Tradeoffs in Introduction Policies for the Anti-Tuberculosis Drug Bedaquiline: A Model-Based Analysis.
New drugs for the treatment of tuberculosis (TB) are becoming available for the first time in over 40 y. Optimal strategies for introducing these drugs have not yet been established. The objective of this study was to compare different strategies for introducing the new TB drug bedaquiline based on patients' resistance patterns. We created a Markov decision model to follow a hypothetical cohort of multidrug-resistant (MDR) TB patients under different bedaquiline use strategies. The explored strategies included making bedaquiline available to all patients with MDR TB, restricting bedaquiline usage to patients with MDR plus additional resistance and withholding bedaquiline introduction completely. We compared these strategies according to life expectancy, risks of acquired resistance, and the expected number and health outcomes of secondary cases. For our simulated cohort, the mean (2.5th, 97.5th percentile) life expectancy from time of initiation of MDR TB treatment at age 30 was 36.0 y (33.5, 38.7) assuming all patients with MDR TB received bedaquiline, 35.1 y (34.4, 35.8) assuming patients with pre-extensively drug-resistant (PreXDR) and extensively drug-resistant (XDR) TB received bedaquiline, and 34.9 y (34.6, 35.2) assuming only patients with XDR TB received bedaquiline. Although providing bedaquiline to all MDR patients resulted in the highest life expectancy for our initial cohort averaged across all parameter sets, for parameter sets in which bedaquiline conferred high risks of added mortality and only small reductions in median time to culture conversion, the optimal strategy would be to withhold use even from patients with the most extensive resistance. Across all parameter sets, the most liberal bedaquiline use strategies consistently increased the risk of bedaquiline resistance but decreased the risk of resistance to other MDR drugs. In almost all cases, more liberal bedaquiline use strategies reduced the expected number of secondary cases and resulting life years lost. The generalizability of our results is limited by the lack of available data about drug effects among individuals with HIV co-infection, drug interactions, and other sources of heterogeneity, as well as changing recommendations for MDR TB treatment. If mortality benefits can be empirically verified, our results provide support for expanding bedaquiline access to all patients with MDR TB. Such expansion could improve patients' health, protect background MDR TB drugs, and decrease transmission, but would likely result in greater resistance to bedaquiline.


Evaluation of Echocardiographic Abnormalities in HIV Positive Patients Treated with Antiretroviral Medications.
Echocardiography is a reliable means for the diagnosis of functional and valvular diseases of the heart in HIV positive and HIV negative patients. The current study was to evaluate echocardiographic abnormalities in HIV positive patients under an antiretroviral therapy (ART) program in Tehran, Imam Khomeini Hospital, Iran. This is a descriptive cross-sectional study, conducted among 231 HIV-1 positive patients under ART. All HIV positive patients including 150 men (65%) and 81 women (35%) (mean age of 41 years) were assessed by trans-thoracic echocardiography (TTE) in Imam Khomeini Hospital, over the period from 2013 to 2014. The mean CD4 count was 408 cell/μl, and the average left ventricular ejection fraction (LVEF) was 59.5%. There was an inverse correlation between age and LVEF level. Nevirapine users showed a significantly higher LVEF than non-users. Left ventricular systolic dysfunction (LVSD) was diagnosed in 5.6% along with the increase in age, while left ventricular diastolic dysfunction (LVDD) was reported in 19.5% of patients associated with age and smoking. Here, the mean systolic pulmonary arterial pressure (SPAP) was only 20 mmHg and just four percent of the patients suffered pulmonary hypertension. Almost 44% had a heart valve disorder among which mitral valve prolapse is the most common problem. Pericardial effusion was not found in any patients. It seems that heart disorders with no suggestive symptoms in HIV positive patients, and mainly older adults who have traditional risk factors for heart diseases, should be seriously considered by health providers.


Composition of guttation fluid from rye, wheat, and barley seedlings.
This work was undertaken to determine the kinds and amount of substances that would account for the previously demonstrated differential growth of Claviceps purpurea on guttation fluids from Rosen rye, Genesee wheat, and Traill barley seedlings. Chromatographic methods were used for determining amino acids and sugars, spot tests and spectrometric methods for inorganic materials, and microbiological methods for vitamins.Total sugar content is about equal in rye and barley fluids, but lower in wheat. Glucose is the principal sugar component of the rye and barley fluids and galactose highest in wheat. Most of the amino acid in all 3 fluids is aspartic acid or asparagine. Barley fluid is far higher than the other 2 in total amino acids, with wheat the lowest. Most inorganic elements are found to be highest in barley and lowest in wheat, with the exception of iron where rye is highest and barley lowest. Barley fluid is highest in choline, p-aminobenzoic acid, thiamine, and uracil, while rye is highest in inositol and pyridoxine. Wheat is much lower than the other 2 in choline and inositol.


Hemagglutinin-esterase-specific monoclonal antibodies alter the neuropathogenicity of mouse hepatitis virus.
Some of mouse hepatitis virus strains contain an optional envelope glycoprotein, hemagglutinin-esterase (HE) protein. To understand the functional significance of this protein, monoclonal antibodies (MAbs) specific for this protein were generated and used for passive immunization of mice. None of these MAbs showed any virus-neutralizing activity in vitro; however, mice passively immunized with the purified MAbs were protected from lethal infection by the JHM strain of mouse hepatitis virus. Passive immunization altered the pathogenicity such that the virus caused subacute and chronic demyelination instead of acute lethal encephalitis. Virus titers in the brains of the immunized mice were significantly lower than those for the nonimmunized control mice, suggesting that the virus replication or spread was inhibited. In addition, histopathological analysis indicated that the spread of virus in the brain and spinal cord was significantly inhibited in the immunized mice. Furthermore, the mononuclear cell infiltration in the immunized mice appeared earlier than in the nonimmunized mice, suggesting that the exogenous antibody might have activated host immune responses, and thus facilitated clearance of the virus or virus-infected cells. The same protective effects were observed for both JHM(2) and JHM(3) viruses, which expressed different amounts of the HE protein. In contrast, mice infected with At11f, a variant of JHM which does not express the HE protein, were not protected by these MAbs, suggesting that protection was mediated by the specific interaction between the MAb and the HE protein. Thus, the mechanism of protection by the exogenous HE-specific MAbs may represent the early activation of innate immune mechanisms in response to the interaction between the MAbs and the HE protein.


Ambulatory blood pressure and 10-year risk of cardiovascular and noncardiovascular mortality: the Ohasama study.
The objective of this study was to elucidate the long-term prognostic significance of ambulatory blood pressure. Ambulatory and casual blood pressure values were obtained from 1332 subjects (872 women and 460 men) aged >or=40 years from the general population of a rural Japanese community. Survival was then followed for 14 370 patient years and analyzed by a Cox hazard model adjusted for possible confounding factors. There were 72 cardiovascular deaths during the 10.8-year follow-up. The relationship between 24-hour systolic blood pressure and the cardiovascular mortality risk was U-shaped in the first 5 years, then changed to J-shaped over the rest of the 10.8-year follow-up. After censoring the first 2 years of data, the risk flattened until it again increased for the fifth quintile of 24-hour systolic blood pressure for the 10.8-year follow-up period. For 24-hour diastolic blood pressure, the J-shaped relationship remained unchanged, regardless of follow-up duration and censoring. Ambulatory systolic blood pressure values consistently showed stronger predictive power for cardiovascular mortality risk than did casual systolic blood pressure in the 10.8-year follow-up data, whereas such relationships became more marked after censoring the first 2 years. When nighttime and daytime systolic blood pressure values were simultaneously included in the same Cox model, only nighttime blood pressure significantly predicted the cardiovascular mortality risk for the 10.8-year follow-up data. We conclude that the relationship between ambulatory systolic blood pressure and cardiovascular mortality is not U-shaped or J-shaped, and that nighttime blood pressure has better prognostic value than daytime blood pressure.


Matrix Metalloproteinase-9 Level and Gene Polymorphism in Sleep Disordered Breathing Patients with or without Cardiovascular Disorders.
Obstructive sleep apnea syndrome (OSAS) is associated with increased cardiovascular morbidity and mortality. We aimed to investigate the matrix metalloproteinase-9 (MMP-9) level and MMP-9 gene polymorphism in sleep apnea patients with or without cardiovascular disease. Case-control study. Two hundred nine patients [Mean age (±SD), 47 (±12) yrs; M/F, 170/39] diagnosed with sleep-disordered breathing were included in the study. Serum MMP-9 level was performed using enzyme-linked immunosorbant assay (ELISA) and MMP-9 gene polymorphism with polymerase chain reaction-restriction fragment length polymorphism. We divided the patient group into two subgroups: (1) patients with confirmed cardiovascular disease, i.e. CV-P Group and (2) patients without cardiovascular disease, CV-N Group. We compared all parameters between the two groups. There were 56 OSAS patients with cardiovascular disorder (CV-positive group) and 153 OSAS patients without cardiovascular disorder (CV-negative group). CC, CT and TT genotype distributions between groups were similar [31 (55%), 25 (45%), 0 (0%) vs 88 (57%), 61 (40%), 4 (3%); respectively, p>0.05]. MMP-9 level was significantly higher in CV-P patients (442.7±139.3 pg/mL) than in CV-N patients (364.4±165.0 pg/mL; p=0.0018). Our results showed that the presence of MMP-9 polymorphism was not associated with cardiovascular disease. MMP-9 level was higher in OSAS patients with cardiovascular disorders than without cardiovascular disorders. Finally, MMP-9 genotype was not associated with serum MMP-9 levels.


[Postoperative pain in children: a gender approach].
The objective of this study was to verify and describe, from a gender focus, the associations between gender and specific postoperative pain variables in pediatrics. This is a cross-sectional study of 77 children between 6 and 13 years of age (M=9 years; sd=2.2 years), ASA I and II, 77.9% from low-income classes, 68.8% boys and 32.8% girls. Data were collected on the first postoperative (1st PO) day through semi-structured interviews and four measurement scales. The main baseline diseases were adenotonsillitis and fractures. Prevalence of pain on the 1st PO was 91.7% for girls and 75.5% for boys (p>0.05). No association was found between pain intensity and gender. The most used pain descriptors were it cuts and it squeezes. The preferred scale was the EFMC (with faces from a Brazilian cartoon: Monica's Gang). Pediatric pain management is still inadequate and gender may influence the pain response.


