Rosalind Franklin University of Medicine and Science

BACKGROUND: The declining activity of the growth hormone--insulin-like growth factor I (IGF-I) axis with advancing age may contribute to the decrease in lean body mass and the increase in mass of adipose tissue that occur with aging. METHODS: To test this hypothesis, we studied 21 healthy men from 61 to 81 years old who had plasma IGF-I concentrations of less than 350 U per liter during a six-month base-line period and a six-month treatment period that followed. During the treatment period, 12 men (group 1) received approximately 0.03 mg of biosynthetic human growth hormone per kilogram of body weight subcutaneously three times a week, and 9 men (group 2) received no treatment. Plasma IGF-I levels were measured monthly. At the end of each period we measured lean body mass, the mass of adipose tissue, skin thickness (epidermis plus dermis), and bone density at nine skeletal sites. RESULTS: In group 1, the mean plasma IGF-I level rose into the youthful range of 500 to 1500 U per liter during treatment, whereas in group 2 it remained below 350 U per liter. The administration of human growth hormone for six months in group 1 was accompanied by an 8.8 percent increase in lean body mass, a 14.4 percent decrease in adipose-tissue mass, and a 1.6 percent increase in average lumbar vertebral bone density (P less than 0.05 in each instance). Skin thickness increased 7.1 percent (P = 0.07). There was no significant change in the bone density of the radius or proximal femur. In group 2 there was no significant change in lean body mass, the mass of adipose tissue, skin thickness, or bone density during treatment. CONCLUSIONS: Diminished secretion of growth hormone is responsible in part for the decrease of lean body mass, the expansion of adipose-tissue mass, and the thinning of the skin that occur in old age.

BACKGROUND: The International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT) produced its first guidelines in 2005 and renewed them in 2011. Recently published high-quality clinical trials on the effect of conservative treatment approaches (braces and exercises) for idiopathic scoliosis prompted us to update the last guidelines' version. The objective was to align the guidelines with the new scientific evidence to assure faster knowledge transfer into clinical practice of conservative treatment for idiopathic scoliosis (CTIS). METHODS: Physicians, researchers and allied health practitioners working in the area of CTIS were involved in the development of the 2016 guidelines. Multiple literature reviews reviewing the evidence on CTIS (assessment, bracing, physiotherapy, physiotherapeutic scoliosis-specific exercises (PSSE) and other CTIS) were conducted. Documents, recommendations and practical approach flow charts were developed using a Delphi procedure. The process was completed with the Consensus Session held during the first combined SOSORT/IRSSD Meeting held in Banff, Canada, in May 2016. RESULTS: = 14). According to the agreed strength and level of evidence rating scale, there were 2 recommendations on bracing and 1 recommendation on PSSE that reached level of recommendation "I" and level of evidence "II". Three recommendations reached strength of recommendation A based on the level of evidence I (2 for bracing and one for assessment); 39 recommendations reached strength of recommendation B (20 for bracing, 13 for PSSE, and 6 for assessment).The number of paper for each level of evidence for each treatment is shown in Table 8. CONCLUSION: The 2016 SOSORT guidelines were developed based on the current evidence on CTIS. Over the last 5 years, high-quality evidence has started to emerge, particularly in the areas of efficacy of bracing (one large multicentre trial) and PSSE (three single-centre randomized controlled trials). Several grade A recommendations were presented. Despite the growing high-quality evidence, the heterogeneity of the study protocols limits generalizability of the recommendations. There is a need for standardization of research methods of conservative treatment effectiveness, as recognized by SOSORT and the Scoliosis Research Society (SRS) non-operative management Committee.

