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Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFRmutations compared to EGFRwild-type patients. Our single-center experience on the KEYNOTE-001 trial suggested that pembrolizumab-treated EGFR-mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR-mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD-L1) expression ≥50%.

In the present work, a neural network able to formulate fats with three ingredients derived from soybean (one refined oil and two hydrogenated base stocks) was built and trained. The training of the network was accomplished with data on the solid fat content (SFC) of 112 products, association with the proportions of the raw material used in their formulation. After the training, the network furnished, from the requested solid profiles, the possible formulations for the desired product. According to the statistical analysis applied to the results obtained, larger mean errors were observed in products with very low SFC and the smallest errors were found in products with high SFC. Regarding different temperatures, the network performance was more accurate for 10, 20, and 25°C than for 30, 35, and 37.5°C, where the lower measurements resulted in larger relative errors. According to evaluation by industrial experts, all the responses furnished by the network after its training were considered within the acceptable variation limits. For these experts, the network knowledge generalization (accomplished with products not presented during the training) was considered highly efficient (nearly 100%).

Abstract: In the present work, a neural network able to formulate fats with three ingredients derived from soybean (one refined oil and two hydrogenated base stocks) was built and trained. The training of the network was accomplished with data on the solid fat content (SFC) of 112 products, association with the proportions of the raw material used in their formulation. After the training, the network furnished, from the requested solid profiles, the possible formulations for the desired product. According to the statistical analysis applied to the results obtained, larger mean errors were observed in products with very low SFC and the smallest errors were found in products with high SFC. Regarding different temperatures, the network performance was more accurate for 10, 20, and 25C than for 30, 35, and 37.5C, where the lower measurements resulted in larger relative errors. According to evaluation by industrial experts, all the responses furnished by the network after its training were considered within the acceptable variation limits. For these experts, the network knowledge generalization (accomplished with products not presented during the training) was considered highly efficient (nearly 100%).

An NAD(P)-dependent malic enzyme with a specific activity of 40.6 mumol of NADH/min/mg of protein and an isoelectric point of 5.4 was purified to apparent homogeneity from canine small intestinal mucosal mitochondria. The purification procedure employed ammonium sulfate fractionation, Sepharose CL 6B gel filtration, chromatography on DEAE-cellulose to remove the interfering malate dehydrogenase, and affinity chromatography on 2',5'-ADP-Sepharose and NAD-agarose to take advantage of the dual coenzyme specificity. Antibody prepared from the purified enzyme produced a single peak upon cross-rocket immunoelectrophoresis against the mitochondrial sonicate. Continuous polyacrylamide gel electrophoresis showed NAD and NADP activity co-migrating with the native protein band. A single band of protein having an apparent Mr = 62,000 was seen on sodium dodecyl sulfate electrophoresis. At pH 7.3, gel filtration revealed a single peak of activity with NAD and NADP corresponding to an apparent Mr = 282,000. Gradient gel polyacrylamide electrophoresis at pH 9.0 indicated an additional broad band of activity corresponding to a Mr = 141,000. Under physiological conditions therefore the protein appears to exist as a tetramer of Mr = 282,000 composed of four equal subunits, whereas at elevated pH values during electrophoresis, partial dissociation to a dimeric species occurs.

