A process mining- deep learning approach to predict survival in a cohort of hospitalized COVID-19 patients.

BACKGROUND: Various machine learning and artificial intelligence methods have been used to predict outcomes of hospitalized COVID-19 patients. However, process mining has not yet been used for COVID-19 prediction. We developed a process mining/deep learning approach to predict mortality among COVID-19 patients and updated the prediction in 6-h intervals during the first 72 h after hospital admission. METHODS: The process mining/deep learning model produced temporal information related to the variables and incorporated demographic and clinical data to predict mortality. The mortality prediction was updated in 6-h intervals during the first 72 h after hospital admission. Moreover, the performance of the model was compared with published and self-developed traditional machine learning models that did not use time as a variable. The performance was compared using the Area Under the Receiver Operator Curve (AUROC), accuracy, sensitivity, and specificity. RESULTS: The proposed process mining/deep learning model outperformed the comparison models in almost all time intervals with a robust AUROC above 80% on a dataset that was imbalanced. CONCLUSIONS: Our proposed process mining/deep learning model performed significantly better than commonly used machine learning approaches that ignore time information. Thus, time information should be incorporated in models to predict outcomes more accurately.

[Infant mortality in Germany (2008-2012)--lower in the former German Democratic Republic?]. / Säuglingssterblichkeit in Deutschland (2008-2012)--niedriger im Osten?

BACKGROUND: German infant mortality is ranked near the median of European countries. In Germany infant mortality is significantly higher in the German Federal Republic compared with the former German Democratic Republic. This is often used as reason for a call for structural requirements and minimum caseload for the care for very low birth weight infants. METHOD: Neonatal and infant mortality were calculated for the 16 German federal states with data from the German statistical federal office for the years 2008-2012. RESULTS: Considerable variations were found for the neonatal (1.34-3.61‰, total Germany 2.31‰) and the infant (2.38-5.20‰, 3.47‰) mortality. The rate of stillborn infants was 3.56‰. A lower neonatal mortality in the former German Democratic Republic (1.62‰ vs. 2.44‰, p<0.0001, Chi-squared test) could not be confirmed for preterm infants with birth weight less than 1 500 g. In the former German Democratic Republic stillbirth was significantly more frequent in preterm infants with birth weight 500-999 g (p<0.0001). Combined stillbirth and neonatal mortality showed no difference between the German Federal Republic and former German Democratic Republic (5.45‰ and 5.29‰, respectively, n.s.; infants less than 500 g birth weight were excluded). The average number of preterm infants per perinatal centre and federal state had no influence on state specific neonatal mortality. CONCLUSION: If stillborn infants were accounted for no difference was found between the German Federal Republic and the former German Democratic Republic regarding mortality. Comparing infant mortality of different countries has to account for stillborn infants. Considerable variation of neonatal mortality is persisting throughout Germany despite structural requirements and introduction of a minimum caseload since 2005. A lower infant mortality in the former German Democratic Republic and implications drawn from are not supported by the presented nationwide data from the German statistical federal office.

Computed tomography (CT) colonography with CT arteriography and venography for the workup of intestinal transplant candidates.

Prior to intestinal transplantation, prospective candidates must undergo a series of radiologic examinations to address a variety of clinical issues. To date, little literature exists to guide physicians in this preoperative assessment. Multiple imaging studies can provide overlapping information. We have developed a simple two- or three-test protocol to streamline the workup. Sixteen adult patients presented as potential intestinal transplant candidates to Georgetown University Hospital. All but two patients underwent the full protocol of a biphasic IV contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis with rectal carbon dioxide, an upper gastrointestinal study with small bowel follow through, and fistulogram when appropriate. Three-dimensional (3-D) reconstructions of the vascular anatomy as well as the colon were also generated. A telephone survey to other transplant centers was additionally conducted to compare radiographic evaluations. Overall, 15 of the 16 scans were diagnostic. One patient required a barium enema. Mean examinations per patient was 2.4. Only one of seven other centers was performing CT colonography in prospective intestinal transplant candidates. Our protocol provided all the necessary anatomic information needed to evaluate prospective transplant candidates. CT colonography with angiography is a suitable alternative to more time-consuming radiological studies.

Calcium and phosphor intake in preterm infants: sensitivity and specifity of 6-hour urine samples to detect deficiency.