Interprofessional education is a collaborative approach to develop healthcare students as future interprofessional team members and a recommendation suggested by the Institute of Medicine. Complex medical issues can be best addressed by interprofessional teams. Training future healthcare providers to work in such teams will help facilitate this model resulting in improved healthcare outcomes for patients. In this paper, three universities, the Rosalind Franklin University of Medicine and Science, the University of Florida and the University of Washington describe their training curricula models of collaborative and interprofessional education.The models represent a didactic program, a community-based experience and an interprofessional-simulation experience. The didactic program emphasizes interprofessional team building skills, knowledge of professions, patient centered care, service learning, the impact of culture on healthcare delivery and an interprofessional clinical component. The community-based experience demonstrates how interprofessional collaborations provide service to patients and how the environment and availability of resources impact one's health status. The interprofessional-simulation experience describes clinical team skills training in both formative and summative simulations used to develop skills in communication and leadership.One common theme leading to a successful experience among these three interprofessional models included helping students to understand their own professional identity while gaining an understanding of other professional's roles on the health care team. Commitment from departments and colleges, diverse calendar agreements, curricular mapping, mentor and faculty training, a sense of community, adequate physical space, technology, and community relationships were all identified as critical resources for a successful program. Summary recommendations for best practices included the need for administrative support, interprofessional programmatic infrastructure, committed faculty, and the recognition of student participation as key components to success for anyone developing an IPE centered program.

The authors studied 538 patients who had sustained minor head trauma, which was defined as a history of unconsciousness of 20 minutes or less, a Glasgow Coma Scale score of 13 to 15, and hospitalization not exceeding 48 hours. Of these patients, 424 were evaluated 3 months after injury. The follow-up evaluation included a history of events since the accident, assessment of subjective complaints and objective measures such as employment status, a neurological examination, a psychosocial assessment designed for estimating life stress, and a neuropsychological test battery to measure higher cortical function. Of these 424 patients, 79% complained of persistent headaches, and 59% described problems with memory. Of the patients who had been gainfully employed before the accident, 34% were unemployed 3 months later. Comparisons were then made between the employed and the unemployed groups. Three explanations for the high rate of unemployment were examined. (a) Evidence of organic brain damage: Although the neurological examination was completely normal in nearly all patients, neuropsychological testing demonstrated some problems with attention, concentration, memory, or judgment in most of the 69 patients evaluated. (b) Psychological responses to the injury: Emotional stress caused by persistent symptoms seems to be a significant factor in the long term disability of these patients. (c) Litigation and compensation: These factors have a minimal role in determining outcome after minor head injury. In conclusion, the most striking observations of these studies are the high rates of morbidity and unemployment in patients 3 months after a seemingly insignificant head injury and the evidence that many of these patients may have, in fact, suffered organic brain damage. (Neurosurgery 9:221-228, 1981)

The fibrous collagens are ubiquitous in animals and form the structural basis of all mammalian connective tissues, including those of the heart, vasculature, skin, cornea, bones, and tendons. However, in comparison with what is known of their production, turnover and physiological structure, very little is understood regarding the three-dimensional arrangement of collagen molecules in naturally occurring fibrils. This knowledge may provide insight into key biological processes such as fibrillo-genesis and tissue remodeling and into diseases such as heart disease and cancer. Here we present a crystallographic determination of the collagen type I supermolecular structure, where the molecular conformation of each collagen segment found within the naturally occurring crystallographic unit cell has been defined (P1, a approximately 40.0 A, b approximately 27.0 A, c approximately 678 A, alpha approximately 89.2 degrees , beta approximately 94.6 degrees , gamma approximately 105.6 degrees ; reflections: 414, overlapping, 232, and nonoverlapping, 182; resolution, 5.16 A axial and 11.1 A equatorial). This structure shows that the molecular packing topology of the collagen molecule is such that packing neighbors are arranged to form a supertwisted (discontinuous) right-handed microfibril that interdigitates with neighboring microfibrils. This interdigitation establishes the crystallographic superlattice, which is formed of quasihexagonally packed collagen molecules. In addition, the molecular packing structure of collagen shown here provides information concerning the potential modes of action of two prominent molecules involved in human health and disease: decorin and the Matrix Metallo-Proteinase (MMP) collagenase.