A randomized study of telephonic care support in populations at risk for musculoskeletal preference-sensitive surgeries.
The rate of elective surgeries varies dramatically by geography in the United States. For many of these surgeries, there is not clear evidence of their relative merits over alternate treatment choices and there are significant tradeoffs in short- and long-term risks and benefits of selecting one treatment option over another. Conditions and symptoms for which there is this lack of a single clear evidence-based treatment choice present great opportunities for patient and provider collaboration on decision making; back pain and joint osteoarthritis are two such ailments. A number of decision aids are in active use to encourage this shared decision-making process. Decision aids have been assessed in formal studies that demonstrate increases in patient knowledge, increases in patient-provider engagement, and reduction in surgery rates. These studies have not widely demonstrated the added benefit of health coaching in support of shared decision making nor have they commonly provided strong evidence of cost reductions. In order to add to this evidence base, we undertook a comparative study testing the relative impact on health utilization and costs of active outreach through interactive voice response technology to encourage health coaching in support of shared decision making in comparison to mailed outreach or no outreach. This study focused on individuals with back pain or joint pain. We conducted four waves of stratified randomized comparisons for individuals with risk for back, hip, or knee surgery who did not have claims-based evidence of one or more of five chronic conditions and were eligible for population care management services within three large regional health plans in the United States. An interactive voice response (IVR) form of outreach that included the capability for individuals to directly connect with health coaches telephonically, known as AutoDialog(®), was compared to a control (mailed outreach or natural levels of inbound calling depending on the study wave). In total, the study include 24,167 adults with commercial and Medicare Advantage private coverage at three health plans and at risk for lumbar back surgery, hip repair/replacement, or knee repair/replacement. Interactive voice response outreach led to 10.7 (P-value < .0001) times as many inbound calls within 30 days as the control. Over 180 days, the IVR group ("intervention") had 67 percent (P-value < .0001) more health coach communications and agreed to be sent 3.2 (P-value < .0001) time as many DVD- and/or booklet-based decision aids. Targeted surgeries were reduced by 6.7 percent (P-value = .6039). Overall costs were lower by 4.9 percent (P-value = .055). Costs that were not related to maternity, cancer, trauma and substance abuse ("actionable costs") were reduced by 6.5 percent (P-value = .0286). IVR with a transfer-to-health coach-option significantly increased levels of health coaching compared to mailed or no outreach and lead to significantly reduced actionable medical costs. Providing high levels of health coaching to individuals with these types of risks appears to have produced important levels of actionable medical cost reductions. We believe this impact resulted from more informed and engaged health care decision making.


The computer bandwagon--has everyone else jumped on?
A survey of 1,179 dentists in Kansas and Missouri was mailed in an effort to determine their current use of computers. There was a completed return of 458 surveys (39 percent). Of those responding, 64.4 percent indicated they had a computer in their home or office. Of those with computers, 73 percent were IBM or IBM compatible, 11.5 percent were Macintosh and 15.5 percent were other. Comparison of this survey with a similar survey completed in Indiana indicates that computer usage by dentists appears to be increasing but not at the same rate as the advances in computer technology.


Prenatal maternal infections and children's socioemotional development: findings from the UK Millennium Cohort Study.
Previous research suggests that prenatal maternal infections may be associated with increased odds of children having a neurodevelopmental disorder. However, little evidence exists on associations with broader child outcomes, especially subclinical symptoms. Participants were the N = 14,021 members of the population-representative UK Millennium Cohort Study. We examined associations between prenatal maternal infections, both maternal-reported and hospital-recorded, and children's socioemotional development, using the Strengths and Difficulties Questionnaire (SDQ) at age three. Maternal-reported prenatal infections were associated with increased emotional symptoms, after adjusting for several potential confounds and covariates. Hospital-recorded prenatal infections were not associated with children's socioemotional outcomes, after adjusting for potential confounding and covarying factors. Findings suggest that prenatal maternal infections, particularly those which the mothers remember months later, may be associated with increased emotional problems in early childhood. This emphasises the need for screening for and preventing infections during pregnancy. Further, the occurrence of prenatal infection indicates the potential need for early intervention for children's emotional difficulties.


Conformational changes induced in the envelope glycoproteins of the human and simian immunodeficiency viruses by soluble receptor binding.
We have investigated the molecular basis of biological differences observed among cell line-adapted isolates of the human immunodeficiency virus types 1 and 2 (HIV-1 and HIV-2) and the simian immunodeficiency virus (SIV) in response to receptor binding by using a soluble form of CD4 (sCD4) as a receptor mimic. We find that sCD4 binds to the envelope glycoproteins of all of the HIV-1 isolates tested with affinities within a threefold range, whereas those of the HIV-2 and SIV isolates have relative affinities for sCD4 two- to eightfold lower than those of HIV-1. Treatment of infected cells with sCD4 induced the dissociation of gp120 from gp41 and increased the exposure of a cryptic gp41 epitope on all of the HIV-1 isolates. By contrast, neither dissociation of the outer envelope glycoprotein nor increased exposure of the transmembrane glycoprotein was observed when sCD4 bound to HIV-2- or SIV-infected cells. Moreover, immunoprecipitation with sCD4 resulted in the coprecipitation of the surface and transmembrane glycoproteins from virions of the HIV-2 and SIV isolates, whereas the surface envelope glycoprotein alone was precipitated from HIV-1. However, treatment of HIV-1-, HIV-2-, and SIV-infected cells with sCD4 did result in an increase in exposure of their V2 and V3 loops, as detected by enhanced antibody reactivity. This demonstrates that receptor binding to the outer envelope glycoprotein induces certain conformational changes which are common to all of these viruses and others which are restricted to cell line-passaged isolates of HIV-1.


Prevention of cuff injury of the intubation tube by blunt window opening in tracheostomy.
One of the intraoperative complications of tracheostomy under general anesthesia is cuff injury of the intubation tube. In the present study, we investigated whether a blunt tracheal opening is a useful method to avoid cuff injury. A retrospective cohort study was conducted to examine patients who underwent tracheostomy under general anesthesia at a single institution from January 1, 2017 to July 31, 2021. Electrocautery was used to thin the connective tissue between the tracheal rings, and bluntly open the trachea with mosquito forceps or similar instruments. Primary outcomes included cuff injury rate, number of surgeons involved, and career as otolaryngologist at the time of surgery. The secondary outcome was perioperative complications. Of the 64 cases, 3 had cuff injuries. 2 of the 3 had cuff injuries during the creation of an anteriorly based flap. 16 surgeons were involved ranging from the first to sixth year as an otolaryngologist, with the third year of otolaryngologist being the most common. The median physician year for instructors was 18 years. The most common postoperative complication was granulation in 9 cases. There were no cases of incorrect cannula insertion or difficulty in cannula insertion. A blunt tracheal opening was considered useful as a method to prevent cuff injury.


[Evaluation of prenatal assistance in the point of view of puerperas and hetalth care professionals].
The aim of this study was to evaluate the prenatal assistance in a public maternity hospital in the point of view of puerperas and health care professionals. Nineteen puerperas and six health professionals took part in the study. The puerperas answered a semi-structured interview and the health professionals took part in a focus group. The discourse analysis was based on in-depth hermeneutics. The main results pointed out that users showed a deep appreciation for the health professionals. Concerning the professional's view, pregnant women had a wrong knowledge of health during pregnancy. As regards the nutrition appointments, puerperas pointed out they had room for dialogue, support and encouragement. In conclusion, prenatal health education should consider that each woman is a unique individual with her own background. Bonding is of paramount importance for pregnant women to get involved with health-related issues.


Selective activation of nociceptors by P2X receptor agonists in normal and inflamed rat skin.
1. ATP can elicit pain in humans and, together with other P2X channel agonists, can produce nocifensive responses in rodents. We used the rat in vitro skin-nerve preparation to quantify primary afferent responses to ATP and its stable analogue alpha,beta-methylene ATP in normal and carrageenan-inflamed skin. 2. Both ATP and alpha,beta-methylene ATP were found to specifically activate the peripheral terminals of Adelta and C-fibre nociceptors in the skin. Thirty-nine per cent of the nociceptors tested responded to the maximal dose of alpha,beta-methylene ATP (5 mM). In contrast, non-nociceptive, low-threshold mechano-sensitive fibres were never activated by the same agonist concentrations. 3. Amongst the nociceptor population, C-mechanoheat fibres (C-MH or polymodal nociceptors) were markedly more responsive to P2X agonists than mechanonociceptors (C-M nociceptors) with Adelta- or C-fibre axons. Both C-mechanoheat and C-mechanonociceptors were activated by alpha,beta-methylene ATP doses as low as 50 microM. 4. In skin inflamed with carrageenan 3-4 h before recording both the number of responsive C-fibre nociceptors and their response magnitude increased. The increased neural response under inflammatory conditions was largely observed in C-mechanoheat or polymodal nociceptors. After low doses of P2X agonists C-MH fibres but not C-M fibres developed elevated ongoing activity and this effect was only seen after carrageenan inflammation. The time course of alpha,beta-methylene ATP-evoked discharges in nociceptors was found to correlate well with the time course of behavioural nocifensive responses in rats to the same agonist described in a previous study (Hamilton et al. 1999). 5. We conclude that the rapid increase in the number of alpha,beta-methylene ATP responsive nociceptors and the increased magnitude of the neural response following carrageenan inflammation explains why very low concentrations of such agonists can cause pain in inflammatory states.


A clinical and neuropathologic study of silk suture as an embolic agent for brain arteriovenous malformations.
To evaluate the safety and efficacy of silk suture as an agent for preoperative embolization of cerebral arteriovenous malformations. Clinical and histopathologic results were analyzed in six patients who underwent embolization of cerebral arteriovenous malformations using silk suture in combination with other agents. Three of the patients treated with silk hemorrhaged after embolization, and two of these patients died. Neuropathologic analysis of four patients showed acute perivascular inflammation, sometimes quite severe. The inflammatory response to silk may explain its effectiveness in producing vascular occlusion. However, a fulminate vasculitis theoretically can predispose to delayed hemorrhage. Other problems with silk include the pressure required to inject the agent and the inability to determine the final site of deposition of the silk. Although other embolic agents may share some of these potential difficulties, we feel that the disadvantages outweigh the advantages of silk as an embolic agent.