Aim of the present study was to test whether six-hour (6 h) urine specimens predict the 24-hour (24 h) mineral homeostasis in individual infants born preterm. Urinary Calcium (Ca) and Phosphate (P) concentrations were studied in 60 stable infants; gestational age 34 (25-42) weeks. In 58 infants four 6 h urine specimens and in 2 infants all spot urine specimens obtained within 24 h were analyzed. In 39 infants born preterm coefficients of variation were 0.42 (SD 0.26) and 0.41 (SD 0.26) for Ca and P measurements in the four 6 h urine specimens obtained within 24 h, respectively, The mineral homeostasis of the infants was defined as Ca or P surplus homeostasis if the 24 h urinary concentrations were ≥1 mmol/l. The sensitivity, specificity, and PPV of a 6 h urinary specimen to predict Ca deficiency homeostasis (24 h urinary Ca <1 mmol/l) were 0.93 (0.77-0.98; 95%CI), 0.72 (0.43-0.90) and 0.90 (0.74-0.96). The sensitivity, specificity and PPV for urinary P were 0.8 (0.38-0.96), 0.97 (0.85-0.995), and 0.8 (0.38-0.96). In conclusion, in infants born preterm on regular 3 or 4 h feedings, 6 h urine sampling is sufficiently precise for prediction of Ca and P mineral deficiency homeostasis (PPV 0.92 and 0.83). However, measurements at regular intervals (twice weekly) are recommended not to miss any infant in mineral deficiency homeostasis.

[Current outcome quality in the care of preterm infants with birth weight less than 1 500 g as a basis for regionalisation of risk pregnancies]. / Aktuelle Ergebnisqualität der Versorgung von Frühgeborenen <1 500 g Geburtsgewicht als Grundlage für eine Regionalisierung der Risikogeburten.

BACKGROUND: For preterm infants an association between patient volume and mortality has been described. METHODS: Outcome variables were evaluated for 28 hospitals in Baden-Württemberg for the years 2004-2008. Hospitals with high patient volume were compared to hospitals with a lower patient volume. RESULTS: Outcomes for 1 164 infants in 2008 and for 4 775 infants in 2004-2008 were analysed. In 2008, mortality of preterm infants less than 32 weeks gestational age (GA) was 9.2% (n=402) in the 5 major hospitals compared to 6.5% (n=520) in the other hospitals (combined mortality 7.7%, n. s., chi-square test). In the years 2004-2008, mortality showed a greater variation in hospitals with a patient volume below 50 and mean mortality was 21.1% higher for infants less than 500 g BW. Hospitals with a patient volume >or= 50 had a lower mortality for infants with BW below 500 g and between 500 g and 749 g (18% and 11%, chi-square test: p<0.05 and <0.01, respectively). For preterm infants with GA below 24 weeks and between 24 and 25 weeks, patient volume and mortality were negatively correlated (p<0.01 and <0.0001, respectively). For infants with a BW >or= 750 g or a GA >or= 26 weeks patient volume had no effect on outcome. CONCLUSION: Regionalisation of preterm infants with BW less than 750 g and a GA less than 26 weeks may contribute to reduce mortality. Infants with BW >or= 750 g and a GA >or= 26 weeks may not benefit from indirect quality indicators such as patient volume.

[Thoracic alterations after surgical closure of the ductus arteriosus botallo in preterm infants]. / Thoraxveränderungen nach operativem Ductus-arteriosus-Botallo-Verschluss bei Frühgeborenen.

BACKGROUND: Left-sided thoracotomy for ligation of patent ductus arteriosus (PDA) dissects the musculus latissimus dorsi and notches a small part of the musculus trapezius. After ductal closure the 4 (th) and 5 (th) rib are adapted. This follow-up study investigated if mid- or long-term consequences on the thorax occur after this procedure. PATIENTS AND METHODS: Status of the thoracic scar, functionality of the shoulder and presence of scapulata alata or scoliosis was evaluated at median age of 6 years (range: 2.9-11.9) in 57 pre-term infants (30 male; gestational age 26 weeks (24-32); birth weight 805 g (450-2140)). RESULTS: Scoliosis was diagnosed in 1 patient (=1.8%) with Rubinstein-Taybi syndrome. The length of the thoracic scar (13.8 cm; 9.4-25.5) correlated with the patient's age (r=0.61; p=0.001). The scar was relocatable except for one case. The distance of the ventral end of the scar to the nipple was 2 cm or less in 22% of the female patients. None of the patients showed impaired function of the shoulder. Scapula alata was found in 16 (28%) patients. CONCLUSION: Thoracotomy for PDA ligation was not associated with an increased risk for scoliosis or disturbed function of the shoulder. One quarter of all infants developed scapula alata which meant an aesthetic issue for some parents.

Effect of oestradiol and progesterone replacement on bronchopulmonary dysplasia in extremely preterm infants.