It is now 10 years since the last technical review on preventative foot care was published (1), which was followed by an American Diabetes Association (ADA) position statement on preventive foot care in diabetes (2). Many studies have been published proposing a range of tests that might usefully identify patients at risk of foot ulceration, creating confusion among practitioners as to which screening tests should be adopted in clinical practice. A task force was therefore assembled by the ADA to address and concisely summarize recent literature in this area and then recommend what should be included in the comprehensive foot exam for adult patients with diabetes. The committee was cochaired by the immediate past and current chairs of the ADA Foot Care Interest Group (A.J.M.B. and D.G.A.), with other panel members representing primary care, orthopedic and vascular surgery, physical therapy, podiatric medicine and surgery, and the American Association of Clinical Endocrinologists. The lifetime risk of a person with diabetes developing a foot ulcer may be as high as 25%, whereas the annual incidence of foot ulcers is ∼2% (3–7). Up to 50% of older patients with type 2 diabetes have one or more risk factors for foot ulceration (3,6). A number of component causes, most importantly peripheral neuropathy, interact to complete the causal pathway to foot ulceration (1,3–5). A list of the principal contributory factors that might result in foot ulcer development is provided in Table 1. View this table: Table 1— Risk factors for foot ulcers The most common triad of causes that interact and ultimately result in ulceration has been identified as neuropathy, deformity, and trauma (5). As identification of those patients at risk of foot problems is the first step in preventing such complications, this report will focus on key components of the …

OBJECTIVE: To prospectively determine risk factors for foot infection in a cohort of people with diabetes. RESEARCH DESIGN AND METHODS: We evaluated then followed 1,666 consecutive diabetic patients enrolled in a managed care-based outpatient clinic in a 2-year longitudinal outcomes study. At enrollment, patients underwent a standardized general medical examination and detailed foot assessment and were educated about proper foot care. They were then rescreened at scheduled intervals and also seen promptly if they developed any foot problem. RESULTS: During the evaluation period, 151 (9.1%) patients developed 199 foot infections, all but one involving a wound or penetrating injury. Most patients had infections involving only the soft tissue, but 19.9% had bone culture-proven osteomyelitis. For those who developed a foot infection, compared with those who did not, the risk of hospitalization was 55.7 times greater (95% CI 30.3-102.2; P < 0.001) and the risk of amputation was 154.5 times greater (58.5-468.5; P < 0.001). Foot wounds preceded all but one infection. Significant (P < 0.05) independent risk factors for foot infection from a multivariate analysis included wounds that penetrated to bone (odds ratio 6.7), wounds with a duration >30 days (4.7), recurrent wounds (2.4), wounds with a traumatic etiology (2.4), and presence of peripheral vascular disease (1.9). CONCLUSIONS: Foot infections occur relatively frequently in individuals with diabetes, almost always follow trauma, and dramatically increase the risk of hospitalization and amputation. Efforts to prevent infections should be targeted at people with traumatic foot wounds, especially those that are chronic, deep, recurrent, or associated with peripheral vascular disease.

The Levels of Emotional Awareness Scale (LEAS) is based on a new cognitive-developmental model of emotional experience. The scale poses evocative interpersonal situations and elicits descriptions of the emotional responses of self and others which are scored using specific structural criteria. Forty undergraduates (20 of each sex) were tested. Interrater reliability and intratest homogeneity of the LEAS were strong. The LEAS was significantly correlated with two measures of maturity: the Washington University Sentence Completion Test (SCT) of Ego Development, and the Parental Descriptions Scale-a cognitive-developmental measure of object representation. In addition, the LEAS correlated positively with openness to experience and emotional range but not with measures of specific emotions, repression or the number of words used in the LEAS responses. These findings suggest that it is the level of emotion, not the specific quality of emotion, that is tapped by the LEAS.