The optimal management of anti-thrombotic therapy after valve replacement: certainties and uncertainties.
Anti-thrombotic therapy after valve replacement encompasses a number of different situations. Long-term anticoagulation of mechanical prostheses uses vitamin K antagonists with a target international normalized ratio adapted to the characteristics of the prosthesis and the patient. The association of low-dose aspirin is systematic in the American guidelines and more restrictive in the European guidelines. Early heparin therapy is frequently used early after mechanical valve replacement, although there are no precise recommendations regarding timing, type, and dose of drug. Direct oral anticoagulants are presently contraindicated in patients with mechanical prosthesis. The main advantage of bioprostheses is the absence of long-term anticoagulant therapy. Early anticoagulation is indicated after valve replacement for mitral bioprostheses, whereas aspirin is now favoured early after bioprosthetic valve replacement in the aortic position. Early dual antiplatelet therapy is indicated after transcatheter aortic valve implantation, followed by single antiplatelet therapy. However, this relies on low levels of evidence and optimization of anti-thrombotic therapy is warranted in these high-risk patients. Although guidelines are consistent in most instances, discrepancies and the low-level of evidence of certain recommendations highlight the need for further controlled trials, in particular with regard to the combination of antiplatelet therapy with oral anticoagulant and the early post-operative anti-thrombotic therapy following the procedure.


Blood lactic acid levels after artificial heart implantation.
The aim of this study is to investigate blood lactic acid levels after the placement of the AbioCor implantable replacement heart to determine whether circulatory support with the AbioCor device results in adequate tissue perfusion. Tissue perfusion may not be adequate during cardiac surgery, especially with the use of cardiopulmonary bypass (CPB). Inadequate perfusion is usually associated with anaerobic metabolism, metabolic acidosis, and lactate accumulation. Ten calves had implantation of the AbioCor by means of a right thoracotomy. Standard cardiopulmonary bypass was performed during surgery. Lactic acid levels and blood gas analyses were measured. All animals were monitored for pressures in the aorta, pulmonary artery, and left and right atria. The output of the AbioCor was calculated based on beat rate and stroke volume. All animals were rapidly weaned off cardiopulmonary bypass to full AbioCor support and had normal hemodynamics with normal filling pressures. The lactic acid levels were elevated after surgery, peaked at 8 to 12 hours, and then gradually decreased to the normal range 24 hours after surgery. There was a positive relationship between lactate levels, oxygen consumption, and extraction rate, that is, the lactic acid levels were higher in the presence of increased oxygen consumption and increased oxygen extraction rate. There was a negative relationship between lactate levels and oxygen delivery, and arterial and venous oxygen content, that is, the lactic acid levels were higher when oxygen delivery and arterial and venous oxygen contents were low. The pathophysiology of lactic acidosis is uncertain, but is most likely due to inadequate perfusion during cardiopulmonary bypass, and lactate washout after adequate perfusion has been established. The return to aerobic metabolism with clearance of lactate demonstrates that the AbioCor is able to provide complete circulatory support with normal tissue perfusion.


Inactivation-deficient human skeletal muscle Na+ channels (hNav1.4-L443C/A444W) in stably transfected HEK-293 cells.
After transient transfection of an hNav1.4-L443C/A444W mutant clone, HEK-293 cells exhibited large inactivation-deficient Na+currents. We subsequently established a stable cell line expressing robust inactivation-deficient Na+currents. Persistent late Na+currents were far more sensitive to block by class 1 anti-arrhythmic flecainide, mexiletine, propafenone, and amiodarone at 10 microM than peak Na+currents. Such results support a hypothesis that persistent late Na+currents are in vivo targets for class 1 anti-arrhythmic drugs at their therapeutic plasma concentrations. Stably transfected HEK-293 cells expressing robust inactivation-deficient Na+currents will likely be suitable for screening novel drugs that target persistent late Na+currents selectively.


Feasibility of safe ultra-high (EQD(2)>100 Gy) dose escalation on dominant intra-prostatic lesions (DILs) by Helical Tomotheraphy.
to verify the possibility of using Helical Tomotherapy to safely escalate dose to single or multiple highly radioresistant dominant intra-prostatic lesions (DILs) as assessed by functional magnetic resonance imaging (MRI). in seven intermediate/high risk patients, T2WI, T1WI and DWI MRI imaging showed evidence of one DIL in four patients and two DILs in three patients in the peripheral zone of the prostate. The planning strategy was to deliver median doses of 80, 90, 100 and 120 Gy to PTVDIL while delivering 71.4 Gy/28 fractions (EQD(2)=75 Gy) to the remaining portion of PTV. A higher priority was assigned to rectal constraints relative to DIL coverage. Rectal NTCP calculations were performed using the most recently available model data. the median dose to DIL could safely be escalated to at least 100 Gy (EQD(2,α/β=10)=113 Gy) without violating safe constraints for the organs at risk. Typical rectal NTCP values were around or below 1-3% for G3 toxicity and 5-7% for G2-G3 toxicity. For the 100 Gy DIL dose boost strategy, mean D95% of DIL and PTVDIL were 98.8 Gy and 86.7 Gy, respectively. The constraints for bladder, urethra and femoral heads were always respected. IGRT by Helical Tomotherapy may permit the safe escalation of EQD(2,α/β=10) to at least 113 Gy to DILs without significantly increasing rectal NTCP compared to plans without dose escalation. A Phase I-II clinical study is warranted.


Shedding Light on Graphene Quantum Dots: Key Synthetic Strategies, Characterization Tools, and Cutting-Edge Applications.
During the last 20 years, the scientific community has shown growing interest towards carbonaceous nanomaterials due to their appealing mechanical, thermal, and optical features, depending on the specific nanoforms. Among these, graphene quantum dots (GQDs) recently emerged as one of the most promising nanomaterials due to their outstanding electrical properties, chemical stability, and intense and tunable photoluminescence, as it is witnessed by a booming number of reported applications, ranging from the biological field to the photovoltaic market. To date, a plethora of synthetic protocols have been investigated to modulate the portfolio of features that GQDs possess and to facilitate the use of these materials for target applications. Considering the number of publications and the rapid evolution of this flourishing field of research, this review aims at providing a broad overview of the most widely established synthetic protocols and offering a detailed review of some specific applications that are attracting researchers' interest.


Tremor in 48,XXYY syndrome.
The 48,XXYY syndrome is a form of sex chromosome aneuploidy presenting in 1:18,000 males. Tremor has been previously reported in 47,XXY and 47,XYY syndromes, but has not been well described in 48,XXYY syndrome. Ten males with 48,XXYY syndrome had a standardized neurological examination and videotaping, which included the Clinical Rating Scale for Tremor and the International Cooperative Ataxia Rating Scale. All 10 cases had postural and kinetic tremor on physical examination. Other findings included mild gait ataxia, dysarthria, and nystagmus. Three cases are reviewed. Tremor is a common finding in children and young adults with 48,XXYY syndrome. Dosage alteration of genes on the sex chromosomes may be involved in the pathogenesis of this tremor. Karyotyping should be considered in individuals presenting with tremor and a history of developmental delay, learning disabilities, tall stature, or microorchidism.


The evolution of alternative cryptic female choice strategies in age-structured populations.
Cryptic female choice is a potentially important aspect of the sexual selection process. According to the theory of sexual dialectics, postcopulation manipulation of relative male fertilization success can provide an avenue by which females can circumvent attempts by males to control female reproduction. Here I use stochastic models to investigate the evolution of cryptic female choice in populations with and without age structure. In populations without age structure, cryptic female choice will evolve only when (1) precopulatory mate choice by females is inefficient, (2) variation in male fitness is correlated with a trait upon which a female can base her choice of mates, and (3) the cost of multiple mating is not too high. In populations with age structure, similar conditions apply. However, selection sometimes favors females that employ alternative strategies of female choice at different ages. These results help to define the types of biological systems in which we should expect to see the evolution of cryptic female choice. They also illustrate that the evolution of choice strategies in females may be complex and may mirror in some important respects the evolution of alternative mating tactics in males.


Breast Cancer Risk and Mammographic Density Assessed with Semiautomated and Fully Automated Methods and BI-RADS.
Purpose To compare three metrics of breast density on full-field digital mammographic (FFDM) images as predictors of future breast cancer risk. Materials and Methods This institutional review board-approved study included 125 women with invasive breast cancer and 274 age- and race-matched control subjects who underwent screening FFDM during 2004-2013 and provided informed consent. The percentage of density and dense area were assessed semiautomatically with software (Cumulus 4.0; University of Toronto, Toronto, Canada), and volumetric percentage of density and dense volume were assessed automatically with software (Volpara; Volpara Solutions, Wellington, New Zealand). Clinical Breast Imaging Reporting and Data System (BI-RADS) classifications of breast density were extracted from mammography reports. Odds ratios and 95% confidence intervals (CIs) were estimated by using conditional logistic regression stratified according to age and race and adjusted for body mass index, parity, and menopausal status, and the area under the receiver operating characteristic curve (AUC) was computed. Results The adjusted odds ratios and 95% CIs for each standard deviation increment of the percentage of density, dense area, volumetric percentage of density, and dense volume were 1.61 (95% CI: 1.19, 2.19), 1.49 (95% CI: 1.15, 1.92), 1.54 (95% CI: 1.12, 2.10), and 1.41 (95% CI: 1.11, 1.80), respectively. Odds ratios for women with extremely dense breasts compared with those with scattered areas of fibroglandular density were 2.06 (95% CI: 0.85, 4.97) and 2.05 (95% CI: 0.90, 4.64) for BI-RADS and Volpara density classifications, respectively. Clinical BI-RADS was more accurate (AUC, 0.68; 95% CI: 0.63, 0.74) than Volpara (AUC, 0.64; 95% CI: 0.58, 0.70) and continuous measures of percentage of density (AUC, 0.66; 95% CI: 0.60, 0.72), dense area (AUC, 0.66; 95% CI: 0.60, 0.72), volumetric percentage of density (AUC, 0.64; 95% CI: 0.58, 0.70), and density volume (AUC, 0.65; 95% CI: 0.59, 0.71), although the AUC differences were not statistically significant. Conclusion Mammographic density on FFDM images was positively associated with breast cancer risk by using the computer assisted methods and BI-RADS. BI-RADS classification was as accurate as computer-assisted methods for discrimination of patients from control subjects. © RSNA, 2016.


Public health operations in the JSOTF-P.
Medical personnel have a proven operational and strategic role as part of Counterinsurgency (COIN) and Foreign Internal Defense (FID) operations. In addition to the traditional employment of medical assets in Medical Civic Action Programs, commanders can utilize their medical resources in a teaching and educational capacity to effectively target an entire village (men, women, and children), with minimal logistical support. In the Joint Special Operations Task Force-Philippines, Environmental Science Engineer Officers and veterinarians added additional capabilities and facilitated educational programs that stimulate the coordination of local, military, and government resources to improve public health infrastructure and make a sustainable, lasting impact.


