction in pain intensity, compared with 14% of placebo-treated patients (p < 0.05). 84% of all milnacipran patients escalated to the highest dose (200 mg/day) with no tolerability issues. Most adverse events were mild to moderate in intensity, and transient in duration. These results suggest that milnacipran may have the potential to relieve not only pain but several of the other symptoms associated with fibromyalgia., (2004 John Wiley & Sons, Ltd.)

Objective: This study was designed to compare 3 commonly used methodologies for assessing clinical pain during trials involving patients diagnosed with fibromyalgia syndrome. Baseline characteristics, characteristics over time, and compliance were evaluated for each of the methods., Methods: Fourteen patients diagnosed with fibromyalgia syndrome were asked to monitor their symptoms of pain using 3 different strategies over a 12-week period: 1) real-time pain reports were collected on an electronic diary using randomly-scheduled audible prompts; 2) end-of-week reports asked patients to rate their mean pain over the past week on the electronic diary; and 3) monthly in-clinic reports asked patients to rate their mean pain for the week using a traditional paper and pencil diary., Results: Significantly different baseline values were obtained for the 3 methods. Paper and pencil produced the highest values, and real-time pain reports produced the lowest baseline values. Pain ratings were more likely to reflect decreases in the 2 methods relying on recall than the real-time strategy. The average adherence with pain monitoring using the electronic diary was 85%, which was superior to the adherence for the recall measures completed during the clinic visits., Conclusion: Pain assessment methods relying on recall might contribute to an apparent improvement in clinical trials in the absence of an intervention; such an effect has been considered a "placebo response." Future clinical trials might consider using a real-time approach to pain assessment, which in this study appeared to mitigate against seeing improvement in the absence of an intervention and demonstrated higher levels of patient adherence.

The complication rate of transesophageal echocardiography (TEE) performed in clinical settings outside the emergency department (ED) has been reported to be 1% to 3%. The rate of complications of performing TEE in the ED has not been established. The purpose of this study was to determine the rate of complications associated TEE with carried out on ED patients, and to investigate parameters that might predict complications. A retrospective chart review was carried out on consecutive ED patients undergoing TEE at a major referral center. Complications were abstracted. Parameters to predict complications were assessed, including age, gender, vital signs, pulse oximetry values, serum bicarbonate level, and hematocrit level. A total of 142 patients underwent TEE in the ED during the study period; 88 of these were trauma patients. There were 18 (12.6%) complications: death (1), respiratory insufficiency/failure (7), hypotension (3), emesis (4), agitation (2), and cardiac dysrhythmia (1). None of the tested variables predicted a complication. TEE carried out in the ED has a higher complication rate than has been reported in other clinical settings.

The awareness of carpal tunnel syndrome by the lay public has increased dramatically in recent years, with an apparent shift in patient-population presentation. We prospectively studied steroid injection and wrist splinting in 76 hands in 57 patients, presenting without advanced disease or associated medical conditions, by standard evaluation and protocol of treatment. The average age of the patients was 38 years; 50 women and 7 men were included. Follow-up examination after simultaneous steroid injection and splinting averaged 11 months. Ten hands were noted to be symptom-free at the final evaluation. Women were noted to have a significant decrease in the rate of symptom resolution when compared to men. Patients, 40 years of age or younger, were also noted to have a significant decrease in the rate of symptom resolution when compared to patients over 40 years of age. No significant differences were noted when comparing symptom duration prior to treatment or workers' compensation insurance status to final symptom resolution. Young women are the least likely to have resolution of carpal tunnel syndrome symptoms when treated conservatively.

The reversible autophosphorylation of the pp60c-src family tyrosine kinase, p56lyn has been characterized by a simple procedure that involves the examination of the enzyme catalyzed radioisotope exchange between ATP and ADP. The equilibrium constant of the reaction was determined to be 3.31 and corresponded to a standard free energy of hydrolysis of the phosphotyrosine bond in p56lyn of -8.08 kcal/mol. GDP was capable of substituting for ADP as phosphate acceptor so that p56lyn displayed a nucleoside diphosphate kinase activity.

