Sanford Children's Specialty Clinic

BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin-affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. © 2018 by John Wiley & Sons, Inc.

Abstract BioID is a unique method to screen for physiologically relevant protein interactions that occur in living cells. This technique harnesses a promiscuous biotin ligase to biotinylate proteins based on proximity. The ligase is fused to a protein of interest and expressed in cells, where it biotinylates proximal endogenous proteins. Because it is a rare protein modification in nature, biotinylation of these endogenous proteins by BioID fusion proteins enables their selective isolation and identification with standard biotin‐affinity capture. Proteins identified by BioID are candidate interactors for the protein of interest. BioID can be applied to insoluble proteins, can identify weak and/or transient interactions, and is amenable to temporal regulation. Initially applied to mammalian cells, BioID has potential application in a variety of cell types from diverse species. © 2018 by John Wiley & Sons, Inc.

BACKGROUND: Osteoporosis and osteopenia are associated with increased fracture incidence in postmenopausal women. We aimed to determine the comparative effectiveness of various available pharmacological therapies. METHODS: We searched MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, ISI Web of Science, and Scopus for randomized controlled trials that enrolled postmenopausal women with primary osteoporosis and evaluated the risk of hip, vertebral, or nonvertebral fractures. A network meta-analysis was conducted using the multivariate random effects method. RESULTS: We included 107 trials (193,987 postmenopausal women; mean age, 66 years; 55% white; median follow-up, 28 months). A significant reduction in hip fractures was observed with romosozumab, alendronate, zoledronate, risedronate, denosumab, estrogen with progesterone, and calcium in combination with vitamin D. A significant reduction in nonvertebral fractures was observed with abaloparatide, romosozumab, denosumab, teriparatide, alendronate, risedronate, zoledronate, lasofoxifene, tibolone, estrogen with progesterone, and vitamin D. A significant reduction in vertebral fractures was observed with abaloparatide, teriparatide, parathyroid hormone 1-84, romosozumab, strontium ranelate, denosumab, zoledronate, risedronate, alendronate, ibandronate, raloxifene, bazedoxifene, lasofoxifene, estrogen with progesterone, tibolone, and calcitonin. Teriparatide, abaloparatide, denosumab, and romosozumab were associated with the highest relative risk reductions, whereas ibandronate and selective estrogen receptor modulators had lower efficacy. The evidence for the treatment of fractures with vitamin D and calcium remains limited despite numerous large trials. CONCLUSIONS: This network meta-analysis provides comparative effective estimates for the various available treatments to reduce the risk of fragility fractures in postmenopausal women.

Respiratory distress presents as tachypnea, nasal flaring, retractions, and grunting and may progress to respiratory failure if not readily recognized and managed. Causes of respiratory distress vary and may not lie within the lung. A thorough history, physical examination, and radiographic and laboratory findings will aid in the differential diagnosis. Common causes include transient tachypnea of the newborn, neonatal pneumonia, respiratory distress syndrome (RDS), and meconium aspiration syndrome (MAS). Strong evidence reveals an inverse relationship between gestational age and respiratory morbidity. (1)(2)(9)(25)(26) Expert opinion recommends careful consideration about elective delivery without labor at less than 39 weeks’ gestation. Extensive evidence, including randomized control trials, cohort studies, and expert opinion, supports maternal group B streptococcus screening, intrapartum antibiotic prophylaxis, and appropriate followup of high-risk newborns according to guidelines established by the Centers for Disease Control and Prevention. (4)(29)(31)(32)(34) Following these best-practice strategies is effective in preventing neonatal pneumonia and its complications. (31)(32)(34). On the basis of strong evidence, including randomized control trials and Cochrane Reviews, administration of antenatal corticosteroids (5) and postnatal surfactant (6) decrease respiratory morbidity associated with RDS. Trends in perinatal management strategies to prevent MAS have changed. There is strong evidence that amnioinfusion, (49) oropharyngeal and nasopharyngeal suctioning at the perineum, (45) or intubation and endotracheal suctioning of vigorous infants (46)(47) do not decrease MAS or its complications. Some research and expert opinion supports endotracheal suctioning of nonvigorous meconium-stained infants (8) and induction of labor at 41 weeks’ gestation (7) to prevent MAS.

NBIA characterizes a class of neurodegenerative diseases that feature a prominent extrapyramidal movement disorder, intellectual deterioration, and a characteristic deposition of iron in the basal ganglia. The diagnosis of NBIA is made on the basis of the combination of representative clinical features along with MR imaging evidence of iron accumulation. In many cases, confirmatory molecular genetic testing is now available as well. A number of new subtypes of NBIA have recently been described, with distinct neuroradiologic and clinical features. This article outlines the known subtypes of NBIA, delineates their clinical and radiographic features, and suggests an algorithm for evaluation.