Ethanol stimulates the plasma membrane calcium pump from human erythrocytes.
The plasma membrane Ca(2+)-ATPase from human erythrocytes can be stimulated by different treatments such as addition of calmodulin or acidic phospholipids and controlled proteolysis. In this report we show that short chain alkyl alcohols also stimulated this enzyme. At 5% (v/v) ethanol, the maximal velocity of the enzyme was about 2.4-fold higher than in the control, and thus, was also higher than the maximal velocity obtained in the presence of calmodulin (about 2-fold). When ethanol and calmodulin were present simultaneously, the stimulatory effect was additive (3.4-fold stimulation). On the other hand, the stimulatory effect of ethanol was preserved after treatment of the enzyme with trypsin to stimulate the Ca(2+)-ATPase and render it independent of calmodulin, thus suggesting that the interaction of ethanol and calmodulin with the Ca(2+)-ATPase occurred through a different mechanism. Other short chain alkyl alcohols (methanol, n-propanol and n-butanol) stimulated the Ca(2+)-ATPase activity to the same extent than ethanol but with different efficacy. Thus, the larger the carbon number, the lower the concentration needed to get the same maximal stimulation. Ethanol also increased the affinity of the enzyme for ATP to a larger extent and additively, when compared to calmodulin. All the effects of ethanol mentioned above were identically observed on the membrane-bound enzyme (i.e., erythrocyte ghosts) ruling out any effect of the alcohols attributable to the solubilized purified enzyme. Furthermore, Ca2+ transport by inside-out vesicles was also stimulated by ethanol, showing both the same concentration-dependence as the Ca(2+)-ATPase activity and the additive effect observed when calmodulin was also present. The stimulatory effect of ethanol was significant at pharmacological concentrations, thus suggesting potential implications of toxicological relevance.


Evaluation of a Natural Language Processing Approach to Identify Social Determinants of Health in Electronic Health Records in a Diverse Community Cohort.
Health care systems in the United States are increasingly interested in measuring and addressing social determinants of health (SDoH). Advances in electronic health record systems and Natural Language Processing (NLP) create a unique opportunity to systematically document patient SDoH from digitized free-text provider notes. Patient SDoH status [recorded by Your Current Life Situation (YCLS) Survey] and associated provider notes recorded between March 2017 and June 2020 were extracted (32,261 beneficiaries; 50,722 YCLS surveys; 485,425 provider notes).NLP patterns were generated using a machine learning test statistic (Term Frequency-Inverse Document Frequency). Patterns were developed and assessed in a training, training validation, and final validation dataset (64%, 16%, and 20% of total data, respectively).NLP models analyzed SDoH-specific categories (housing, medical care, and transportation needs) and a combined SDoH metric. Model performance was assessed using sensitivity, specificity, and Cohen κ statistic, assuming the YCLS Survey to be the gold standard. Within the training validation dataset, NLP models showed strong sensitivity and specificity, with moderate agreement with the YCLS Survey (Housing: sensitivity=0.67, specificity=0.89, κ=0.51; Medical care: sensitivity=0.55, specificity=0.73, κ=0.20; Transportation: sensitivity=0.79, specificity=0.87, κ=0.58). Model performance in the training and training validation datasets were comparable.In the final validation dataset, a combined SDoH prediction metric showed sensitivity=0.77, specificity=0.69, κ=0.45. This NLP algorithm demonstrated moderate performance in identification of unmet patient social needs. This novel approach may enable improved targeting of interventions, allocation of limited resources and monitoring a health care system's addressing its patients' SDoH needs.


Further Comparison of 4 Display Modes for a Multi-Resolution Foveated Laparoscope.
Background. To overcome field of view and ergonomic limitations of standard laparoscopes, we are developing a multi-resolution foveated laparoscope (MRFL), which can simultaneously obtain both wide- and zoomed-in-view images. To facilitate the effectiveness of our MRFL, we have been investigating various ways of organizing and visualizing dual-view multi-resolution images acquired by the MRFL. In our prior study, we implemented and compared 6 display modes for the MRFL, assuming a typical clinical environment where a standard (but limited) resolution monitor is available. To take full advantage of our MRFL, displays having sufficient screen resolutions might be advantageous. The present study aims to further understand the effects of view configurations through displays with a standard high-definition (HD) resolution and a 4K resolution. In this study, we compare 3 display modes for limited-resolution displays against a new mode for sufficient-resolution displays. Methods. Twenty subjects performed 3 evaluation trials of a touching task with each display mode in an emulated MRFL environment. Various objective measurements including task completion time and the number of collisions, and subjective preference were recorded. Results. The new mode showed a better task completion time than the other modes, while it maintained a low number of collisions similar to the others. Moreover, the majority of participants selected the new mode as their most preferred one. Conclusions. With a sufficient display resolution, the co-registration between the unblocked and unwarped wide context view and the high-resolution zoomed-in view offered by the new mode was highly effective on both task performance and user preference.


Asymmetry in children's salivary cortisol and alpha-amylase in the context of marital conflict: links to children's emotional security and adjustment.
Recent research supports the promise of examining interactive models of physiological processes on children's adjustment. The present study investigates interactions between children's autonomic nervous system activity and adrenocortical functioning in the context of marital discord; specifically, testing models of concurrent responses proposed by Bauer et al. ([2002] Developmental and Behavioral Pediatrics 23:102-113) in the prediction of children's behavioral responses to conflict and adjustment. Asymmetry and symmetry in children's salivary alpha-amylase and cortisol were examined in 195 children (M age = 8 years) in response to viewing conflict vignettes. Results were partially consistent with an interactive model in the context of high marital discord; asymmetry among higher alpha-amylase and lower cortisol related to higher emotional insecurity and concurrent and subsequent maladjustment. In contrast, patterns of symmetrical responses were related to greater maladjustment for children exposed to lower levels of marital discord, supporting an additive model. Findings support the importance of a multisystem approach to investigating the adaptiveness of children's physiological stress responses, while also highlighting the value of considering physiological responses in the context of family risk.


Arthroscopic primary rotator cuff repairs in patients aged younger than 45 years.
The purpose of this study was to evaluate the mechanism of injury, patient characteristics, tear size, and clinical outcomes after arthroscopic primary rotator cuff repair of full-thickness tears in patients aged younger than 45 years. A total of 70 consecutive patients were reviewed in a retrospective, multicenter (2 institutions) study evaluating prospectively collected data. Fifty-three patients, with a mean age of 37.5 years (range, 16.2 to 44.9 years), were available for follow-up at a mean of 35.8 months (range, 13.8 to 59.1 months). Exclusion criteria included patients with revision procedures, repair of partial tears, and follow-up of less than 12 months. Follow-up evaluation included physical examination with dynamometer strength testing and clinical outcome measures including the Single Assessment Numeric Evaluation score, American Shoulder and Elbow Surgeons (ASES) score, Constant-Murley score, pain score on a visual analog scale, and Simple Shoulder Test score. A total of 60% of the patients (32 of 53) had a traumatic etiology, with 38% (12 of 32) of these related to an athletic event. Of the tears, 36 (68%) were medium tears. Concomitant procedures performed at the time of rotator cuff repair included acromioplasty (51), biceps tenodesis or tenotomy (24), distal clavicle excision (10), anteroinferior stabilization (2), and labral repair (1). The mean postoperative ASES score was 84.6 (range, 21.6 to 100.0), with 2 patients recording ASES scores of less than 50 (21.7 and 41.7) at final follow-up. In the 38 patients available for clinical follow-up examination, forward flexion improved from 158.7° (range, 45° to 180°) to 168.4° (range, 120° to 180°) (P = .014). At the time of follow-up, no patients had undergone revision surgery. On the basis of poor clinical outcome scores, 2 patients (4.0%) were considered failures. Arthroscopic primary rotator cuff repair of full-thickness tears in patients aged younger than 45 years results in improved outcomes with regard to pain, subjective patient satisfaction, and shoulder function. Level IV, therapeutic case series.


Designing an internal audit process for physician billing compliance.
An internal audit process is central to an effective compliance program. When based on pertinent Federal regulatory guidelines and executed by staff with appropriate technical expertise, an internal audit limits opportunities for noncompliant physician billing and reduces the risk of incurring financial penalties. The design of an effective internal audit process will incorporate uniform internal audit procedures, communication mechanisms, and educational initiatives to correct any deficiencies that are identified. For healthcare organizations that are involved with physician group practices, review of physician documentation is particularly important. This review provides essential information on potential areas of risk and offers a focus for future education of physicians regarding appropriate billing and documentation.


Temperamental Differences in Children's Reactions to Peer Victimization.
This research examined the hypothesis that temperament and sex moderate the contribution of peer victimization to children's subsequent adjustment (aggression and depressive symptoms). Children (125 boys, 158 girls; M age = 7.95 years, SD = 0.32; 77.7% White, 22.3% minority) and teachers reported on overt and relational victimization. Parents rated children's temperament (inhibitory control and negative emotionality) and depressive symptoms, and teachers reported on children's overt and relational aggression. Across a 1-year period, (a) overt victimization predicted overt aggression in girls with poor inhibitory control, (b) overt and relational victimization predicted depressive symptoms in girls with high negative emotionality, and (c) relational victimization predicted depressive symptoms in boys with low negative emotionality. This research helps to explain individual variation in children's reactions to peer victimization and has implications for Person × Environment models of development. Moreover, this research informs the development of targeted intervention programs for victimized youth that bolster specific resources depending on their temperament.


Studies on the mechanism of depletion of striatal dopamine by alpha-methyl-m-tyrosine.
These experiments were designed to study the mechanism of depletion of dopamine (DA) in the striatum produced by alpha-methyl-m-tyrosine (alpha-MMT). alpha-Methyl-m-tyramine (alpha-MMTA), the metabolite of alpha-MMT, appears to be the active DA-depleting agent, since the administration of a decarboxylase inhibitor before alpha-MMT markedly reduced both the formation of alpha-MMTA and the depletion of DA. After injection of alpha-MMT (100 mg/kg i.p.), the striatal concentration of homovanillic acid (HVA) rose by 41% at 1 hour. This is probably due to an increase in DA metabolism, since alpha-MMT markedly enhanced the decline of DA produced by alpha-methyl-p-tyrosine (alpha-MPT). At 2, 3 and 4 hours after alpha-MMT, the concentration of HVA and dihydroxyphenylacetic acid was below control level. The decrease in dihydroxyphenylacetic acid is due partially to a decreased formation of dihydroxyphenylacetic acid from DA. In striatal slices, both alpha-MMT and alpha-MMTA decreased the formation of 3H-H2O and the accumulation of 3H-DA from 1-3,5-3H-tyrosine. Alpha-MMT did not alter the specific activity of 3H-tyrosine or release 3H-DA from the slices, but it did inhibit the activity of tyrosine hydroxylase in striatal homogenates at low concentrations of tyrosine (10 muM). Alpha-MMTA released both newly synthesized and exogenously accumulated 3H-DA from striatal slices. At low concentrations of alpha-MMTA, the percent reduction in 3H-H2O was much greater than the percentage of 3H-DA released into the medium. However, at higher concentrations, the inhibition of 3H-H2O reached a maximum while 3H-DA release kept increasing. These results suggest that both inhibition of tyrosine hydroxylase activity and DA release from storage sites by alpha-MMTA may account for the depletion of DA produced by the injection of alpha-MMT.