OBJECTIVE: To study whether postnatal replacement of oestradiol and progesterone may help to prevent bronchopulmonary dysplasia (BPD). METHODS: This randomised placebo-controlled double-blind study enrolled 83 infants of <29 weeks gestational age and 1000 g birth weight requiring mechanical ventilation within 12 h after birth. Oestradiol (2.5 mg/kg/day) and progesterone (22.5 mg/kg/day) were given by continuous intravenous infusion of a standard lipid emulsion (15 ml/kg/day) in the replacement group (ESTRA-PRO). The placebo group received the same lipid emulsion without oestradiol or progesterone. A replacement period of at least 2 weeks but not >4 weeks was strived for and defined as "according to protocol". The primary outcome variable was the incidence of BPD or death. RESULTS: The median birth weight was 670 g (min-max 400-990 g) and the gestational age 25 weeks (23.1-28.1 weeks). The incidence of BPD or death was 48% in the placebo group and 44% in the ESTRA-PRO group (p = 0.38, one-sided testing, intention to treat analysis). In infants treated according to protocol, 32% (9 of 28) in the placebo group and 14% (3 of 21) in the ESTRA-PRO group developed BPD (p = 0.08). CONCLUSION: Replacement of oestradiol and progesterone was not effective for prevention of BPD or death in extremely preterm born infants. Better-powered trials are needed to evaluate this new approach.

Late response to radiochemotherapy in pediatric glioblastoma: report on two patients treated according to HIT-GBM protocols.

High-grade gliomas in children are rare and the best treatment is undetermined. The German language group study HIT-GBM compares various induction protocols for subsequent patient cohorts. Currently, cisplatinum, etoposide, ifosfamide, and vincristine are given simultaneously with extended-field radiotherapy. Imaging is done 3 weeks after to define treatment response, followed by 6-weekly controls during consolidation with lomustine, vincristine, and prednisone. The authors report on 2 patients with incompletely resected glioblastoma multiforme in which response was lacking 3 weeks after radiochemotherapy but became evident 12 weeks later. This suggests that later time points are required to assess induction protocol response.

Effects of postnatal estradiol and progesterone replacement in extremely preterm infants.

The fetus is supplied from the placenta with estradiol (E2) and progesterone (P) in increasing amounts during gestation. After delivery of a premature infant, placental supply is disrupted, resulting in a rapid decrease in E2 and P. Replacement of these placental hormones may restore intrauterine conditions and may be beneficial for bone mineral accretion, clinical course, and outcome. Thirty female infants with a median gestational age of 26.6 weeks (between 24.1-28.7) and a birth weight of 675 g (370-990) were randomized to receive E2 and P replacement, aiming to maintain plasma levels equaling the intrauterine levels, or no replacement. The E2 and P replacement was started iv and was followed by transepidermal administration for a total duration of 6 weeks. Repeated measurements included plasma levels of E2, P, FSH, and LH; uterine volume; calcium and phosphorus in spot urine specimens; and bone mineral accretion by single photon absorption densitometry. Further, the incidence of chronic lung disease and various clinical outcome data were recorded. The plasma levels of E2 and P were within the intrauterine range with median replacements of 2.30 mg/kg x day E2 (1.13-6.23) and 21.20 mg/kg x day P (11.23-27.36), iv. Three- and 6-fold higher doses of E2 and P were needed via the transepidermal route. The uterine volumes increased, and FSH and LH as indicators for biological effectiveness were significantly lowered with replacement. The bone mineral accretion rates tended to be higher, and the incidence of chronic lung disease tended to be lower (0% vs. 29%; P = 0.097). E2 and P replacement via iv and transepidermal routes is capable of maintaining plasma levels as high as those in utero with biological effectiveness. Trends toward improved postnatal bone mineral accretion and less chronic lung disease were found with the hormone replacement. Further and more extensive studies are warranted to address the role of this new approach in the care of extremely premature infants.

Follow-up examination at the age of 15 months of extremely preterm infants after postnatal estradiol and progesterone replacement.