Respiratory distress is common, affecting up to 7% of all term newborns, (1) and is increasingly common in even modest prematurity. Preventive and therapeutic measures for some of the most common underlying causes are well studied and when implemented can reduce the burden of disease. (2)(3)(4)(5)(6)(7)(8) Failure to readily recognize symptoms and treat the underlying cause of respiratory distress in the newborn can lead to short- and long-term complications, including chronic lung disease, respiratory failure, and even death.After completing this article, the reader should be able to:Respiratory distress is one of the most common reasons an infant is admitted to the neonatal intensive care unit. (1) Fifteen percent of term infants and 29% of late preterm infants admitted to the neonatal intensive care unit develop significant respiratory morbidity; this is even higher for infants born before 34 weeks’ gestation. (2) Certain risk factors increase the likelihood of neonatal respiratory disease. These factors include prematurity, meconium-stained amniotic fluid (MSAF), caesarian section delivery, gestational diabetes, maternal chorioamnionitis, or prenatal ultrasonographic findings, such as oligohydramnios or structural lung abnormalities. (2)(9)(10)(11)(12)(13)(14) However, predicting which infants will become symptomatic is not always possible before birth. Regardless of the cause, if not recognized and managed quickly, respiratory distress can escalate to respiratory failure and cardiopulmonary arrest. Therefore, it is imperative that any health care practitioner caring for newborn infants can readily recognize the signs and symptoms of respiratory distress, differentiate various causes, and initiate management strategies to prevent significant complications or death.Respiratory distress in the newborn is recognized as one or more signs of increased work of breathing, such as tachypnea, nasal flaring, chest retractions, or grunting. (1)(15) Normally, the newborn’s respiratory rate is 30 to 60 breaths per minute. Tachypnea is defined as a respiratory rate greater than 60 breaths per minute. (15) Tachypnea is a compensatory mechanism for hypercarbia, hypoxemia, or acidosis (both metabolic and respiratory), (16) making it a common but nonspecific finding in a large variety of respiratory, cardiovascular, metabolic, or systemic diseases. Pulmonary disease may incite tachypnea, especially in neonates. The natural elastic property of the lungs is to deflate. When balanced by the outward recoil of the chest wall, functional residual capacity (FRC) occurs at the end of expiration to prevent alveoli from collapsing. The newborn chest wall, composed primarily of cartilage, is more pliable, predisposing neonatal lungs to pulmonary atelectasis and decreased FRC. (16)(17)(18) Pulmonary compliance refers to a given change in volume (ΔVolume) for every given change in pressure (ΔPressure), essentially the ability of the alveoli to fill with air under a set pressure. If lung compliance is decreased, such as with transient tachypnea of the newborn (TTN), respiratory distress syndrome (RDS), pneumonia, or pulmonary edema, there is a decrease in tidal volume. To achieve sufficient minute ventilation, the respiratory rate must increase. Hypoxemia further increases tachypnea. (16)(18) Therefore, affected newborns present with marked tachypnea. Because tachypnea is a nonspecific symptom, additional clinical findings aid in narrowing the cause to a respiratory disorder.Increased work of breathing results from mismatched pulmonary mechanics from increased airway resistance (ΔPressure/Volumetric Flow), decreased lung compliance (ΔVolume/ ΔPressure), or both. Airway resistance increases when there is obstruction of air flow. The critical importance of airway radius is indicated in the equation R = V(8lη/πr(4)), where R is resistance, V is flow, l is length, η is viscosity, and r is radius. (19) If the airway radius is halved, resistance increases 16-fold. Nasal flaring is a compensatory symptom that increases upper airway diameter and reduces resistance and work of breathing. Retractions, evident by the use of accessory muscles in the neck, rib cage, sternum, or abdomen, occur when lung compliance is poor or airway resistance is high. Noisy breathing may indicate increased airway resistance, and the type of noise auscultated may help localize airway obstruction (Table 1). Stertor is a sonorous snoring sound heard over extrathoracic airways that indicates nasopharyngeal obstruction. Stridor is a high-pitched, monophonic breath sound that indicates obstruction at the larynx, glottis, or subglottic area. Wheezing may also be high pitched but is typically polyphonic, is heard on expiration, and indicates tracheobronchial obstruction. Grunting is an expiratory sound caused by sudden closure of the glottis during expiration in an attempt to maintain FRC and prevent alveolar atelectasis. Because lung compliance is worse at very low or very high FRC, achieving and maintaining physiologic FRC is essential in the management of respiratory disorders with poor compliance, such as RDS or TTN. On the other end of the spectrum, meconium aspiration syndrome (MAS) is an example of lower airway obstruction with air trapping. These newborns often have high lung volumes, which adversely affects their lung compliance. Regardless of the cause, it is vital to recognize symptoms and act quickly. If the newborn cannot sustain the extra work of breathing to meet its respiratory needs, respiratory failure follows. This failure may manifest as impaired oxygenation (cyanosis) or ventilation (respiratory acidosis). Without prompt intervention, respiratory arrest is imminent.The causes of respiratory distress in a newborn are diverse and multisystemic. Pulmonary causes may be related to alterations during normal lung development or transition to extrauterine life. Normal lung development occurs in 5 phases (20) (Table 2). Respiratory disease may result from developmental abnormalities that occur before or after birth. Early developmental malformations include tracheoesophageal fistula, bronchopulmonary sequestration (abnormal mass of pulmonary tissue not connected to the tracheobronchial tree), and bronchogenic cysts (abnormal branching of the tracheobronchial tree). Later in gestation, parenchymal lung malformations, including congenital cystic adenomatoid malformation or pulmonary hypoplasia from congenital diaphragmatic hernia or severe oligohydramnios, may develop. More common respiratory diseases, such as TTN, RDS, neonatal pneumonia, MAS, and persistent pulmonary hypertension of the newborn (PPHN), result from complications during the prenatal to postnatal transition period. Although mature alveoli are present at 36 weeks’ gestation, a great deal of alveolar septation and microvascular maturation occur postnatally. The lungs are not fully developed until ages 2 to 5 years. (20)(21) Therefore, developmental lung disease can also occur after birth. Bronchopulmonary dysplasia (BPD), for example, is a significant lung disease that complicates prematurity due to arrested alveolarization in developing lungs exposed to mechanical ventilation, oxygen, and other inflammatory mediators before normal development is complete. As defined by an ongoing oxygen requirement at 36 weeks’ adjusted gestational age, BPD affects up to 32% of premature infants and 50% of very low-birth-weight infants. (22)The underlying cause of respiratory distress in a newborn varies and does not always lie within the lungs (15) (Table 3). Thus, after initial resuscitation and stabilization, it is important to use a detailed history, physical examination, and radiographic and laboratory findings to determine a more specific diagnosis and appropriately tailor management. A thorough history may guide in identifying risk factors associated with common causes of neonatal respiratory distress (Table 4). A detailed physical examination should focus beyond the lungs to identify nonpulmonary causes, such as airway obstruction, abnormalities of the chest wall, cardiovascular disease, or neuromuscular disease, that may initially present as respiratory distress in a newborn. Radiographic findings can identify diaphragmatic paralysis, congenital pulmonary malformations, and intrathoracic space–occupying lesions, such as pneumothorax, mediastinal mass, and congenital diaphragmatic hernia, that can compromise lung expansion. Significant tachypnea without increased work of breathing should prompt additional laboratory investigation to identify metabolic acidosis or sepsis. Hypoglycemia, hypomagnesemia, and hematologic abnormalities may result in a depressed ventilatory drive or impaired oxygen transport to the peripheral tissues, so laboratory evaluation should also be considered with these clinical findings. Hypermagnesemia may contribute to respiratory distress and affect a newborn’s capacity to respond to resuscitation due to hypotonia and a depressed respiratory drive or even apnea.Cardiovascular disease may be difficult to distinguish from pulmonary causes of respiratory distress (Table 5). Most congenital heart defects present with cyanosis, tachypnea, or respiratory distress from cardiac failure. Timing may be an important clue to differentiation because very few congenital heart defects present immediately after birth; more often they present several hours to days after delivery as the ductus arteriosus closes. (2) Table 5 aids in this differentiation.Pulmonary hypertension should be considered in any infant with respiratory distress and cyanosis. This condition results when there is a failure to transition from in utero to postnatal pulmonary circulation after delivery. Pulmonary vascular resistance remains high, resulting in cyanosis from impaired pulmonary blood flow and right-to-left shunting of blood across the foramen ovale and ductus arteriosus. Shunting further contributes to systemic hypoxemia and metabolic acidemia—both of which contribute to ongoing increased pulmonary vascular resistance. PPHN may be primary or secondary to respiratory disease, particularly congenital diaphragmatic hernia, MAS, or RDS. When PPHN occurs without concurrent pulmonary disease, differentiating from cyanotic heart disease is difficult. The response to ventilation with 100% oxygen (hyperoxia test) can help distinguish the 2 conditions. In some neonates with PPHN, the Pao2 will increase to above 100 mm Hg, whereas it will not increase above 45 mm Hg in infants with cyanotic heart defects that have circulatory mixing. (5)(23)Four case scenarios are highlighted to help in identifying the most common causes of respiratory distress in the newborn followed by discussion about the pathophysiology, risk factors, prevention, and management strategies for each disorder.A 3.2-kg female infant is delivered by caesarean section at 38 weeks’ gestational age without a trial of labor. Her Apgar scores are 9 and 9 at 1 and 5 minutes, respectively. She develops tachypnea and subcostal retractions with nasal flaring at 1 hour of life. Temperature is 97.9°F (36.6°C), pulse is 165 beats per minute, and respiratory rate is 74 breaths per minute. Aside from increased work of breathing, her physical examination findings are normal. The chest radiograph is shown in Figure 1. She requires supplemental oxygen via nasal cannula with a fraction of inspired oxygen (Fio2) of 0.3 for 36 hours. She then weans to room air. Her respiratory rate is 35 breaths per minute, and she has no increased