The reinforcing (rewarding) effects of psychomotor stimulants (cocaine and amphetamine) depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens (Wise, 1981; for review, see Koob, 1992), perhaps especially the shell subregion (Bassareo and Di Chiara, 1997). Prominent theories of addiction are based on adaptations associated with both sensitization to and withdrawal from repeated exposure to psychomotor stimulants (Robinson and Berridge, 1993; Koob and Le Moal, 2001). Great progress has been achieved toward revealing the nature of cellular and molecular adaptations in animal models of addiction (Hyman and Malenka, 2001; Koob and Le Moal, 2001; Nestler, 2001), many of which are similar, if not identical, to those implicated in models of learning and memory (Hyman and Malenka, 2001; Nestler, 2001). One challenge in addiction research is to understand how molecular and cellular adaptations are related to altered functioning of neural systems that underlie compulsive drug-seeking behavior. This review highlights associative influences on psychomotor stimulant addiction, building on the view that plasticity in neural systems converging on the nucleus accumbens (Nac) and dorsal striatum (DS) is usurped by chronic drug selfadministration, leading to the aberrant engagement of pavlovian and instrumental learning processes. At a systems level, one product of the gradual strengthening or “consolidation ” of behavior arising from the reinforcing action of drugs may be the eventual progression of addiction to a form of habit-based learning, in which voluntary control over drug use is lost and the propensity to relapse is high and readily precipitated by exposure to drug-associated stimuli (O’Brien and McLellan, 1996; Robbins

IMPORTANCE: The literature focuses on mortality among children younger than 5 years. Comparable information on nonfatal health outcomes among these children and the fatal and nonfatal burden of diseases and injuries among older children and adolescents is scarce. OBJECTIVE: To determine levels and trends in the fatal and nonfatal burden of diseases and injuries among younger children (aged <5 years), older children (aged 5-9 years), and adolescents (aged 10-19 years) between 1990 and 2013 in 188 countries from the Global Burden of Disease (GBD) 2013 study. EVIDENCE REVIEW: Data from vital registration, verbal autopsy studies, maternal and child death surveillance, and other sources covering 14,244 site-years (ie, years of cause of death data by geography) from 1980 through 2013 were used to estimate cause-specific mortality. Data from 35,620 epidemiological sources were used to estimate the prevalence of the diseases and sequelae in the GBD 2013 study. Cause-specific mortality for most causes was estimated using the Cause of Death Ensemble Model strategy. For some infectious diseases (eg, HIV infection/AIDS, measles, hepatitis B) where the disease process is complex or the cause of death data were insufficient or unavailable, we used natural history models. For most nonfatal health outcomes, DisMod-MR 2.0, a Bayesian metaregression tool, was used to meta-analyze the epidemiological data to generate prevalence estimates. FINDINGS: Of the 7.7 (95% uncertainty interval [UI], 7.4-8.1) million deaths among children and adolescents globally in 2013, 6.28 million occurred among younger children, 0.48 million among older children, and 0.97 million among adolescents. In 2013, the leading causes of death were lower respiratory tract infections among younger children (905.059 deaths; 95% UI, 810,304-998,125), diarrheal diseases among older children (38,325 deaths; 95% UI, 30,365-47,678), and road injuries among adolescents (115,186 deaths; 95% UI, 105,185-124,870). Iron deficiency anemia was the leading cause of years lived with disability among children and adolescents, affecting 619 (95% UI, 618-621) million in 2013. Large between-country variations exist in mortality from leading causes among children and adolescents. Countries with rapid declines in all-cause mortality between 1990 and 2013 also experienced large declines in most leading causes of death, whereas countries with the slowest declines had stagnant or increasing trends in the leading causes of death. In 2013, Nigeria had a 12% global share of deaths from lower respiratory tract infections and a 38% global share of deaths from malaria. India had 33% of the world's deaths from neonatal encephalopathy. Half of the world's diarrheal deaths among children and adolescents occurred in just 5 countries: India, Democratic Republic of the Congo, Pakistan, Nigeria, and Ethiopia. CONCLUSIONS AND RELEVANCE: Understanding the levels and trends of the leading causes of death and disability among children and adolescents is critical to guide investment and inform policies. Monitoring these trends over time is also key to understanding where interventions are having an impact. Proven interventions exist to prevent or treat the leading causes of unnecessary death and disability among children and adolescents. The findings presented here show that these are underused and give guidance to policy makers in countries where more attention is needed.