We reviewed 108 patients with upper urinary tract tumors who underwent surgical treatment during a 10-year period (87 men and 21 women with a mean age of 63.5 years). Of the tumors 97% were unilateral and only 3 patients had bilateral tumors. Two-thirds of the patients had a single tumor focus and a third had 2 or more tumor foci. Additionally, there were 31 patients (28.7%) with previous and/or simultaneous bladder tumors. Nephroureterectomy was performed in 92 cases, nephrectomy in 6 and a conservative operation in 13. In 65 cases lymphadenectomy was added. The survival rates at 5 and 10 years were 67 and 65%, respectively. Of the patients 90% with cancer-related deaths had high grade tumors. Of the 15 patients with positive lymph nodes 87% died of metastasis compared to 8% of the 50 patients with negative lymph nodes. Nine patients (8.7%) had relapse in the upper urinary tract, 6 (5.8%) in the ipsilateral ureter and 3 (2.9%) in the contralateral ureter. Of these 3 patients 2 had recurrent multifocal bladder tumors. For patients who present with an upper urinary tract tumor the risk of a bladder cancer was approximately 9% and that of a contralateral urothelial tumor was 1%.

Allogeneic immunocompetent T cells injected into chicken embryos induce a graft-versus-host reaction (GVHR) whose most prominent manifestation is splenic hyperplasia. The highly inbred CC and CB strains of chickens used here are, respectively, homozygous for the B4 or B12 MHC haplotypes. By means of a panel of immunological reagents, including alloantisera and monoclonal antibodies against public domains of the T-cell receptor, CD4, CD8, and the inducible interleukin-2-receptor light chain (CD25), it is shown that the bulk of cells in the enlarged spleen are of host origin and do not express markers typical of mature T or B lymphocytes. Among recipient splenocytes, the quantitatively most important population consists of TCR alpha beta-TCR gamma delta- CD4-CD8+CD25+ (TCR0) lymphocytes. Donor cells encountered in the spleen prevalently exhibit a TCR alpha beta+CD4+CD8-CD25+ phenotype and proliferate in vivo. The data demonstrate that nonspecific host and potentially specific donor-derived cellular elements contribute to splenomegaly.

Matched samples of bone from the lumbar spine and tibia were obtained at autopsy from three adult males who had no known evidence of metabolic bone disease at the time of their demise. The soluble noncollagenous bone proteins were quantitatively extracted from these samples and assayed for the relative content of two bone-associated proteins, osteocalcin and osteonectin. When compared to trabecular bone, cortical bone had higher levels of osteocalcin and much lower levels of osteonectin. When concentration is expressed per gram of dried bone, the osteocalcin excess in cortical bone ranged from 30- to 32-fold, and the osteonectin excess in trabecular bone ranged from 21- to 47-fold. These differences were significant (P less than 0.01) using analysis of variance. We conclude that the human skeleton is not homogeneous with regard to these biochemical markers and that cortical and trabecular bone are biochemically quite distinct. This implies that these two types of bone may be subject to distinct regulatory mechanisms and that global assessments of skeletal function and bone quality based upon soluble markers should be applied with caution. The data also imply that a differential assessment of skeletal performance may be possible using biochemical serum markers.

Cyclic peptides have been extracted with methanol from Amanita virosa and separated by preparative HPLC. Six peptides were obtained: phalloidin and five new peptides recently identified by Faulstich as virotoxins. We have compared the interaction of these six peptides with actin in vitro. They increased the rate of polymerization of actin and protected F-actin against several denaturating agents: proteases, heat, chaotropic ions, cytochalasin B, and DNAse I. The five virotoxins have therefore the same biological properties as phalloidin. However, the differential spectra of interaction between actin and the five virotoxins are different than the differential spectra between actin and phalloidin, thus it appears that the molecular interaction of actin with virotoxins is different than with phalloidin. The five virotoxins have the same activity. Although these virotoxins have different functional groups on amino acids 1 and 7, it is concluded that these two amino acids are of minor importance in the interaction of these peptides with actin.