work of breathing.TTN, also known as retained fetal lung fluid syndrome, presents with early respiratory distress in term and late-preterm infants. TTN is a frequent cause of respiratory distress in newborns and is caused by impaired fetal lung fluid clearance. Normally in utero, the fetal airspaces and air sacs are fluid filled. For effective gas exchange to occur after birth, this fluid must be cleared from the alveolar airspaces. Late in gestation and before birth, the chloride and fluid-secreting channels in the lung epithelium are reversed so that fluid absorption predominates and fluid is removed from the lungs. This process is enhanced by labor, so that delivery before labor onset increases the risk of retained fetal lung fluid. (20) Factors that increase the clearance of lung fluid include antenatal corticosteroids, fetal thorax compression with uterine contractions, and a release of fetal adrenaline in labor, which enhances uptake of lung fluids. (24)Infants with TTN usually present with tachypnea and increased work of breathing, which persists for 24 to 72 hours. Chest radiographs reveal excess diffuse parenchymal infiltrates due to fluid in the interstitium, fluid in the interlobar fissure, and occasionally pleural effusions (Figure 1). Management is supportive. Infants may require supplemental oxygen, and frequently the distending forces of continuous positive airway pressure (CPAP) are necessary to assist in maintaining alveolar integrity and driving fluid into circulation. Blood gases often reveal a mild respiratory acidosis and hypoxemia. The course of TTN is self-limited and does not usually require mechanical ventilation.Preventive measures may include avoiding elective caesarean section before the onset of labor in infants younger than 39 weeks’ gestation. This is because the most common risk factors for TTN include delivery before 39 weeks’ gestation, (1)(2)(3)(9)(25)(26) precipitous delivery, fetal distress, maternal sedation, and maternal diabetes. Although it is well known that premature infants have a higher risk of respiratory problems, the consequences of early-term delivery (37–38 weeks’ gestation) are underrecognized. Early-term infants have an increased risk of requiring respiratory support, mechanical ventilation, and neonatal service; delivery by caesarean section in this population is common and further increases risk. (25) In addition, a single course of antenatal of at hours before an elective term caesarean delivery respiratory infants. On the of and a about elective delivery before onset of labor at than 39 weeks’ gestation and to be of the increased risk of respiratory in late preterm and early-term infant is born by delivery at 39 weeks’ gestational age after of for hours. Apgar scores are and at 1 and 5 minutes, respectively. requires an of in the delivery is and has are Temperature is pulse is beats per minute, and respiratory rate is breaths per minute. given and tachypnea and requires and ventilation for increased work of breathing, respiratory and oxygen requirement during the hours. The chest radiograph is shown in Figure in the newborn may be or in Infants may amniotic via at the of birth, or (20) is the most common of neonatal and is at birth. is the most common that affects term infants. occurs when the is to the The most common are and of the and the pulmonary and physiologic the newborn at higher risk of The respiratory and the decreased of pulmonary result in decreased clearance of from the respiratory also have and which is even more in the premature factors for include of maternal and prematurity. (1) Infants present with increased work of breathing and oxygen Chest often diffuse parenchymal infiltrates with air or effusions may also be In to infants and neonatal is of a blood and fluid and is for any symptomatic the newborn with or a of and an are the initial For infants have in a neonatal intensive care unit for more than such as and require Infants develop in the or at are to have caused by respiratory respiratory and and and and Infants with caused by present in the newborn of with a but no or may also be present to days after Chest diffuse and a blood with a of or without requires systemic and Regardless of the newborns with require care in to infants will require not supplemental oxygen but also and mechanical measures include and for cardiovascular PPHN is a common of neonatal the of of neonatal and its complications on maternal and of newborns at high risk after delivery. caring for newborns should be able to recognize infants and has must also which infants require additional and after birth. have by the for and and by the of and the of and for management of infants. Infants require additional include born to are or with a history of affected by or with an but delivered at than weeks’ gestation, with of hours or or with The for these is followed by to every at hours before may be for are at low risk for For should be and if is of should be is for with In to are in clinical and may be by but are not for of maternal and the of has decreased from per to 0.3 case per However, and to occur with as the Most of the term infants affected are born to without or with an but or and not during labor. are born to hours before delivery or for increase the burden of disease. it is imperative to appropriately any newborn with the risk factors after birth. to any infant develops signs or symptoms of requires a evaluation blood and fluid and If maternal is but the infant has no signs or symptoms of disease, a evaluation and blood with for at is not require a evaluation and for but is not necessary clinical infants should be for hours. to these will decrease the of neonatal and for early and that may prevent complications, such as PPHN or is delivered via delivery because of preterm labor at weeks’ gestation. Apgar scores are and at 1 and 5 minutes, respectively. The infant is cyanotic and requires immediately after delivery. has subcostal retractions, and nasal decreased air in the lung Temperature is pulse is beats per minute, and respiratory rate is breaths per minute. requires an of chest radiograph is shown in Figure also known as disease, is a common cause of respiratory disease in the premature RDS is also in infants have in RDS is caused by a of alveolar which increases in resulting in and low lung as diffuse infiltrates on radiograph (Figure 1). Pulmonary a in the of RDS and contributes to the development of air lung fluid is to in the decreased of channels in the lung and a in the 2 days after in premature infants. Infants typically on onset of by the after with RDS typically present within the several hours of often immediately after delivery. infants have marked respiratory distress with tachypnea, nasal flaring, and Grunting occurs when an infant to maintain an FRC in the of lungs by As the infant the expiratory this glottis, there is a and increased residual volume that the airway and also an expiratory Infants with RDS have cyanosis and require supplemental of RDS may respond to the distending of but more severe require and of into the lungs. there are no that if and when to of in the 2 hours of for all premature infants younger than 30 weeks’ gestation. with ventilation (CPAP) and and for infants require more than to oxygen to maintain an greater than mm In a management it is important to the of antenatal corticosteroids, the clinical radiographic findings, and the oxygen course of RDS is self-limited and typically by age to days in with the and as the infant to (20) of mechanical ventilation before this is and should with to lung Infants not with should be for the of a ductus arteriosus or other congenital heart disease. The infant initially with of and should also be for (20) On it is to initiate in the newborn with RDS because may present in the and findings on chest radiographs can be from premature will lower the of RDS. However, to prevent premature have with the rate of premature of all in To infants will clinical the use of maternal antenatal of reduce the of RDS, and in infants age to weeks’ gestation. female infant is delivered via caesarean section at weeks’ gestational age because of large for gestational age The amniotic fluid is with She is and cyanotic at with respiratory Apgar scores are 2 and at 1 and 5 minutes, respectively. Temperature is pulse is beats per minute, and respiratory rate is breaths per minute. examination findings are significant for marked increased work of breathing with nasal flaring, subcostal and retractions, a and in lung Her chest radiograph is shown in Figure occurs when the meconium before birth. Infants born are at risk for aspiration of meconium in utero or immediately after birth. infant is born and develops respiratory distress after delivery, which cannot be to cause, is as is composed of amniotic and is present in the as early as weeks’ gestation but is not present in the lower until 34 weeks’ is in infants younger than weeks’ gestation. In the or acidosis may result in a and of the resulting in meconium in may occur in utero or immediately after as the is to the newborn and as it The of meconium is to The causes airway and a with release of As meconium the obstruction which results in air and The chest radiograph initially with diffuse parenchymal In lungs become with of atelectasis and alveolar (Figure 1). is by the in resulting in so radiographs may of RDS with low lung Although air may occur with other respiratory of the pneumothorax, and PPHN are common in (Figure is at strategies to the oxygen is and and mechanical ventilation may also be considered in severe with is common and reduces the for oxygenation and the risk of Because results in a alveolar are not by pulmonary blood severe hypoxemia may result and further increases pulmonary vascular resistance. PPHN by and right-to-left shunting at the ductus arteriosus. is a pulmonary without systemic is often with ventilation in severe of to maintain oxygenation and ventilation and reduce the for of is because meconium is a for pulmonary compromise is common after As as 50% of affected infants are as airway disease during their of and persistent pulmonary is in as as years. of the significant associated with MAS, measures are and nasopharyngeal on the meconium-stained infant after delivery of the but before delivery of the and initially to be an effective However, a trial in that this does not prevent or decrease the for mechanical ventilation or of on the is no immediately after also a for all meconium-stained infants until a large trial that and infants born no and increased the rate of This finding has by a change in in of the depressed infant as defined by a low heart rate beats per poor and no respiratory and the breathing infant is not of all are Although the of has decreased during the to of these will develop infants weeks’ gestation) developed However, a that of labor at weeks’ gestation reduces the risk of and without the risk of caesarean Therefore, not to beyond weeks’ gestation. In addition, in fetal heart rate have for that may help prevent in utero aspiration of or of into the amniotic has as a to decrease the of Although is for the with oligohydramnios, does not indicate a risk of to severe or to readily recognize respiratory distress in the newborn and physiologic abnormalities associated with each of the various causes will guide management. Although the measures is early and of the common neonatal respiratory will decrease short- and long-term complications and related of infants.