OBJECTIVES: To determine: a) the frequency of premonitory signs and symptoms before cardiac arrest in patients on the general medical wards of a hospital; b) any characteristic patterns in nurse and physician responses to these signs and symptoms; and c) whether cardiac arrests on the ward occur more frequently in patients discharged from the medical intensive care unit (ICU) than in other patients. DESIGN: Case series of consecutive patients who had an inhospital cardiac arrest over a 20-month period. SETTING: General medical wards of a 1,000-bed urban public hospital. PATIENTS: There were 21,505 total admissions to the medical service in this period. Patients whose cardiac arrests occurred in the Emergency Room and ICU and patients with do-not-resuscitate orders were excluded from the study. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: There were a total of 150 cardiac arrests on the medical wards (cardiac arrest rate: 7.0/1,000 patients) with a hospital mortality rate of 91%. In 99 of 150 cases, a nurse or physician documented deterioration in the patient's condition within 6 hrs of cardiac arrest. Common findings included: a) failure of the nurse to notify a physician of a deterioration in the patient's mental status; b) failure of the physician to obtain or interpret an arterial blood gas measurement in the setting of respiratory distress; and c) failure of the ICU triage physician to stabilize the patient's condition before transferring the patient to the ICU. Former ICU patients (cardiac arrest rate: 14.7/1,000 patients) were more likely to suffer cardiac arrest than other patients (cardiac arrest rate: 6.8/1,000 patients) (p = .004). CONCLUSIONS: Cardiac arrests on the general wards of the hospital are commonly preceded by premonitory signs and symptoms. Strategies to prevent cardiac arrest should include training for nurses and physicians that concentrates on cardiopulmonary stabilization and how to respond to neurologic and respiratory deterioration. Special attention should also be devoted to patients who have been discharged from the ICU who are at greater risk for cardiac arrest after ICU discharge than are other medical patients.

The reinforcing (rewarding) effects of psychomotor stimulants (cocaine and amphetamine) depend on the mesocorticolimbic dopamine system innervating the nucleus accumbens ([Wise, 1981][1]; for review, see[Koob, 1992][2]), perhaps especially the shell subregion ([Bassareo and Di Chiara, 1997][3]).

BACKGROUND: The International Scientific Society on Scoliosis Orthopaedic and Rehabilitation Treatment (SOSORT), that produced its first Guidelines in 2005, felt the need to revise them and increase their scientific quality. The aim is to offer to all professionals and their patients an evidence-based updated review of the actual evidence on conservative treatment of idiopathic scoliosis (CTIS). METHODS: All types of professionals (specialty physicians, and allied health professionals) engaged in CTIS have been involved together with a methodologist and a patient representative. A review of all the relevant literature and of the existing Guidelines have been performed. Documents, recommendations, and practical approach flow charts have been developed according to a Delphi procedure. A methodological and practical review has been made, and a final Consensus Session was held during the 2011 Barcelona SOSORT Meeting. RESULTS: The contents of the document are: methodology; generalities on idiopathic scoliosis; approach to CTIS in different patients, with practical flow-charts; literature review and recommendations on assessment, bracing, physiotherapy, Physiotherapeutic Specific Exercises (PSE) and other CTIS. Sixty-five recommendations have been given, divided in the following topics: Bracing (20 recommendations), PSE to prevent scoliosis progression during growth (8), PSE during brace treatment and surgical therapy (5), Other conservative treatments (3), Respiratory function and exercises (3), Sports activities (6), Assessment (20). No recommendations reached a Strength of Evidence level I; 2 were level II; 7 level III; and 20 level IV; through the Consensus procedure 26 reached level V and 10 level VI. The Strength of Recommendations was Grade A for 13, B for 49 and C for 3; none had grade D. CONCLUSION: These Guidelines have been a big effort of SOSORT to paint the actual situation of CTIS, starting from the evidence, and filling all the gray areas using a scientific method. According to results, it is possible to understand the lack of research in general on CTIS. SOSORT invites researchers to join, and clinicians to develop good research strategies to allow in the future to support or refute these recommendations according to new and stronger evidence.