Challenging a 15-year-old claim: The North Atlantic Oscillation index as a predictor of spring migration phenology of birds.
Many migrant bird species that breed in the Northern Hemisphere show advancement in spring arrival dates. The North Atlantic Oscillation (NAO) index is one of the climatic variables that have been most often investigated and shown to be correlated with these changes in spring arrival. Although the NAO is often claimed to be a good predictor or even to have a marked effect on interannual changes in spring migration phenology of Northern Hemisphere breeding birds, the results on relations between spring migration phenology and NAO show a large variety, ranging from no, over weak, to a strong association. Several factors, such as geographic location, migration phase, and the NAO index time window, have been suggested to partly explain these observed differences in association. A combination of a literature meta-analysis, and a meta-analysis and sliding time window analysis of a dataset of 23 short- and long-distance migrants from the constant-effort trapping garden at Helgoland, Germany, however, paints a completely different picture. We found a statistically significant overall effect size of the NAO on spring migration phenology (coefficient = -0.14, SE = 0.054), but this on average only explains 0%-6% of the variance in spring migration phenology across all species. As such, the value and biological meaning of the NAO as a general predictor or explanatory variable for climate change effects on migration phenology of birds, seems highly questionable. We found little to no definite support for previously suggested factors, such as geographic location, migration phenology phase, or the NAO time window, to explain the heterogeneity in correlation differences. We, however, did find compelling evidence that the lack of accounting for trends in both time series has led to strongly inflated (spurious) correlations in many studies (coefficient = -0.13, SE = 0.019).


On the importance of prereactive complexes in molecule-radical reactions: hydrogen abstraction from aldehydes by OH.
In this work, the OH + formaldehyde and OH + acetaldehyde reactions have been characterized using accurate ab initio methods with large basis sets. The results clearly indicate that the reaction occurs by hydrogen abstraction, and that the OH addition channel is unfavorable. Close to zero (for formaldehyde) and negative (for acetaldehyde) activation energy values are obtained, which are in excellent agreement with the experimentally observed values. The reaction rate constants, calculated using the classical transition-state theory as applied to a complex mechanism involving the formation of a prereactive complex, reproduce very well the reported experimental results. Consideration of the prereactive complex is shown to be essential for the determination of the height of the energy barrier and thus for the correct calculation of the tunneling factor.


Clinical significance of night-to-night sleep variability in insomnia.
To evaluate the clinical relevance of night-to-night variability of sleep schedules and insomnia symptoms. The sample consisted of 455 patients (193 men, mean age=48) seeking treatment for insomnia in a sleep medicine clinic. All participants received group cognitive behavioral therapy for insomnia (CBTI). Variability in sleep parameters was assessed using sleep diary data. Two composite scores were computed, a behavioral schedule composite score (BCS) and insomnia symptom composite score (ICS). The Insomnia Severity Index, the Beck Depression Inventory, and the Morningness-Eveningness Composite Scale were administered at baseline and post-treatment. Results revealed that greater BCS scores were significantly associated with younger age, eveningness chronotype, and greater depression severity (p<0.001). Both depression severity and eveningness chronotype independently predicted variability in sleep schedules (p<0.001). Finally, CBTI resulted in reduced sleep variability for all sleep diary variables except bedtime. Post-treatment symptom reductions in depression severity were greater among those with high versus low baseline BCS scores (p<0.001). Results suggest that variability in sleep schedules predict reduction in insomnia and depressive severity following group CBTI. Schedule variability may be particularly important to assess and address among patients with high depression symptoms and those with the evening chronotype.


Induction of cell cycle arrest and apoptosis in human colon adenocarcinoma cell lines by beta-carotene through down-regulation of cyclin A and Bcl-2 family proteins.
Although the pharmacological role of beta-carotene in the prevention and treatment of colon cancer has received increasing attention, little is known about the molecular mechanisms of action of this carotenoid. The present study demonstrates that beta-carotene, a natural pigment widely present in fruit and vegetables, inhibits the growth of several human colon adenocarcinoma cell lines (COLO 320 HSR, LS-174, HT-29 and WiDr) by inducing cell cycle arrest in G(2)/M phase and apoptosis. These effects were dose and time dependent and strictly related to cell ability to accumulate the carotenoid. COLO 320 HSR cells incorporated beta-carotene to a greater extent than LS-174, HT-29 and WiDr cells and, concomitantly, they exhibited a higher sensitivity to the growth inhibitory effects of the carotenoid. At inhibitory concentrations beta-carotene reduced the expression of cyclin A, a key regulator of G(2)/M progression. Neither p21 nor p27, two cyclin kinase inhibitors, were significantly modified by carotenoid treatment. With respect to apoptosis induction, decreased levels of the apoptosis blocking proteins Bcl-2 and Bcl-xL were also observed. On the other hand, no changes in expression of the apoptosis promoter protein Bax were detected. This study represents a novel aspect of the biological profile of beta-carotene and a new step in elucidating the underlying molecular mechanisms of its antitumor action. In addition, since cell growth inhibitory effects were reached at beta-carotene concentrations achievable in vivo following its supplementation, this study provides a rational approach for the use of beta-carotene in colon cancer.


Cancer-related urinary proteinase inhibitor, EDC1: a new method for its isolation and evidence for multiple forms.
During the past several years, numerous laboratories have reported isolation and purification of proteinase inhibitors from human urine. Many of these molecules were incompletely characterized and some of them may have been artifacts in part because of harsh procedures used for their isolation. Consequently, there is disagreement and confusion regarding the biochemical characteristics of these inhibitors. We previously reported the isolation of a proteinase inhibitor, EDC1, from the urine of a leukemic patient. This molecule, M(r) 30 kDa, was antigenically related to plasma inter-alpha-trypsin inhibitor (IATI) and inhibited the growth of a virally transformed B cell line. Immunoreactive EDC1 was also the major component of low molecular weight proteinuria observed in cancer patients. We now report a new method for the isolation of EDC1 from urine of patients with adenocarcinomas of colon and lung and melanoma and compare its partial amino acid sequence with that of HI 30, a proteinase inhibitor previously isolated from pooled normal urine by Hochstrasser et al. [Hoppe-Seyler's Z Physiol Chem 357:153-162, 1976]. Our method involves i) a batchwise cation exchange, ii) gel filtration chromatography, iii) anion exchange chromatography on FPLC, and iv) reverse phase C18 chromatography on HPLC. This method is mild and results in an overall yield of 0.4 to 1.2 mg of EDC1/liter urine. On the basis of the partial N-terminal amino acid sequence of its N terminal (38 residues) and middle regions (29 residues), EDC1 appears to be identical with HI30. Surprisingly, during this isolation procedure, another proteinase inhibitor, M(r) 22 kDa, which cross-reacted with antisera to EDC1 and IATI, was also isolated. The 22 kDa molecule was a major component of the IATI related urinary molecules and was identical with the 30 kDa EDC1 in which first the 15 N terminal residues were clipped. The lower M(r) inhibitor was not an artifact formed during storage or isolation procedure because the Western blot analysis of fresh cancer and normal urine revealed the 30 and 22 kDa molecules. Thus, both the 30 kDa EDC1 (or HI30) and its clipped variant, the 22 kDa molecule, are physiologic components of IATI related urinary proteinase inhibitors and excretion of both forms may be increased in patients with advanced cancer.


Long-term risk of pneumothorax in asthmatic children: A 12-year population-based cohort study.
Pneumothorax is a life-threatening complication during acute asthma attack. However, long-term risk of pneumothorax in asthmatic children remains unknown.In this retrospective cohort study, 333,657 children were defined as asthma cohort and a 1:1 matched non-asthma cohort were generated from 2000 to 2011. At the end of 2012, the incidence of pneumothorax in asthma and non-asthma cohorts and asthma to non-asthma hazard ratios (HRs) with confidence intervals (CIs) of pneumothorax were analyzed.The incidence of pneumothorax was 1.35-fold higher in the asthma cohort than that in the non-asthma cohort. The asthma to non-asthma HRs of pneumothorax were higher in children younger than 6 years (1.76, 95% CI: 1.21-2.57) and in girls (2.27; 95% CI: 1.23-4.16). The HRs of pneumothorax were higher in asthmatic children with more asthma-related out-patient clinic visits/per year (>5 visits; HR: 2.81; 95% CI: 1.79-4.42), more emergency department visits/per year (>4 visits; HR: 1.68; 95% CI: 1.02-2.78), and longer hospitalization days due to asthma (>4 days; HR: 3.42; 95% CI: 1.52-6.94) (P < .0001, the trend test).Asthmatic children had greater risk for pneumothorax, particularly in young children and in those with severe and uncontrolled asthma.