Challenging environmental conditions, including heat and humidity, cold, and altitude, pose particular risks to the health of Olympic and other high-level athletes. As a further commitment to athlete safety, the International Olympic Committee (IOC) Medical Commission convened a panel of experts to review the scientific evidence base, reach consensus, and underscore practical safety guidelines and new research priorities regarding the unique environmental challenges Olympic and other international-level athletes face. For non-aquatic events, external thermal load is dependent on ambient temperature, humidity, wind speed and solar radiation, while clothing and protective gear can measurably increase thermal strain and prompt premature fatigue. In swimmers, body heat loss is the direct result of convection at a rate that is proportional to the effective water velocity around the swimmer and the temperature difference between the skin and the water. Other cold exposure and conditions, such as during Alpine skiing, biathlon and other sliding sports, facilitate body heat transfer to the environment, potentially leading to hypothermia and/or frostbite; although metabolic heat production during these activities usually increases well above the rate of body heat loss, and protective clothing and limited exposure time in certain events reduces these clinical risks as well. Most athletic events are held at altitudes that pose little to no health risks; and training exposures are typically brief and well-tolerated. While these and other environment-related threats to performance and safety can be lessened or averted by implementing a variety of individual and event preventative measures, more research and evidence-based guidelines and recommendations are needed. In the mean time, the IOC Medical Commission and International Sport Federations have implemented new guidelines and taken additional steps to mitigate risk even further.