These experiments were performed to determine the factor(s) that regulate lactic acid production and utilization by rat tumors in vivo. Arteriovenous differences for glucose and lactic, pyruvic, 3-OH-butyric, and acetoacetic acids were measured across “tissue-isolated” Walker 256 sarcocarcinomas and Morris 5123C hepatomas in fasted rats anesthetized with sodium pentobarbital. Twenty-six per cent of the sarcocarcinomas (n = 53) and 48% of the hepatomas (n = 29) utilized blood lactic acid. The remainder released lactic acid into the venous blood. The steady-state rate of glucose consumption was similar in both lactate-producing and lactate-utilizing tumors. The range of lactate concentrations in the blood leaving the tumors was narrower than the range of lactate concentrations in the blood entering the tumors. This difference was caused by tumor lactic acid production at low arterial lactate concentrations and tumor lactic acid utilization at high arterial lactate concentrations. Individual tumors changed from lactic acid production to lactic acid utilization in a matter of minutes in response to an increase in the arterial lactic acid concentration. Mean lactic plus pyruvic acid concentrations and lactic/pyruvic acid ratios in the tumor venous blood were 2.15 +/- 0.22 and 23.4 +/- 3.7 mM, respectively, for Walker sarcocarcinoma 256 (n = 18) and 1.28 +/- 0.13 and 48.1 +/- 5.1 mM, respectively, for hepatoma 5123C (n = 11). The results suggest: that a steady-state lactic plus pyruvic acid concentration and lactic/pyruvic acid ratio are maintained in the tumor cell cytoplasm by the active glycolytic pathway and by lactic acid dehydrogenase; that the tumor intracellular concentrations equilibrate with the arterial blood and that the tumor steady state is expressed in the tumor venous blood; and that tumor lactic acid production or utilization results from the equilibration between the variable arterial lactic acid concentration and the more constant tumor intracellular steady-state lactic acid concentration. Since the arterial lactate concentration may be less than, greater than, or equal to the intracellular steady-state concentration, an individual tumor may produce, utilize or neither produce nor utilize lactic acid.

An NAD(P)+-dependent ‘malic’ enzyme is shown to be present in mitochondria from small-intestinal mucosa. The intracellular location, activity and regulatory kinetic properties of the enzyme suggest that it participates in the major energy-producing pathway for net oxidation of glutamine-derived tricarboxylic acid-cycle intermediates.

With the present annual average of 200,000 reported cases and 5,200 deaths—a death for every 39 cases reported—whooping cough warrants the concerted attention of clinicians and health officers. Its prevalence depends on the high index of communicability and the profuse dissemination of pertussis bacilli before cardinal clinical symptoms are well established. With quarantine so frequently delayed until the contagious period has nearly passed, new cases are inevitable. As pertussis is fatal only during the first few years of life, preventive inoculations should be undertaken as early as active immunization is likely to result.Since 1916 Danish investigators have used a pertussis vaccine which contains 10,000,000,000 bacilli per cubic centimeter. Although their total dose of 2.2 cc. failed to prevent the disease, "fewer whooping cough deaths occurred when the inoculations were completed before the disease broke out."1To increase the dose appreciably without risk and possibly to enhance its potency,

INTRODUCTION The problem of high infant mortality in summer has received much attention, but of the various factors bearing on this problem, such as high outside- and room-temperature, humidity, etc., the factor of clothing has received relatively little attention. As a result of studies on puppies, we pointed out in a previous communication,1 that the clothing may so seriously interfere with the loss of body heat at moderately high temperatures as to cause the death of the animal. Not that the necessity of scanty clothing for the infant at high temperatures has not been recognized, but it has never been the object of scientific inquiry. For the adult Rubner2 has furnished very valuable data with regard to the prevention of heat loss by clothing, while for the infant no such data are available.We therefore set out to furnish some more accurate data showing the influence of clothing

The treatment of pyloric stenosis is a topic which is still very much under discussion. This is mainly due to the fact that some clinicians advocate immediate operation while others get excellent results in many cases without such a radical procedure. Good results are often obtained without surgery because the spasm frequently relaxes when certain dietary measures are instituted. Operation, soon after the diagnosis is made, doubtless subjects many infants to unnecessary operation. On the other hand, persistence in unsuccessful feeding may increase the surgical risk.The statement occasionally made by some pediatricians that the diagnosis of pyloric stenosis is synonymous with indication for operation is not in accord with the opinion held by the foremost surgeons in this field. Thus Downes,1 points out very clearly that medical treatment is justifiable for a period of from seven to ten days, provided the patient does not lose too much weight

Malnourished children constitute that great heterogeneous group who are appreciably (10 or more per cent) below weight for height and age. Every country, race and stratum of society has its quota of such children. The more carefully each underweight child is studied, however, the more convincing is the evidence that the condition is usually due to a limited number of causes, and that its correction and prevention are closely associated with the two fundamental requisites for growth—proper food and ample rest. Excellent treatises by Smith,1 Emerson2 and Kaiser3 show what can be accomplished by the class or group method of treatment, now used more or less extensively in clinics, schools and outpatient departments. I shall attempt to give a brief outline of a simple, intensive, individual method of treatment for the malnourished child brought to the physician's office. It has been used in several hundred instances during