Traditional diagnostic systems went beyond empirical evidence on the structure of mental health. Consequently, these diagnoses do not depict psychopathology accurately, and their validity in research and utility in clinicalpractice are therefore limited. The Hierarchical Taxonomy of Psychopathology (HiTOP) consortium proposed a model based on structural evidence. It addresses problems of diagnostic heterogeneity, comorbidity, and unreliability. We review the HiTOP model, supporting evidence, and conceptualization of psychopathology in this hierarchical dimensional framework. The system is not yet comprehensive, and we describe the processes for improving and expanding it. We summarize data on the ability of HiTOP to predict and explain etiology (genetic, environmental, and neurobiological), risk factors, outcomes, and treatment response. We describe progress in the development of HiTOP-based measures and in clinical implementation of the system. Finally, we review outstanding challenges and the research agenda. HiTOP is of practical utility already, and its ongoing development will produce a transformative map of psychopathology.

OBJECTIVE: The authors assess the present position of catatonia in diagnostic classification systems and consider the merits of designating catatonia as a separate diagnostic category with defined criteria. METHOD: Following the logical steps to establish diagnostic validity when the etiology of a syndrome is unknown, the authors review the literature on the features that delineate catatonia as a syndrome, the prevalence and response to treatment of catatonia, and the conditions that are associated with catatonia. RESULTS: Catatonia is a well-defined syndrome that can be reliably ascertained. Although more than 40 motor signs of catatonia are known, the presence of two prominent features for 24 hours or longer is sufficient to identify the syndrome. Catatonia is found in about 10% of acutely ill psychiatric inpatients and is more commonly observed in persons with mood disorder than in those with schizophrenia. It is found in many conditions and presents mainly as retarded-stuporous or excited-delirious forms. Catatonia responds to specific treatments, including sedative anticonvulsants (barbiturates and benzodiazepines) and ECT. CONCLUSIONS: Catatonia can be distinguished from other behavioral syndromes by a recognizable cluster of clinical features. Catatonia is sufficiently common to warrant classification as an independent syndrome. It can be reliably identified, has a typical course when appropriately treated, responds to specific treatments, and is worsened by other treatments. It is associated with many pathophysiologic processes and most often with mood disorder. These findings, which are consistent with established methods of defining distinct diagnostic groupings, support consideration of catatonia as an individual category in psychiatric diagnostic systems.

MicroRNAs (miRNAs) in body fluids are candidate diagnostics for a variety of conditions and diseases, including breast cancer. One premise for using extracellular miRNAs to diagnose disease is the notion that the abundance of the miRNAs in body fluids reflects their abundance in the abnormal cells causing the disease. As a result, the search for such diagnostics in body fluids has focused on miRNAs that are abundant in the cells of origin. Here we report that released miRNAs do not necessarily reflect the abundance of miRNA in the cell of origin. We find that release of miRNAs from cells into blood, milk and ductal fluids is selective and that the selection of released miRNAs may correlate with malignancy. In particular, the bulk of miR-451 and miR-1246 produced by malignant mammary epithelial cells was released, but the majority of these miRNAs produced by non-malignant mammary epithelial cells was retained. Our findings suggest the existence of a cellular selection mechanism for miRNA release and indicate that the extracellular and cellular miRNA profiles differ. This selective release of miRNAs is an important consideration for the identification of circulating miRNAs as biomarkers of disease.

Two-pore-domain potassium (K(+)) channels are substrates for resting K(+) currents in neurons. They are major targets for endogenous modulators, as well as for clinically important compounds such as volatile anesthetics. In the current study, we report on the CNS distribution in the rat and mouse of mRNA encoding seven two-pore-domain K(+) channel family members: TASK-1 (KCNK3), TASK-2 (KCNK5), TASK-3 (KCNK9), TREK-1 (KCNK2), TREK-2 (KCNK10), TRAAK (KCNK4), and TWIK-1 (KCNK1). All of these genes were expressed in dorsal root ganglia, and for all of the genes except TASK-2, there was a differential distribution in the CNS. For TASK-1, highest mRNA accumulation was seen in the cerebellum and somatic motoneurons. TASK-3 was much more widely distributed, with robust expression in all brain regions, with particularly high expression in somatic motoneurons, cerebellar granule neurons, the locus ceruleus, and raphe nuclei and in various nuclei of the hypothalamus. TREK-1 was highest in the striatum and in parts of the cortex (layer IV) and hippocampus (CA2 pyramidal neurons). mRNA for TRAAK also was highest in the cortex, whereas expression of TREK-2 was primarily restricted to the cerebellar granule cell layer. There was widespread distribution of TWIK-1, with highest levels in the cerebellar granule cell layer, thalamic reticular nucleus, and piriform cortex. The differential expression of each of these genes likely contributes to characteristic excitability properties in distinct populations of neurons, as well as to diversity in their susceptibility to modulation.