Objective. To evaluate deaths of children from families in which faith healing was practiced in lieu of medical care and to determine if such deaths were preventable. Design. Cases of child fatality in faith-healing sects were reviewed. Probability of survival for each was then estimated based on expected survival rates for children with similar disorders who receive medical care. Participants. One hundred seventy-two children who died between 1975 and 1995 and were identified by referral or record search. Criteria for inclusion were evidence that parents withheld medical care because of reliance on religious rituals and documentation sufficient to determine the cause of death. Results. One hundred forty fatalities were from conditions for which survival rates with medical care would have exceeded 90%. Eighteen more had expected survival rates of >50%. All but 3 of the remainder would likely have had some benefit from clinical help. Conclusions. When faith healing is used to the exclusion of medical treatment, the number of preventable child fatalities and the associated suffering are substantial and warrant public concern. Existing laws may be inadequate to protect children from this form of medical neglect.

Children with limited or no ability to ambulate frequently sustain fragility fractures. Joint contractures, scoliosis, hip dysplasia, and metallic implants often prevent reliable measures of bone mineral density (BMD) in the proximal femur and lumbar spine, where BMD is commonly measured. Further, the relevance of lumbar spine BMD to fracture risk in this population is questionable. In an effort to obtain bone density measures that are both technically feasible and clinically relevant, a technique was developed involving dual-energy X-ray absorptiometry (DXA) measures of the distal femur projected in the lateral plane. The purpose of this study is to test the hypothesis that these new measures of BMD correlate with fractures in children with limited or no ability to ambulate. The relationship between distal femur BMD Z-scores and fracture history was assessed in a cross-sectional study of 619 children aged 6 to 18 years with muscular dystrophy or moderate to severe cerebral palsy compiled from eight centers. There was a strong correlation between fracture history and BMD Z-scores in the distal femur; 35% to 42% of those with BMD Z-scores less than -5 had fractured compared with 13% to 15% of those with BMD Z-scores greater than -1. Risk ratios were 1.06 to 1.15 (95% confidence interval 1.04-1.22), meaning a 6% to 15% increased risk of fracture with each 1.0 decrease in BMD Z-score. In clinical practice, DXA measure of BMD in the distal femur is the technique of choice for the assessment of children with impaired mobility.