We report our experience with extracorporeal lithotripsy (Dornier HM3) in a series of 26 children with a mean age of 11.6 years, treated for 3 1/2 years. 12 children (46%) had a previous history of calculi and 7 (27%) had already undergone surgery on the same side. Treatment requires two transducer investigations before lithotripsy. With the exception of minor modifications the technique is the same as in the adult. Three (9.7%) postlithotripsy complications were noted, requiring 2 drainage procedures to be carried out on the urinary tract. At 3 months, the success rate (no residual calculi on the plain abdominal film) was 60.7%. This study confirms the efficacy of lithotripsy in the treatment of urinary lithiasis in children.

Upper urinary tract lithiasis is a rare condition in children in comparison to its incidence in the adult population. The distribution of lithiasis in children has been reported to be 56% for idiopathic lithiasis, 20% for metabolic lithiasis, and 25% for lithiasis associated with uropathy. Extracorporeal shock wave lithotripsy (ESWL) has become the treatment of choice for upper urinary tract calculi in the adult patient as well as in children after minor changes and complementary material had permitted the utilization of the Dornier HM-3 lithotripter in these small patients. The reported 3-month success rates range from 47% to 83%, according to the number of patients or kidneys free from calculi. The series reported in the literature have a mean of about 60% completely stone-free kidneys evidenced on the X-ray of the abdomen without preparation at 3 months. Its indications and results are comparable with those of ESWL in the adult. However, the long-term results have as yet not been evaluated and, to date, its hypothetical effects on renal growth or arterial pressure have not yet been elucidated.

The response of trunk neural crest cells taken from precise levels of the neural axis and cultured together with adjacent somites to Brain-derived neurotrophic factor (BDNF), was examined in cultures grown in a chemically defined medium. In control cultures, the number of neural crest-derived neurons expressing the HNK-1 epitope, increased as a function of somitic level in a caudorostral direction. Treatment of cultures with increasing concentrations of BDNF (50 pg/ml to 1 ng/ml) resulted in a 1.5- to 6-fold stimulation in the number of neurons developing from crest cells excised at advanced and post-migratory stages, whereas early migrating crest cells were responsive only to concentrations equal to or higher than 1 ng/ml of BDNF. Nerve growth factor used at 5 and 30 ng/ml had no effect on survival of HNK-1-positive cells at any of the somitic levels tested. In an attempt to identify the subpopulation of HNK-1-immunoreactive neurons responding to BDNF, control and treated cultures were stained for the HNK-1 antibody in combination with substance P (SP) antibodies (as a marker for sensory neurons). SP immunoreactivity localized to a subpopulation of phase-bright, HNK-1-positive neurons. The absolute number of SP-positive neurons increased 2- to 4-fold upon BDNF treatment; however, their relative proportion within the population expressing the HNK-1 epitope remained essentially unchanged from control to treated cultures (on day 1, 20% as compared to 23.3% and on day 2, 44.6% compared to 49.7% for control and treated cultures, respectively). Taken together, these data suggest that BDNF stimulates primary neuronal differentiation of SP expressing neurons, and/or their survival.

In their study of a homogeneous series of 108 patients operated for a transitional cell tumor of the upper urinary tract, the authors emphasize the following points: --every third tumor has several foci, and it is very difficult to make a complete inventory of all tumoral foci before surgery; --the great majority of these tumors are unilateral. Bilateral recurrence following radical unilateral excision is quite exceptional; --low-grade superficial tumors virtually never invade the lymph nodes, and their prognosis is excellent as a rule; --grade III carcinomas area almost always infiltrating and present high risks of lymph node invasion. Lymph node involvement means that the evolution will be lethal in all cases. None of the patients having invaded lymph nodes survived; --metastases appear soon, usually within the first 24 months, but mainly between the 6th and 12th months following surgery; --20% of the patients in this series died of metastases; --the actuarial survival rate after 5 years is 68%.