A randomized controlled pilot study was performed with a sample of extremely preterm infants to evaluate the impact of postnatal estradiol and progesterone replacement on postnatal bone mineral accretion. Twenty-five of 30 infants in the pilot study survived, and of these, 24 infants were available for the follow-up examination at a median chronological age of 18.1 months (minimum-maximum, 17.0--20.6) corresponding to a corrected age of 14.8 months (minimum-maximum, 12.9--17.4). Somatic growth data and bone mineralization showed no differences between the hormone-treated and control group infants. The deviation of the skeletal age from the corrected age was 0.0 months (minimum-maximum, -7.7 to 7.4) for hormone-treated infants compared with -1.7 months (minimum-maximum, -7.5 to 5.9) for the control group. The Bayley scales mental and psychomotor developmental indexes were 89 (minimum-maximum, 71--107) and 101 (minimum-maximum, 49--121) for the hormone-treated infants and 93 (minimum-maximum, 49--111) and 71 (minimum-maximum, 49--121) for the control group infants, respectively (mental developmental index, P = 1.0; psychomotor developmental index, P = 0.14). The normal psychomotor development in the hormone-treated infants compared with the below average development in the control group infants is encouraging and indicates the potentially important integrative role of sex steroids for the developing brain. Larger studies on the effects of the postnatal replacement of estradiol and progesterone in extremely preterm infants are warranted.

Interleukin-2 binding proteins in sera from normal subjects and multiple sclerosis patients.

We previously reported elevations of interleukin 2 (IL-2) in the serum of patients with chronic progressive MS. Using gel chromatography, protein A sepharose affinity chromatography, and ELISAs for IL-2 and the IL-2 soluble receptor, we now demonstrate that this cytokine is bound to serum proteins. These serum proteins include antibodies to IL-2, soluble IL-2 receptors, and high-molecular-weight proteins. Using a CTLL cell assay, a serum fraction corresponding to IgG antibodies to IL-2 inhibited the activity of this cytokine. Thus, we present evidence for potential immunomodulation of a pivotal cytokine in MS by serum proteins.

T cell recognition of myelin proteolipid protein and myelin proteolipid protein peptides in the peripheral blood of multiple sclerosis and control subjects.

Myelin proteolipid protein (PLP) is a prime candidate autoantigen for multiple sclerosis. In order to define potential immunodominant epitopes, T cell lines (TCL) from the peripheral blood of HLA-DR 15(2) MS patients were established which responded to the intact molecule of PLP. These TCL were then tested in individual proliferation assays with a variety of PLP peptides spanning most of the PLP molecule. Multiple peptides were recognized by TCL from the MS population, with more than one peptide often recognized by lines from the same individual. Three immunodominant peptides were identified which were recognized by the majority of MS patients. Estimated frequency analyses were then performed on the peripheral blood of HLA-DR15(2)-positive MS and control subjects using TCL initiated by the three immunodominant peptides, 40-60, 95-117, and 185-206. TCL from HLA-DR15 MS subjects recognized peptide 95-117 significantly more often than TCL from control subjects.

Management of the extremely preterm infant: is the replacement of estradiol and progesterone beneficial?

This review presents data to suggest that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants. During pregnancy, maternal plasma levels of estradiol and progesterone increase up to 100-fold compared to the nonpregnant status. The fetus is also exposed to these increasing hormone levels. After delivery, estradiol and progesterone levels drop by a factor of 100 within 1 day. Whereas this is a physiological condition for an infant born at term, preterm delivery means withdrawal from the placental supply of these hormones at an earlier developmental stage. Seventy years ago, the idea was raised that preterm infants may benefit from the replacement of estrogens. Studies in which estrogen was injected subcutaneously showed only a slightly better bodyweight gain compared to placebo-treated controls and therefore routine use was not established. The effective treatment of postmenopausal osteoporosis with hormone replacement therapy led to a pilot study of estradiol and progesterone therapy to prevent osteopenia of prematurity. The highest median bone mineral accretion rate was found in the replacement group when the supplementation with calcium and phosphorus was also sufficient. None of the previous studies dealing with estrogen replacement controlled for achieved plasma levels of estradiol in the infants. In our controlled randomised pilot study with 30 preterm infants (15 in each group), we aimed to maintain intra-uterine plasma levels of estradiol and progesterone. Preterm infants with replacement of estradiol and progesterone for 6 weeks postnatally showed trends to higher bone mineral accumulation. In addition, a trend towards a lower incidence of chronic lung disease was found. Neurodevelopmental follow-up showed normal psychomotor development in infants given estradiol and progesterone, whereas the untreated infants (controls) showed a trend towards delayed development. Recent research emphasises that estradiol and progesterone may be important for brain development. Thus, while there is data indicating that postnatal estradiol and progesterone replacement therapy may be beneficial in preterm infants, experience with this new therapy is limited and extensive research is needed to address the potential benefits and to rule out adverse effects.

Sex steroids in cardiopulmonary bypass.