How cells maintain nuclear shape and position against various intracellular and extracellular forces is not well understood, although defects in nuclear mechanical homeostasis are associated with a variety of human diseases. We estimated the force required to displace and deform the nucleus in adherent living cells with a technique to locally pull the nuclear surface. A minimum pulling force of a few nanonewtons--far greater than typical intracellular motor forces--was required to significantly displace and deform the nucleus. Upon force removal, the original shape and position were restored quickly within a few seconds. This stiff, elastic response required the presence of vimentin, lamin A/C, and SUN (Sad1p, UNC-84)-domain protein linkages, but not F-actin or microtubules. Although F-actin and microtubules are known to exert mechanical forces on the nuclear surface through molecular motor activity, we conclude that the intermediate filament networks maintain nuclear mechanical homeostasis against localized forces.

The observer-blind, randomized, age-stratified, head-to-head study (NCT00423046) comparing immunogenicity and safety of HPV-16/18 and HPV-6/11/16/18 vaccines in healthy women aged 18-45 y was completed. Five y after vaccination, in subjects from the Month 60 according-to-protocol cohort (seronegative and DNA negative for HPV type analyzed at baseline), serum neutralizing antibody (nAb) responses induced by HPV-16/18 vaccine remained 7.8-fold (18-26-y stratum), 5.6-fold (27-35-y stratum) and 2.3-fold (36-45-y stratum) higher than those induced by HPV-6/11/16/18 vaccine for HPV-16. For HPV-18, the fold differences were 12.1, 13.0 and 7.8, respectively. At Month 60, all (100%) subjects in HPV-16/18 vaccine group and the majority (95.7%-97.5%) in HPV-6/11/16/18 vaccine group were seropositive for HPV-16. For HPV-18, the majority (98.1%-100%) of subjects in HPV-16/18 vaccine group were seropositive; however, seropositivity rates in HPV-6/11/16/18 vaccine group decreased considerably (61.1%-76.9%) across the 3 age strata. In the total vaccinated cohort (received ≥1 dose regardless of baseline HPV serostatus and DNA status), geometric mean titers for anti-HPV-16 and anti-HPV-18 nAb were higher in HPV-16/18 vaccine group than in HPV-6/11/16/18 vaccine group. Based on the 5-y data, piece-wise and modified power-law models predicted a longer durability of nAb response for HPV-16/18 vaccine compared to HPV-6/11/16/18 vaccine. Beyond the differences apparent between the vaccines in terms of immunogenicity and modeled persistence of antibody responses, comparative studies including clinical endpoints would be needed to determine whether differences exist in duration of vaccine-induced protection.

Due to their capacity to self-renew, proliferate and generate multi-lineage cells, adult-derived stem cells offer great potential for use in regenerative therapies to stop and/or reverse degenerative diseases such as diabetes, heart failure, Alzheimer's disease and others. However, these subsets of cells can be isolated from different niches, each with differing potential for therapeutic applications. The stromal vascular fraction (SVF), a stem cell enriched and adipose-derived cell population, has garnered interest as a therapeutic in regenerative medicine due to its ability to secrete paracrine factors that accelerate endogenous repair, ease of accessibility and lack of identified major adverse effects. Thus, one can easily understand the rush to employ adipose-derived SVF to treat human disease. Perhaps faster than any other cell preparation, SVF is making its way to clinics worldwide, while critical preclinical research needed to establish SVF safety, efficacy and optimal, standardized clinical procedures are underway. Here, we will provide an overview of the current knowledge driving this phenomenon, its regulatory issues and existing studies, and propose potential unmapped applications. Stem Cells Translational Medicine 2017;6:1096-1108.

The control arm of the phase III VIVIANE (Human PapillomaVIrus: Vaccine Immunogenicity ANd Efficacy; NCT00294047) study in women >25 years was studied to assess risk of progression from cervical HPV infection to detectable cervical intraepithelial neoplasia (CIN). The risk of detecting CIN associated with the same HPV type as the reference infection was analysed using Kaplan-Meier and multivariable Cox models. Infections were categorised depending upon persistence as 6-month persistent infection (6MPI) or infection of any duration. The 4-year interim analysis included 2,838 women, of whom 1,073 (37.8%) experienced 2,615 infections of any duration and 708 (24.9%) experienced 1,130 6MPIs. Infection with oncogenic HPV types significantly increased the risk of detecting CIN grade 2 or greater (CIN2+) versus non-oncogenic types. For 6MPI, the highest risk was associated with HPV-33 (hazard ratio [HR]: 31.9 [8.3-122.2, p < 0.0001]). The next highest risk was with HPV-16 (21.1 [6.3-70.0], p < 0.0001). Similar findings were seen for infections of any duration. Significant risk was also observed for HPV-18, HPV-31, and HPV-45. Concomitant HPV infection or CIN grade 1 or greater associated with a different oncogenic HPV type increased risk. Most women (79.3%) with an HPV infection at baseline cleared detectable infections of any duration, and 69.9% cleared a 6MPI. The risk of progression of HPV infection to CIN2+ in women >25 years in this study was similar to that in women 15-25 years in PATRICIA.