Effectiveness of a gentamicin dosing protocol based on postconceptional age: comparison to published neonatal guidelines.
To evaluate the effectiveness of a gentamicin dosing protocol based on postconceptional age in producing therapeutic serum concentrations and to compare the protocol with commonly used gentamicin dosing guidelines. During the initial three months of this study infants were dosed according to physician discretion (group I). In the subsequent three-month period patients were dosed according to a postconceptional age dosing schedule (group II). Infants were enrolled after being admitted to the Newborn Intensive Care Unit at the University of Miami/Jackson Memorial Medical Center. Infants less than 37 weeks gestational age with normal renal function, not receiving indomethacin, and requiring gentamicin treatment were enrolled. Fifty-nine infants were enrolled into group I (median weight 1300 g [range 720-3300]), postconceptional age 29 weeks [26-37]); and 68 infants were enrolled into group II (weight 970 g [530-3000], postconceptional age 29 weeks [24-36]). Patients in group II were dosed according to the following protocol: postconceptional age less than 30 weeks, 3.0 mg/kg q24h, and postconceptional age 30-37 weeks, 2.5 mg/kg q18h. Peak and trough serum gentamicin concentrations were obtained in all study patients. Pharmacokinetic parameters were calculated from measured serum concentrations. Using the calculated pharmacokinetic data, peak and trough serum concentrations were simulated for five published neonatal dosing guidelines and the proposed postconceptional age protocol. The number of therapeutic serum gentamicin concentrations resulting from the dosing guidelines studied were compared. Measured trough concentrations differed significantly between the two groups with 35 percent of patients in group I and 90 percent of patients in group II having trough values less than 2 mg/L (p less than 0.001). There was no significant difference in measured peak concentrations between groups. Simulated trough concentrations were significantly different when postconceptional age dosing was compared with commonly used protocols (p less than 0.0001) with the highest percentage of concentrations less than 2 mg/L (89 percent) resulting from the proposed postconceptional age guidelines. These data suggest that the proposed postconceptional age protocol is reproducible and reliable in achieving therapeutic gentamicin serum concentrations in neonates.


Peroxisome proliferator-activated receptor γ modulates renal crystal retention associated with high oxalate concentration by regulating tubular epithelial cellular transdifferentiation.
The differentiated phenotype of renal tubular epithelial cell exerts significant effect on crystal adherence. Peroxisome proliferator-activated receptor γ (PPARγ) has been shown to be critical for the regulation of cell transdifferentiation in many physiological and pathological conditions; however, little is known about its role in kidney stone formation. In the current study, we found that temporarily high oxalate concentration significantly decreased PPARγ expression, induced Madin Darby Canine Kidney cell dedifferentiation, and prompted subsequent calcium oxalate (CaOx) crystal adhesion in vitro. Furthermore, cell redifferentiation after the removal of the high oxalate concentration, along with a decreasing affinity to crystals, was an endogenic PPARγ-dependent process. In addition, the PPARγ antagonist GW9662, which can depress total-PPARγ expression and activity, enhanced cell dedifferentiation induced by high oxalate concentration and inhibited cell redifferentiation after removal of the high oxalate concentration. These effects were partially reversed by the PPARγ agonist 15d-PGJ2. Similar results were observed in animals that suffered from temporary hyperoxaluria followed by a recovery period. The active crystal-clearing process occurs through the transphenotypical morphology of renal tubular epithelial cells, reflecting cell transdifferentiation during the recovery period. However, GW9662 delayed cell redifferentiation and increased the secondary temporary crystalluria-induced crystal retention. This detrimental effect was partially reversed by 15d-PGJ2. Taken together, our results revealed that endogenic PPARγ activity plays a vital regulatory role in crystal clearance, subsequent crystal adherence, and CaOx stone formation via manipulating the transdifferentiation of renal tubular epithelial cells.


Muscle function in Saudi children and adolescents: relationship to anthropometric characteristics during growth.
The main purpose of the present study was to determine isokinetic strength and endurance, isometric strength, and anaerobic power for untrained healthy Saudi children and adolescents. The secondary purpose was to evaluate the effects of age in relation to anthropometric characteristics on strength and anaerobic performances. Forty-four (untrained) 11- to 19-year-old boys were grouped by age: 11-13 years, 14-16 years, and 17-19 years. All participants underwent anthropometric measurements, a flexibility test, a vertical jump test, a grip strength test, isokinetic strength measurements (Cybex Norm), and a Wingate anaerobic power test. One-way ANOVA results indicated age-related increases in muscle strength and power. High correlation coefficients that were found among age and strength and anaerobic power indices almost disappeared when fat-free mass (FFM) was controlled for, indicating that the amount of variance in these indices that was explained by age is mostly shared by FFM. In addition, stepwise linear regression models indicated that FFM was the main predictor of strength and power performances. Thus, FFM was the best scaling variable for body size when comparing these age groups of Saudis. Until wide-range normal representative values for isokinetic strength and anaerobic power for Saudi children and adolescents are available, the present study's results can serve as a reference for these indices.


[Arterial thrombotic complications in Crohn's disease].
In a series of 230 observations of Crohn's disease, the authors describe 4 cases of arterial thrombosis; two of them involving cerebral arteries. These complications occurred in young women without any notable risk factor for atheroma. All patients had highly active Crohn's disease when arterial thrombosis occurred: two of them had several episodes of thrombosis and three, extraintestinal manifestations. As the arterial thromboses are often severe, rarely foreseeable and the venous thromboses frequent, the point is whether to use anticoagulants. When Crohn's disease is highly active, but only if there are no hemorrhagic lesions, anticoagulants at prophylactic doses may be recommended. How to define more exactly a high risk thromboses population deserves further investigation.


Oxygen-limited continuous culture and respiratory energy conservation in Escherichia coli.
Escherichia coli B was cultured continuously in succinate-minimal medium under conditions of oxygen limitation in the phauxostat. With decreasing oxygenation and consequent decreasing growth rates, the complement of terminal cytochrome oxidases changed as follows: high growth rates, cytochrome o; intermediate growth rates, cytochromes o and d; lowest growth rates, cytochromes o, d, and a1. Respiratory kinetics exhibited by nongrowing cell suspensions obtained from continuous cultures indicated that terminal oxidase activity was exhibited by cytochrome o (Km for O2 = 0.2 micron; Vmax = 1.1 to 1.5 mumol of O2 per nmol of cytochrome o per min) and cytochrome d (Km for O2 = 0.024 micron; Vmax = 0.7 mumol of O2 per nmol of cytochrome d per min). During oxygen-limited growth, the molar growth yield referred to respiration, and corrected for maintenance respiration [Yo(max)], was 12.6 g (dry weight) per g-atom of oxygen, not significantly different from the succinate-limited value of 12.0 g (dry weight) per g-atom of oxygen. The rate of maintenance respiration of the oxygen-limited culture was only 3.4 mg-atoms of O per g (dry weight) per h, some threefold less than that of the succinate-limited culture. Respiration-driven proton extrusion did not vary with the growth rate or with the complement of terminal oxidases (H+/O = 3.7; standard deviation, 0.07). We conclude that the content of terminal oxidases is without effect on the efficiency of respiratory energy conservation.


Surveillance of West Nile virus disease, Tel Aviv district, Israel, 2005 to 2010.
We present the findings of a six-year surveillance period (2005–2010) of human West Nile virus (WNV) infection in Tel Aviv district, Israel. Initial notifications of positively identified patients received from the Central Virology Laboratory were followed by epidemiological investigations of the local district health office. During 2005–2010, 104 patients, 79 with WNV neuroinvasive and 25 with WNV non-neuroinvasive disease were reported. The median age of the patients with a neuroinvasive disease was 74 years (range: 15 to 95 years) and 53 of such patients had encephalitis, 14 had acute flaccid paralysis, and 12 had meningitis. The case-fatality rate in these patients was 8%. The average annual incidence of neuroinvasive disease during 2005–2010 was 1.08 per 100,000 population. The incidence declined by 86% steadily between 2005 and 2009 (p for trend=0.005), but increased by more than six-fold in 2010. Elderly (≥65 years) men, comprising 25 patients of whom 24 were chronically-ill, had the highest incidence of WNV encephalitis <0.001). These findings are concordant with previous data, at the national level, published in Israel and the United States. Notably, the percentage of previously healthy patients, who developed a neuroinvasive disease was the highest (37%, p=0.001) in the surveillance period in 2010.


Science in Emergency Response at CDC: Structure and Functions.
Recent high-profile activations of the US Centers for Disease Control and Prevention (CDC) Emergency Operations Center (EOC) include responses to the West African Ebola and Zika virus epidemics. Within the EOC, emergency responses are organized according to the Incident Management System, which provides a standardized structure and chain of command, regardless of whether the EOC activation occurs in response to an outbreak, natural disaster, or other type of public health emergency. By embedding key scientific roles, such as the associate director for science, and functions within a Scientific Response Section, the current CDC emergency response structure ensures that both urgent and important science issues receive needed attention. Key functions during emergency responses include internal coordination of scientific work, data management, information dissemination, and scientific publication. We describe a case example involving the ongoing Zika virus response that demonstrates how the scientific response structure can be used to rapidly produce high-quality science needed to answer urgent public health questions and guide policy. Within the context of emergency response, longer-term priorities at CDC include both streamlining administrative requirements and funding mechanisms for scientific research.


Zonulin, regulation of tight junctions, and autoimmune diseases.
Recent studies indicate that besides digestion and absorption of nutrients and water and electrolytes homeostasis, another key function of the intestine is to regulate the trafficking of environmental antigens across the host mucosal barrier. Intestinal tight junctions (TJs) create gradients for the optimal absorption and transport of nutrients and control the balance between tolerance and immunity to nonself antigens. To meet diverse physiological challenges, intestinal epithelial TJs must be modified rapidly and in a coordinated fashion by regulatory systems that orchestrate the state of assembly of the TJ multiprotein network. While considerable knowledge exists about TJ ultrastructure, relatively little is known about their physiological and pathophysiological regulation. Our discovery of zonulin, the only known physiologic modulator of intercellular TJs described so far, has increased our understanding of the intricate mechanisms that regulate the intestinal epithelial paracellular pathway and has led us to appreciate that its upregulation in genetically susceptible individuals leads to autoimmune diseases.


Effects of cholestyramine and diet on small intestinal histomorphometry in rats.
Reports on the effects of cholestyramine on small intestinal structure of rats have produced contradictory data about changes in mucosal histomorphometry, perhaps due to interacting effects of dietary composition. In order to identify effects of cholestyramine and diet on structure of the small intestines, 40 male rats were divided into 4 groups of 10 and fed 1 of each of the following diets for 1 month: standard diet, purified fiber-free diet, standard diet + 2% cholestyramine, or purified fiber-free diet + 2% cholestyramine. Serum concentrations of cholesterol and triglycerides were moderately increased in rats fed the purified fiber-free diet versus the standard diet. Neither total length nor weight of small intestine were affected by either diet or cholestyramine. Mucosal weight was affected by interactions between cholestyramine and diet, indicating that outcome depended upon modulating effects of both variables. Significant interactions were similarly detected among the variables of anatomic site, diet, and cholestyramine for many histomorphometric parameters of intestinal mucosa. Cholestyramine reduced total mucosal thickness in both jejunum and ileum and reduced villus height and villus:crypt ratio in the ileum.