Much has been accomplished during the last few years with the child who is chronically underweight for his height. Through the efforts of Emerson1 and others, the relation of "malnutrition" to physical defects, improper food habits, overfatigue and errors of home and school life has been pointed out. Many underweight children have been made "free to gain" by the removal of these handicaps.In our clinical work with the underweight child, we occasionally encountered children who, although rendered free to gain, failed to increase in weight on account of a persistent anorexia. These children with poor appetite ate less than the required number of calories and were underweight because they ate insufficiently. Physical and laboratory examinations showed them to be free from tuberculosis, anemia, physical defects, diseased tonsils, adenoids and other known causes of anorexia. Their diets were like those on which our other underweight children thrived, containing an

The tolerance of individuals to sugar has been determinedpreviously by testing how much could be given by mouth or how much could be injected at one time subcutaneously or intravenously before sugar appeared in the urine. It was recognized that these methods were open to objections. In order to overcome these objections Woodyatt1 constructed an apparatus permitting a continuous intravenous injection of solutions at any desired rate. The apparatus consists of a motor driven syringe filling and discharging automatically. In this way it was possible for Sansum and Wilder2 to determine the tolerance of adults to dextrose much more accurately than had been possible before. They found that the appearance of the sugar in the urine depends on the amount of sugar injected in a unit of time, independent of the concentration of the sugar solution. The tolerance is expressed in grams of glucose which can be injected

McClure and Sauer1 emphasized the fact that in the study of the relation of summer heat to infant mortality the heat regulatory power of the infant has not received its due consideration. It is evident that a number of factors are at work to maintain a proper heat balance; on the one side such as influence the heat production, on the other such as determine its elimination. We are indebted to Rubner2 and his co-workers for the most important data about the influence of clothing on heat loss. At moderate room temperature a certain amount of clothing reduced the heat loss by conduction and radiation to one-third of the loss through the bare skin. With a temperature of 37 C. the interference with the heat loss may be so great as to cause serious disturbances. This is in the adult who has at his disposal the potent heat

The studies of the relation of heat to the high infant mortality of summer have not yielded uniform results. A more careful review of the procedures which have been employed in these studies readily explains these contradictory conclusions. The external factors, such as food, high outdoor and indoor temperatures, circulation of air, etc., have received most of the attention; while the most important internal factor, i. e., the heat regulatory power of the infant, has been neglected by most authors. The question, then, which confronts us is: the reaction of the infant to the changes in its environment, with special reference to its heat regulation.Heat equilibrium of the organism depends on the proper balance between:I. Heat production,II. Heat elimination.I. Heat production is influenced chiefly by:1. Food,2. Work.1. That food can influence heat production is shown by Rubner,1 who was able to increase

The adoption of the Dick aseptic nursery technic1 at The Cradle in 1929 practically eliminated hand borne cross infections, such as enteritis and impetigo. Figure 1 illustrates the effect of this technic on the number of deaths due to enteritis contracted after admission. During the six years prior to the introduction of this aseptic technic (1923 to 1928) a total of 942 infants was admitted. There were 55 deaths, 53 due to enteritis. In 40 of the fatal cases infection was contracted after admission. During the twelve years since the introduction of the aseptic technic 3,132 infants have been admitted. There were 26 deaths, 6 due to enteritis. In no case was infection contracted after admission. The total mortality rate before the introduction of the aseptic technic was 5.8 per cent and after its introduction 0.8 per cent.There remained, however, the problem of the respiratory cross infections. Nine

The elimination of heat from the body is dependent almost entirely on radiation, conduction and evaporation. While it is possible to determine the sum total of heat loss of an individual, the accurate determination of the parts entering into this sum is beset with difficulties which have not as yet been surmounted. Nevertheless, even relatively simple methods can yield some information, if not of the amount of heat lost by one or the other mechanism, at least about some of the conditions exercising an influence thereon. Thus, a study of the surface temperature gave us some data1—more accurate than available before — concerning the heat loss by conduction and radiation. In this communication we wish to report data with regard to the evaporation of water from the body surface other than the loss of water through lungs and sweat, that is, the so-called insensible perspiration.The observations of