In the United States, nearly 56% of households owned a pet in 2011 according to the 2012 U.S. Pet Ownership &amp; Demographics Sourcebook by the American Veterinary Medical Association. The survey also reports that approximately 70 million dogs and 74 million cats lived in households in the United States during the same year. (1) Human and animal bites are a frequent cause of primary care and emergency department visits for children. It is estimated that 250,000 human bites, 400,000 cat bites, and 4.5 million dog bites occur in the United States each year in both adults and children. (2) In the United States, approximately 10% of all human bites will become infected in a child with a bite wound. The infection rate of dog bites in children is 20%. Cat bite infection rates in children vary but can be up to 50%. Each type of bite wound has a predisposition for sex and/or age. Infected bite wounds manifest with swelling, erythema, and tenderness with or without drainage of the affected site and can lead to serious complications. Most animal bite wounds are polymicrobial in nature. Pasteurella species (spp.) is the most common organism isolated from both cat and dog bites. The microbiology of human bites consists of both aerobic and anaerobic bacteria. Basic medical management of bite wounds includes thorough cleansing and debridement. Irrigation, closure, and need to obtain culture depend on the type of bite wound, the appearance of the wound, the and timing of medical evaluation after the initial injury. Amoxicillin-clavulanate is the antibiotic of choice for prophylaxis and empirical therapy for children who are not allergic to penicillin. With most animal bites being preventable injuries, healthcare providers caring for children have an important role discussing pet safety with the child and the family.

Respiratory syncytial virus (RSV) is a major cause of hospitalizations due to pneumonia and bronchiolitis. Substantial morbidity and socioeconomic burden are associated with RSV infection worldwide. Populations with higher susceptibility to developing severe RSV include premature infants, children with chronic lung disease of prematurity (CLDP) or congenital heart disease (CHD), elderly individuals aged > 65 years, and immunocompromised individuals. In the pediatric population, RSV can lead to long-term sequelae such as wheezing and asthma, which are associated with increased health care costs and reduced quality of life. Treatment for RSV is mainly supportive, and general preventive measures such as good hygiene and isolation are highly recommended. Although vaccine development for RSV has been a global priority, attempts to date have failed to yield a safe and effective product for clinical use. Currently, palivizumab is the only immunoprophylaxis (IP) available to prevent severe RSV in specific high-risk pediatric populations. Well-controlled, randomized clinical trials have established the efficacy of palivizumab in reducing RSV hospitalization (RSVH) in high-risk infants including moderate- to late-preterm infants. However, the American Academy of Pediatrics (AAP), in its 2014 policy, stopped recommending RSV IP use for ≥ 29 weeks' gestational age infants. Revisions to the AAP policy for RSV IP have largely narrowed the proportion of pediatric patients eligible to receive RSV IP and have been associated with an increase in RSVH and morbidity. On the other hand, after reviewing the recent evidence on RSV burden, the National Perinatal Association, in its 2018 clinical practice guidelines, recommended RSV IP use for a wider pediatric population. As the AAP recommendations drive insurance reimbursements for RSV IP, they should be revised to help further mitigate RSV disease burden.

Abstract Traumatic brain injury (TBI) is soon predicted to become the third leading cause of death and disability worldwide. After the primary injury, a complex set of secondary injuries develops hours and days later with prolonged neuroinflammation playing a key role. TBI and other inflammatory conditions are currently being treated in preclinical and clinical trials by a number of cellular therapies. Mesenchymal stem cells (MSC) are of great interest due to their widespread usage, safety, and relative ease to isolate and culture. However, there has been a wide range in efficacy reported using MSC clinically and in preclinical models, likely due to differences in cell preparations and a significant amount of donor variability. In this study, we seek to find a correlation between in vitro activity and in vivo efficacy. We designed assays to explore the responsiveness of MSC to immunological cues to address the immunomodulatory properties of MSC, one of their primary modes of therapeutic activity in TBI. Our results showed intrinsic differences in the immunomodulatory capacity of MSC preparations from different bone marrow and amniotic fluid donors. This difference mirrored the therapeutic capacity of the MSC in an experimental model of TBI, an effect confirmed using siRNA knockdown of COX2 followed by overexpressing COX2. Among the immunomodulatory factors assessed, the therapeutic benefit correlated with the secretion of prostaglandin E2 (PGE2) by MSC prior to treatment, suggesting that measurement of PGE2 could be a very useful potency marker to create an index of predicted efficacy for preparations of MSC to treat TBI.