BACKGROUND: Sex steroids have immunomodulatory effects. No data exist on alterations of sex steroids during cardiopulmonary bypass (CPB). Cardiac surgery with CPB releases an immunological response with complement and cytokine activation. RESULTS: Plasma estradiol and progesterone levels before and immediately after CPB were measured in 11 patients. During CPB, mean estradiol levels decreased from 29 to 15 pg/ml and progesterone levels rose from 0.13 to 0.90 ng/ml. These changes were statistically significant. CONCLUSIONS: These are the first preliminary results evaluating plasma levels of sex steroids during CPB. Whether alterations in estradiol and progesterone levels influence complement and cytokine activation during bypass or vice versa is currently being investigated.

Shear bond strength of a resin composite to enamel etched with maleic or phosphoric acid.

The purpose of this study was to evaluate the effect of 10 per cent maleic and 37 per cent phosphoric acid on the shear bond strength of Z100 composite resin with Scotchbond Multi-Purpose adhesive to primary and permanent tooth enamel. Four groups of 20 teeth each were established: 1, permanent teeth, 10 per cent maleic acid etched for 15 seconds; 2, permanent teeth, 10 per cent maleic acid etched for 30 seconds; 3, permanent teeth, 37 per cent phosphoric acid etched for 15 seconds; 4, primary teeth, 10 per cent maleic acid etched for 15 seconds. Five teeth from each group were randomly assigned for SEM examination of the etched enamel surface. Scotchbond Multi-Purpose primer and adhesive were applied to the etched enamel surface of the remaining 15 teeth and cured following the manufacturer's instructions. Z100 composite resin was placed in a nylon cylinder and cured for two 40 second intervals. Following thermocycling, the specimens were sheared on an universal testing machine and debonded areas were examined visually with a stereo microscope and with SEM. The mean shear bond strengths in MPa were: 1, 17.00; 2, 14.58; 3, 14.66; 4, 11.18. ANOVA and Student-Newman-Keuls analyses revealed no statistically significant difference among the groups. SEM examination showed the majority of specimens fractured at the adhesive-resin interface.

The pressure hold/drop integrity test; its correlation to diffusive flow.

The pressure-drop/hold procedure enables the diffusive flow integrity testing of filters to be performed without breaching the system downstream of the filter. It is not necessary to measure volumetrically the diffused gas on the downstream side of the filter. By means of pressure transducers the pressure loss is determined upstream; thus eliminating the threat of sepsis due to down-stream invasions. The pressure decay exercise can be used to characterize the various filter types. A constancy of filter manufacture is required for a given filter type. Unless the pressure drop exceeds the value established as the maximum allowable decay, the filter is judged to be integral. It qualifies as a sterilizing grade filter. Excessive pressure decays will also eventuate from leaks, as from improperly sealed housings. Performed prior to the filtration, the procedure serves to eliminate the wasteful use of an imperfect system, whether caused by faulty sealing, incorrect filter type or flawed filters. Where leaks are detected, the filter can be reexamined for its integrity. To enable the pressure-drop procedure to serve as an integrity test, the measured pressure decays require being correlated with organism retention data. This is made possible by the arithmetic conversion of the pressure decay curve into the conventional diffusive airflow curve established to have such a correlation. The transformation of the pressure-drop curve into the differential airflow plot is automatically performed by certain of the automated integrity test machines. These devices, utilizing pressure transducers, are capable of measuring small pressure drops with requisite sensitivity; gauges commonly are not. Moreover, as previously stated, the measurements are advantageously made on the upside of the filter. The use of automated test machines is, therefore, recommended for the performance of the pressure hold/drop integrity test in furtherance of the practice of filter integrity testing.

High shear mixer granulation using food grade binders with different thickening power.

Mixer agglomeration, in particular high shear wet granulation, is a unit operation typically used in the pharmaceutical industry to improve the flowability, the compressibility, the dosing accuracy during tableting or the content uniformity of a blend. Thanks to its advantages (production of spherical and dense granules, reduction of production time), this technique can be potentially successful also in the food industry as for example in the production of dietary supplements. In this work four thickening agents (povidone, maltodextrin, k-carrageenan and xanthan gum) have been tested to study their effects on the granule growth behavior and on some technologically relevant granule properties (size, shape, strength and flowability). Experiments highlighted the full feasibility of the process and the possibility of using these agents to get products with satisfactory technological properties. The dependence of product properties on the formulation variables (water and binder amount) has been analyzed according to a multivariate approach and a robust predictive tool for the granule size has been developed. Furthermore it was observed that a reduced amount of binding liquid (water) can be used in the presence of strongly thickening binders with a reduction up to 25%. This would decrease drying time and energy requirement and be beneficial especially in the food and food supply industry where products have generally lower added value than in the pharmaceutical one and reducing production costs is critical.