The coccobacillus of Bordet and Gengou (Haemophilus pertussis) has now been accepted quite universally as the sole causative factor of whooping cough; a filtrable virus plays no role. This pathogen, first isolated with difficulty from the coughed up, glistening pearls of mucus, can now be recovered with relative ease on cough plates exposed during the catarrhal stage. With the proper technic it has been recovered post mortem from alveoli and bronchi. It is not found in any other respiratory disease; intimately exposed immune subjects rarely harbor it. EXPERIMENTAL WHOOPING COUGH Various groups of investigators have produced clinical whooping cough in young monkeys (ringtails, rhesus, chimpanzees) by nasal or intratracheal inoculation of recently isolated cultures. Furthermore, the paroxysmal cough, lymphocytosis and pathologic lesions were produced in monkeys inoculated with bacilli recovered from the finer bronchi of experimentally infected monkeys. To exclude any virus factor, Shibley1 inoculated chimpanzees with a culture

Froelich, in 1897, was the first to report on the leukocytosis and lymphocytosis of pertussis. Students of the blood picture in whooping cough and authors of pediatric textbooks and laboratory manuals stress the diagnostic importance of these changes in the blood. Pertussis is the only disease of the respiratory tract in which they occur. Clinicians are often perplexed, however, by the blood picture early in this disease. Leukocytosis and lymphocytosis may be absent during the fortnight in which the signs and symptoms of the disease gradually become manifest. On the other hand, blood counts may appear elevated, with a preponderance of lymphocytes in young, coughing children who fail to develop the characteristic clinical picture. Many physicians have therefore abandoned blood counts as an aid in early diagnosis. In our work with pertussis, we, too, found the blood picture early in the disease very misleading. We have learned that it is

Although Hüttenbrenner,1 in 1876, gave an accurate clinical description of pyelitis, this disease received very little attention from pediatricians until Escherich,2 in 1894, reported seven cases of what he called "colicystitis." Two years later, Finkelstein 3 found pyelitis to be rather frequent in children, and in 1908 Goeppert's4 monograph on ninety-seven cases appeared. Since then, many publications have dealt with various phases of this disease. Despite the wealth of contributions in recent years, only rarely is neonatal pyelitis referred to. The first two cases were reported in 1901 by Kovalosky and Moro.5 Goeppert's series includes six infants under 3 months. Von Reuss,6 in 1914, remarked: "The occurrence of pyelocystitis in the new-born is not frequent; at any rate, our knowledge of it is very defective." Wieland,7 in 1918, contributed nine cases in infants under 6 months. Finkelstein,8 in 1924, stated that he had

Immunization against whooping cough has been a routine procedure at the Evanston Health Department clinic and at St. Vincent's Infant and Maternity Hospital (Chicago) since 1933. At first the primary object was to collect data on the relative merits of various concentrations of Hemophilus pertussis vaccine and on the optimum time interval between the three doses. During the past six years the purpose has been to obtain data on the potency of alum precipitated vaccine (plain), in combination with diphtheria toxoid, or with diphtheria and tetanus toxoids. Within a few years after these prevention clinics were established, the incidence of whooping cough decreased greatly among the children injected at Evanston, and since 1935 has ceased entirely among the children injected with H. pertussis vaccine at St. Vincent's. It became evident that a reliable test for vaccine conferred immunity was necessary. If an injected vaccine was potent there should be a

On Sept. 1, 1927, Mary J., aged 7 years, accidentally swallowed a twenty-five cent piece (quarter-dollar). Its passage into the stomach was accompanied by much discomfort and pain. The pain was most intense below the sternum. After the coin passed the cardia, relief was instantaneous. Fluoroscopic examination about two hours later showed the coin in the fundus of the stomach. As there were no symptoms, I asked the mother to notify me if any distressing symptoms arose; otherwise, to report when the coin was passed. Three days later, fluoroscopic examination showed that the coin had not left the fundus. There were no symptoms. The child had eaten three hearty meals each day and had had a daily evacuation. Six days after the accident, the coin was still in the fundus. Nine days after the accident, fluoroscopic examination showed the coin still in the fundus. The mother was now quite concerned