BACKGROUND: We present a long-term safety, immunogenicity, and effectiveness study of a quadrivalent human papillomavirus (HPV4) vaccine. METHODS: Sexually naive boys and girls aged 9 to 15 years (N = 1781) were assigned (2:1) to receive HPV4 vaccine or saline placebo at day 1 and months 2 and 6. At month 30, the placebo group (n = 482) received HPV4 vaccine following the same regimen and both cohorts were followed through month 96. Subjects ≥ 16 years were eligible for effectiveness evaluations. The primary objective was to evaluate the long-term anti-HPV6/11/16/18 serological levels. The secondary objective was to estimate vaccine effectiveness against HPV6/11/16/18-related persistent infection or disease. RESULTS: For each of the HPV4 vaccine types, vaccination-induced anti-HPV response persisted through month 96. Among 429 subjects who received HPV4 vaccine at a mean age of 12, none developed HPV6/11/16/18-related disease or persistent infection of ≥ 12 months' duration. Acquisition of new sexual partners (among those ≥ 16 years) was ∼1 per year. Subjects receiving HPV4 vaccine at month 30 (mean age 15 years) had a similar baseline rate of seropositivity to ≥ 1 of the 4 HPV types to those vaccinated at day 1 (mean age 12 years; 1.9% [9 of 474] vs 1.7% [20 of 1157]); however, 4 of the 9 subjects vaccinated at the later age were seropositive to 3 vaccine types, indicating previous HPV exposure. No new significant serious adverse events were observed for 8 years postvaccination in both genders. CONCLUSIONS: When administered to adolescents, the HPV4 vaccine demonstrated durability in clinically effective protection and sustained antibody titers over 8 years.

Background De novo mutations in PURA have recently been described to cause PURA syndrome, a neurodevelopmental disorder characterised by severe intellectual disability (ID), epilepsy, feeding difficulties and neonatal hypotonia. Objectives To delineate the clinical spectrum of PURA syndrome and study genotype-phenotype correlations. Methods Diagnostic or research-based exome or Sanger sequencing was performed in individuals with ID. We systematically collected clinical and mutation data on newly ascertained PURA syndrome individuals, evaluated data of previously reported individuals and performed a computational analysis of photographs. We classified mutations based on predicted effect using 3D in silico models of crystal structures of Drosophila -derived Pur-alpha homologues. Finally, we explored genotype-phenotype correlations by analysis of both recurrent mutations as well as mutation classes. Results We report mutations in PURA (purine-rich element binding protein A) in 32 individuals, the largest cohort described so far. Evaluation of clinical data, including 22 previously published cases, revealed that all have moderate to severe ID and neonatal-onset symptoms, including hypotonia (96%), respiratory problems (57%), feeding difficulties (77%), exaggerated startle response (44%), hypersomnolence (66%) and hypothermia (35%). Epilepsy (54%) and gastrointestinal (69%), ophthalmological (51%) and endocrine problems (42%) were observed frequently. Computational analysis of facial photographs showed subtle facial dysmorphism. No strong genotype-phenotype correlation was identified by subgrouping mutations into functional classes. Conclusion We delineate the clinical spectrum of PURA syndrome with the identification of 32 additional individuals. The identification of one individual through targeted Sanger sequencing points towards the clinical recognisability of the syndrome. Genotype-phenotype analysis showed no significant correlation between mutation classes and disease severity.

BACKGROUND: Blood, urine, and cerebrospinal fluid cultures and admission for antibiotics are considered standard management of febrile neonates (0-28 days). We examined variation in adherence to these recommendations across US pediatric emergency departments (PEDs) and incidence of serious infections (SIs) in febrile neonates. METHODS: Cross-sectional study of neonates with a diagnosis of fever evaluated in 36 PEDs in the 2010 Pediatric Health Information System database. We analyzed performance of recommended management (laboratory testing, antibiotic use, admission to hospital), 48-hour return visits to PED, and diagnoses of SI. RESULTS: Of 2253 neonates meeting study criteria, 369 (16.4%) were evaluated and discharged from the PED; 1884 (83.6%) were admitted. Recommended management occurred in 1497 of 2253 (66.4%; 95% confidence interval, 64.5-68.4) febrile neonates. There was more than twofold variation across the 36 PEDs in adherence to recommended management, recommended testing, and recommended treatment of febrile neonates. There was significant variation in testing and treatment between admitted and discharged neonates (P < .001). A total of 269 in 2253 (11.9%) neonates had SI, of whom 223 (82.9%; 95% confidence interval, 77.9-86.9) received recommended management. CONCLUSIONS: There was wide variation across US PEDs in adherence to recommended management of febrile neonates. One in 6 febrile neonates was discharged from the PED; discharged patients were less likely to receive testing or antibiotic therapy than admitted patients. A majority of neonates with SI received recommended evaluation and management. High rates of SI in admitted patients but low return rates for missed infections in discharged patients suggest a need for additional studies to understand variation from the current recommendations.

BACKGROUND: Heterogeneity in type 2 diabetes presentation and progression suggests that precision medicine interventions could improve clinical outcomes. We undertook a systematic review to determine whether strategies to subclassify type 2 diabetes were associated with high quality evidence, reproducible results and improved outcomes for patients. METHODS: We searched PubMed and Embase for publications that used 'simple subclassification' approaches using simple categorisation of clinical characteristics, or 'complex subclassification' approaches which used machine learning or 'omics approaches in people with established type 2 diabetes. We excluded other diabetes subtypes and those predicting incident type 2 diabetes. We assessed quality, reproducibility and clinical relevance of extracted full-text articles and qualitatively synthesised a summary of subclassification approaches. RESULTS: Here we show data from 51 studies that demonstrate many simple stratification approaches, but none have been replicated and many are not associated with meaningful clinical outcomes. Complex stratification was reviewed in 62 studies and produced reproducible subtypes of type 2 diabetes that are associated with outcomes. Both approaches require a higher grade of evidence but support the premise that type 2 diabetes can be subclassified into clinically meaningful subtypes. CONCLUSION: Critical next steps toward clinical implementation are to test whether subtypes exist in more diverse ancestries and whether tailoring interventions to subtypes will improve outcomes.