Benign and malignant prostatic neoplasms: human studies.
Because the present ability to treat and cure patients with prostate cancer is limited to those patients with pathologically organ-confined disease, it has become increasingly important to diagnose this disease at an early stage, when cure is most likely. Recent advances in imaging may allow the urologist and the pathologist to make the diagnosis of prostate cancer much earlier in the natural course of the disease. It therefore becomes imperative to have methods available to predict which patients have a high probability of progressing so that treatment can be assigned logically and appropriately. Our current methods of prognosis determination (stage and grade) do not allow accurate assessment of tumor behavior in the majority of individual patients with prostate cancer. Therefore, more accurate quantification of nuclear and cellular changes that take place as a tumor progresses to take on the aggressive (metastatic) phenotype are urgently needed. Experimental techniques have proven useful in answering these questions and now seem ready for large-scale testing in clinical studies.


Neuroprotective effect of neuroserpin in oxygen-glucose deprivation- and reoxygenation-treated rat astrocytes in vitro.
Neuroserpin (NSP) reportedly exerts neuroprotective effects in cerebral ischemic animal models and patients; however, the mechanism of protection is poorly understood. We thus attempted to confirm neuroprotective effects of NSP on astrocytes in the ischemic state and then explored the relative mechanisms. Astrocytes from neonatal rats were treated with oxygen-glucose deprivation (OGD) followed by reoxygenation (OGD/R). To confirm the neuroprotective effects of NSP, we measured the cell survival rate, relative lactate dehydrogenase (LDH) release; we also performed morphological methods, namely Hoechst 33342 staining and Annexin V assay. To explore the potential mechanisms of NSP, the release of nitric oxide (NO) and TNF-α related to NSP administration were measured by enzyme-linked immunosorbent assay. The proteins related to the NF-κB, ERK1/2, and PI3K/Akt pathways were investigated by Western blotting. To verify the cause-and-effect relationship between neuroprotection and the NF-κB pathway, a NF-κB pathway inhibitor sc3060 was employed to observe the effects of NSP-induced neuroprotection. We found that NSP significantly increased the cell survival rate and reduced LDH release in OGD/R-treated astrocytes. It also reduced NO/TNF-α release. Western blotting showed that the protein levels of p-IKKBα/β and P65 were upregulated by the OGD/R treatment and such effects were significantly inhibited by NSP administration. The NSP-induced inhibition could be significantly reversed by administration of the NF-κB pathway inhibitor sc3060, whereas, expressions of p-ERK1, p-ERK2, and p-AKT were upregulated by the OGD/R treatment; however, their levels were unchanged by NSP administration. Our results thus verified the neuroprotective effects of NSP in ischemic astrocytes. The potential mechanisms include inhibition of the release of NO/TNF-α and repression of the NF-κB signaling pathways. Our data also indicated that NSP has little influence on the MAPK and PI3K/Akt pathways.


[Carcinogenicity of fuchsin derivatives].
White noninbred rats and linear mice were injected leucoparafuchsine and leucofuchsine isomers subcutaneously and received perorally during the whole life period, while in the experiments on mice--also by means of cutaneous application. The injection of leucoparafuchsine in rats and mice CC57Br resulted in the increased development of hemopoietic system tumors. Leucofuchsine isomers injected in rats and mice C3HA gave rise to the appearance of renal tumors in these animals and caused more frequent development of hepatic and pulmonary neoplasms in mice. In leucoparafuchsine injections the rate of tumors incidence was 35% in rats and in mice--20%, in the experiments with leucofuchsine isomers--33% and 40% accordingly. The results of the experiments evidence an insignificant blastomogenic effect of the compounds under study.


Health- and disease-associated species clusters in complex natural biofilms determine the innate immune response in oral epithelial cells during biofilm maturation.
The aim of the present study was to verify our hypothesis concerning the differential induction of various antimicrobial and immunomodulatory responses in oral epithelial cells by diverse bacterial species clusters. For this purpose, oral biofilms between 1 and 14 days of maturation (36 volunteers) were co-incubated with gingival epithelial cells. Subsequently, human β-defensin (hBD)-2, hBD-3, LL-37, interleukin (IL)-1β, IL-6, IL-8 and IL-10 mRNA expression profiles were quantified by quantitative reverse transcription PCR. The correlation between bacterial species and the host innate immune response was determined by relating these results to existing 16S rRNA phylogenetic analysis by amplicon sequencing (Langfeldt et al. 2014. PLoS One 9: e87449). Data were analysed by multiple factor analysis. Transcription of hBD-2 and hBD-3 was significantly associated with the abundance of species of the Prevotella cluster and the absence of species of the Streptococcus cluster. IL-1β, -6, -8 and -10 mRNA syntheses were significant correlated with Leptotrichia species [Leptotrichia 302H02 (0.448, P < 0.0001), Leptotrichia nbw822e09c1 (0.214, P = 0.008) and Leptotrichia wadei (0.218, P = 0.007)] of the Prevotella cluster. In the third dimension IL-10 and members of the Prevotella cluster were negatively correlated, whereas hBD-3 and IL-1β, IL-6 and IL-8 were positive correlated to axis 3, like members of the Proteobacteria cluster. In conclusion, distinct species of health- and disease-associated bacterial clusters induce antibacterial or immunomodulatory reactions in oral epithelial cells during early stages of bacteria-host interactions.


Effects of maternal absence due to employment on the quality of infant-mother attachment in a low-risk sample.
Recent reports have suggested that day-care experience initiated prior to 12 months of age is associated with increased proportions of infants whose attachment to mother is classified as "insecure-avoidant." However, reviewers have questioned the generality of these findings, noting that samples in which associations between early day-care experience and avoidant attachment patterns have been reported come from high-risk populations, and/or that the infants' day-care settings may not have been of high quality. In the present study, effects of maternal absences on infant-mother attachment quality were assessed in a low-risk, middle-class sample (N = 110). In all instances, substitute care had been initiated at least 4 months prior to the infant's first birthday and was provided in the infant's home by a person unrelated to the baby. Infants were assessed using the Ainsworth Strange Situation when they were 12-13 months of age. Analyses indicated that a significantly greater proportion of infants whose mothers worked outside the home (N = 54) were assigned to the category "insecure-avoidant" as compared to infants whose mothers remained in the home (N = 56) throughout the first year of life. Analyses of demographic and psychological data available for the sample indicated that this relation is dependent upon maternal parity (primi- vs. multiparous mother). The association between attachment quality and work status was significant only for firstborn children of full-time working mothers. The results are interpreted as evidence that the repeated daily separations experienced by infants whose mothers are working full-time constitute a "risk" factor for the development of "insecure-avoidant" infant-mother attachments.


Physical Interaction of T Cells with Dendritic Cells Is Not Required for the Immunomodulatory Effects of the Edible Mushroom Agaricus subrufescens.
Mushrooms are well known for their immunomodulating capacities. However, little is known about how mushroom-stimulated dendritic cells (DCs) affect T cells. Therefore, we investigated the effect of mushroom compounds derived from seven edible mushroom species on DCs, their fate in DCs, and the effect of the mushroom-stimulated DCs on T cells. Each mushroom species stimulated DCs in a different manner as was revealed from the DC's cytokine response. Assessing DC maturation revealed that only one mushroom species, Agaricus subrufescens, induced complete DC maturation. The other six mushroom species upregulated MHC-II and CD86 expression, but did not significantly affect the expression of CD40 and CD11c. Nevertheless, mushroom compounds of all investigated mushroom species are endocytosed by DCs. Endocytosis is most likely mediated by C-type lectin receptors (CLRs) because CLR binding is Ca2+ dependent, and EGTA reduces TNF-α secretion with more than 90%. Laminarin partly inhibited TNF-α secretion indicating that the CLR dectin-1, among other CLRs, is involved in binding mushroom compounds. Stimulated DCs were shown to stimulate T cells; however, physical contact of DCs and T cells is not required. Because CLRs seem to play a prominent role in DC stimulation, mushrooms may function as a carbohydrate containing adjuvant to be used in conjunction with anti-fungal vaccines.


Speaking and breathing in high respiratory drive.
Pulmonary ventilation during speech breathing reflects the sum of the airflow changes used to speak and to meet the metabolic needs of the body. Studying interactions between speaking and breathing may provide insights into the mechanisms of shared respiratory control. The purposes of this study were to determine if healthy subjects exhibit task-specific breathing behaviors in high respiratory drive and to document subjects' perceptions during breathing and speaking under these conditions. Ten men were studied in air and high CO2. Magnetometers were used to estimate lung volume, rib cage and abdomen volumes, minute volume, breathing frequency, tidal volume, inspiratory and expiratory duration, and inspiratory and expiratory flow. Subjects' perceptions were assessed informally. Results indicated that the chest wall kinematic behaviors associated with breathing and speaking in high drive were similar in pattern but differed in the magnitudes of lung volume and rib cage volume events and in inspiratory and expiratory flow. Linguistic influences remained strong, but not as strong as under normal conditions. All subjects reported a heightened sense of breathing-related discomfort during speaking as opposed to breathing in high respiratory drive. We conclude that in healthy subjects breathing behavior associated with speaking in high respiratory drive is guided continuously by shared linguistic and metabolic influences. A parallel-processing model is proposed to explain the behaviors observed.


Formaldehyde in pathology departments.
Toxic effects of formaldehyde in humans are discussed in relation to occupational exposure and tolerance to this agent. Carcinogenic and mutagenic properties of formaldehyde have been reported in animals and this has led to concern about a possible role in human cancer. The current state of affairs is reviewed in the light of a lack of direct evidence linking formaldehyde with cancer in man and in relation to recommended exposure levels. It is important to employ effective means of containment and practical methods for reducing exposure to formaldehyde in pathology departments and post-mortem rooms are described.


Discovery and Development of Pregabalin (Lyrica): The Role of Public Funding.
Pregabalin (Lyrica), a widely used drug that has generated billions in revenue as a treatment for diabetic neuropathy and other conditions, was originally discovered in an academic medical center, largely supported by public funding. We aimed to define the extent of direct federal public funding that contributed to various stages of pregabalin's development prior to US Food and Drug Administration (FDA) approval. We identified key research, scientists, and organizations involved in the development of pregabalin from its discovery through FDA approval. Using key terms (e.g., its indications and mechanism of action), we searched PubMed for relevant publications and determined whether each publication was based on federal public funding using the NIH RePORTER. For each award prior to the drug's FDA approval, we scored its potential relatedness to pregabalin's development based on its title, investigator, and organization, and then examined descriptions of the most relevant awards to aid in defining these relationships. The budgets for all related awards were converted to 2020 dollars. Pregabalin was discovered largely on the basis of publicly funded research at Northwestern University; in 1990, it was licensed to Parke-Davis, which further developed it through its FDA approval in 2004. Most key terms were related to the drug and drug target (n = 5) and organizations involved (n = 5), followed by patent-listed inventors (n = 3). These key terms linked 6,438 core project awards and we identified 37 NIH awards related to pregabalin's development: 9 awards through 1990 ($3.3 million) and 28 from 1991 through 2004 ($10.5 million). Like that of many other widely sold medications, the development of pregabalin relied on public sector as well as industry contributions to its discovery, with relevant NIH awards totaling $13.8 million during its preapproval development.