A prospective (Part I) and a retrospective (Part II) study were used to determine the safety and efficacy of corticosteroids in the treatment of septic shock. In Part I, 172 consecutive patients in septic shock admitted over an 8-year period were treated with either steroid or saline: 43 received dexamethasone (DMP), 43 received methylprednisolone (MPS), and 86 received saline. The study was double-blind and randomized, and the three groups were compared for age, severity of shock, presence of underlying disease, and year of study. In the 86 saline-treated patients, the mortality rate was 38.4% (33/86); in the steroid-treated patients, it was 10.4% (9/86). With MPS the mortality rate was 11.6% (5/43), and with DMP it was 9.3% (4/43). Thus, overall mortality was significantly less in the steroid-treated group than in the control group. Further, there was no significant difference in mortality rate between the DMP- and the MPS-treated patients. In Part II, 328 patients were studied retrospectively. One-hundred sixty were treated without steroid, and 168 were treated with either DMP or MPS. Again, the two groups of patients were compared for severity of shock, underlying disease, age, and year of study. Mortality among patients treated without steroid was 42.5% (68/160) and among patients treated with steroid was 14% (24/168); there was no significant difference in mortality rate between DMP- and MPS-treated patients. In Parts I and II combined, complications occurred in 6% of steroid-treated patients with no significant difference between DMP- and MPS-treated groups.

We investigated the acid-base condition of arterial and mixed venous blood during cardiopulmonary resuscitation in 16 critically ill patients who had arterial and pulmonary arterial catheters in place at the time of cardiac arrest. During cardiopulmonary resuscitation, the arterial blood pH averaged 7.41, whereas the average mixed venous blood pH was 7.15 (P less than 0.001). The mean arterial partial pressure of carbon dioxide (PCO2) was 32 mm Hg, whereas the mixed venous PCO2 was 74 mm Hg (P less than 0.001). In a subgroup of 13 patients in whom blood gases were measured before, as well as during, cardiac arrest, arterial pH, PCO2, and bicarbonate were not significantly changed during arrest. However, mixed venous blood demonstrated striking decreases in pH (P less than 0.001) and increases in PCO2 (P less than 0.004). We conclude that mixed venous blood most accurately reflects the acid-base state during cardiopulmonary resuscitation, especially the rapid increase in PCO2. Arterial blood does not reflect the marked reduction in mixed venous (and therefore tissue) pH, and thus arterial blood gases may fail as appropriate guides for acid-base management in this emergency.

Splice-switching oligonucleotides (SSOs) are short, synthetic, antisense, modified nucleic acids that base-pair with a pre-mRNA and disrupt the normal splicing repertoire of the transcript by blocking the RNA-RNA base-pairing or protein-RNA binding interactions that occur between components of the splicing machinery and the pre-mRNA. Splicing of pre-mRNA is required for the proper expression of the vast majority of protein-coding genes, and thus, targeting the process offers a means to manipulate protein production from a gene. Splicing modulation is particularly valuable in cases of disease caused by mutations that lead to disruption of normal splicing or when interfering with the normal splicing process of a gene transcript may be therapeutic. SSOs offer an effective and specific way to target and alter splicing in a therapeutic manner. Here, we discuss the different approaches used to target and alter pre-mRNA splicing with SSOs. We detail the modifications to the nucleic acids that make them promising therapeutics and discuss the challenges to creating effective SSO drugs. We highlight the development of SSOs designed to treat Duchenne muscular dystrophy and spinal muscular atrophy, which are currently being tested in clinical trials.