Clinical trial of povidone-iodine (Betadine) versus placebo in the pretreatment of corneal ulcers.
To investigate antimicrobial effectiveness of povidone-iodine (Betadine) in reducing bacterial load of corneal ulcers before patients were given antibiotics. Patients with corneal ulcers were randomized to Betadine or placebo group. Ulcers were cultured before and after a 10-minute application of 5% Betadine or preservative-free artificial tears. All patients were then treated with standard antibiotic medications. The number of colony-forming units before and after Betadine or placebo was compared. Eighteen patients were randomized to Betadine and 17 to placebo group. In the Betadine group, 8 (44%) of 18 ulcers were culture-positive, either before and/or after pretreatment, and in the control group, 9 (53%) of 17 were culture positive. There was No statistical difference in colony-forming units change after Betadine versus artificial tears application was detected (P-value = 0.16, t-test). In Betadine group, 3 (17%) of 18 of patients showed improvement, ie, had fewer colonies after drop application; and in the placebo group, 7 (41%) of 17 showed improvement, (P = 0.15, Fisher exact t test.) A single application of 5% Betadine did not reduce the bacterial load of corneal ulcers more than just scraping/rinsing alone. This is likely the result of the lack of penetration deep into the corneal stroma and number of organisms present. Other factors may be involved.


Effects of Integrating Care for Medicare-Medicaid Dually Eligible Seniors in Minnesota.
Individuals dually eligible for Medicare and Medicaid often receive fragmented and inefficient care. Using Minnesota fee-for-service claims, managed care encounters, and enrollment data for 2010-2012, we estimated the likely impact of Minnesota Senior Health Option (MSHO)-seen as the first statewide fully integrated Medicare-Medicaid model-on health care and long-term services and supports use, relative to Minnesota Senior Care Plus (MSC+), a Medicaid-only managed care plan with Medicare fee for service. Estimates suggest that MSHO enrollees had significantly higher use of primary care and, potentially, of community-based services, combined with lower use of hospital-based care than similar MSC+ enrollees. Adopting fully integrated care models like MSHO may have merit in other states.


Activity of the triazole SCH 56592 against disseminated murine coccidioidomycosis.
SCH 56592 (SCH) is a new triazole antifungal with a broad spectrum of activity. In vitro susceptibility testing against five strains of Coccidioides immitis revealed MICs from 0.39 to 3.13 microg/ml and minimal fungicidal concentrations from 1.56 to 3.13 microg/ml. A murine model of systemic coccidioidomycosis was established in female CD-1 mice. Groups received either no treatment or oral therapy with fluconazole at 10 or 100 mg/kg of body weight; itraconazole at 10 or 100 mg/kg; SCH at 0.5, 2, 10, or 25 mg/kg; or its methylcellulose diluent alone. Therapy began 2 days postinfection and continued once daily for 19 days. Surviving mice were euthanized 49 days postinfection, and infectious burdens were determined by culture. All drugs were superior to no-treatment or diluent-treatment controls (P < 0.001) in prolonging survival but were not significantly different from one another. Itraconazole at 100 mg/kg was superior to fluconazole in reduction of CFU in the spleen, liver, and lung (P < 0.01 to 0.001). SCH at 0.5 mg/kg was superior to either fluconazole or itraconazole at 10 mg/kg in reduction of CFU in all three organs (P < 0.05 to 0.001). SCH at 2 mg/kg was not significantly different from itraconazole at 100 mg/kg in all three organs. SCH at 10 and 25 mg/kg was superior to either dose of fluconazole or itraconazole in all three organs (P < 0.05 to 0.001). In terms of reduction of CFU, SCH was > or = 200-fold as potent as fluconazole and > or = 50-fold as potent as itraconazole. There was a clear dose-responsive relationship for SCH in each of the organs. It is noteworthy that SCH effected cures (no detectable C. immitis in any organ) in 1 of 9, 6 of 10, or 9 of 9 surviving mice in animals given 2, 10, or 25 mg/kg, respectively. Neither fluconazole nor itraconazole cured any survivor. SCH has potent, fungicidal activity in vivo against C. immitis. It should be considered for clinical trials in patients with coccidioidomycosis.


Nontesticular cancers in relatives of testicular germ cell tumor (TGCT) patients from multiple-case TGCT families.
Testicular germ cell tumors (TGCT) exhibit striking familial aggregation that remains incompletely explained. To improve the phenotypic definition of familial TGCT (FTGCT), we studied an international cohort of multiple-case TGCT families to determine whether first-degree relatives of FTGCT cases are at increased risk of other types of cancer. We identified 1041 first-degree relatives of TGCT cases in 66 multiple-case TGCT families from Norway and 64 from the United States (combined follow-up of 31,556 person-years). We collected data on all cancers (except nonmelanoma skin cancers) reported by the family informant in these relatives, and we attempted to verify all reported cancer diagnoses through medical or cancer registry records. We calculated observed-to-expected (O/E) standardized incidence ratios, together with 95% confidence intervals (CI), for invasive cancers other than TGCT. We found no increase in risk of cancer overall (Norway O/E = 0.8; 95% CI: 0.6-1.1 and United States O/E = 0.9; 95% CI: 0.7-1.3). Site-specific analyses pooled across the two countries revealed a leukemia excess (O/E = 6.5; 95% CI: 3.0-12.3), deficit of female breast cancer (O/E = 0.0; 95% CI: 0.0-0.6) and increased risk of soft tissue sarcoma (O/E = 7.2; 95% CI: 2.0-18.4); in all instances, these results were based on small case numbers and statistically significant only in Norway. While limited by sample size and potential issues relating to completeness of cancer reporting, this study in multiple-case TGCT families does not support the hypothesis that cancers other than testis cancer contribute to the FTGCT phenotype.


Localization of lower gastrointestinal hemorrhage. Experience with red blood cells labeled in vitro with technetium Tc 99m.
Seventy-six patients clinically suspected of having lower gastrointestinal bleeding were studied by scintigraphy utilizing red blood cells labeled in vitro with technetium Tc 99m. Sixteen patients required emergency surgery; bleeding was accurately localized in 15 (94%). One patient (6%) had a normal scan. A 20-month mean follow-up of the 16 patients showed no recurrent bleeding. Of 60 patients not requiring emergency surgery, bleeding was localized in 11, but the bleeding ceased. Forty-nine of the 60 patients had normal scans and had no further hemorrhaging during hospitalization. A 21-month mean follow-up of 38 of the 49 patients showed no further bleeding episodes or surgical procedures in 29 patients; however, eight patients required surgical procedures, including seven for gastrointestinal malignancies. Scanning of red blood cells labeled in vitro with 99mTc is accurate and efficacious in localization of bleeding sites that require emergency surgery for lower gastrointestinal hemorrhage.


Fractal-like distributions over the rational numbers in high-throughput biological and clinical data.
Recent developments in extracting and processing biological and clinical data are allowing quantitative approaches to studying living systems. High-throughput sequencing (HTS), expression profiles, proteomics, and electronic health records (EHR) are some examples of such technologies. Extracting meaningful information from those technologies requires careful analysis of the large volumes of data they produce. In this note, we present a set of fractal-like distributions that commonly appear in the analysis of such data. The first set of examples are drawn from a HTS experiment. Here, the distributions appear as part of the evaluation of the error rate of the sequencing and the identification of tumorogenic genomic alterations. The other examples are obtained from risk factor evaluation and analysis of relative disease prevalence and co-mordbidity as these appear in EHR. The distributions are also relevant to identification of subclonal populations in tumors and the study of quasi-species and intrahost diversity of viral populations.


Computed tomographic features of portal vein thrombosis in two cats with splenosystemic shunts.
Two spayed female cats presented with hepatic encephalopathy due to hyperammonaemia. On abdominal ultrasound, concurrent portal vein thrombosis and splenosystemic shunts were suspected in both cats. Computed tomographic angiography clearly detected thrombi as non-contrast enhancing intraluminal structures in the main portal vein of both cats. Additionally, splenorenal shunts were revealed in both cats. Follow-up computed tomographic angiography for portal vein thrombosis was performed in both cats, only one of whom received anticoagulant therapy. In the untreated cat, portal vein thrombosis had progressed with the development of an aberrant tortuous vessel. In the cat treated with low-molecular-weight heparin, the thrombus progressively decreased in size and disappeared on follow-up diagnostic imaging. Computed tomographic angiography might be useful for the diagnosis and follow-up of portal vein thrombosis in cats.


Dacarbazine in the management of metastatic melanoma in the era of immune checkpoint therapy: a valid option or obsolete?
Despite the dramatic improvement in both overall survival (OS) and progression-free survival (PFS) in patients with metastatic melanoma treated with immune checkpoint inhibitors, up to 60% will develop treatment resistance and 50% will die from their disease. Therefore, although dacarbazine is no longer a mainstay of modern melanoma management, we examined the extent to, and in which context, it may still play a role. A retrospective analysis of electronic medical records of patients who had received dacarbazine treatment between October 2014 and October 2021, following innate or acquired resistance to immune checkpoint inhibitors, was performed to determine PFS and OS and examine tolerability. Nine patients with locally advanced ( n = 1) or metastatic melanoma ( n = 8) were identified (average age: 74 years, 4 males and 5 females). The number of cycles of dacarbazine ranged from 2 to 45 (mean = 12). One-third of patients developed a complete ( n = 2) or partial ( n = 1) response, two-thirds did not respond to treatment. The median PFS time was 90 days. Common adverse events included blood dyscrasias; one patient developed a grade 3 hepatitis, although it was unclear if this was due to the chemotherapy or the preceding combined immunotherapy. Dacarbazine may still be a valid option in the setting of treatment for refractory, relapsed, or progressive disease. Future studies should focus on the immunomodulatory effects of dacarbazine on the tumor microenvironment, which could be harnessed to potentially restore sensitivity to immune checkpoint-based therapy.