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Advocate Aurora Health, located in the north‐central United States, is the result of a merger between two large health care organizations in April 2018. The health care system comprises 26 hospitals, offers more than 500 sites of care, and employs 75,000 team members. This article discusses the effects that coronavirus disease 2019 had on the perioperative services departments while directors and site leaders were still managing the complexities of the merger. Included are strategies used to address the challenges created by the pandemic, special considerations based on level‐of‐care capacity, the effect that the hold on elective surgeries had on staffing assignments, the reactivation process when elective surgery resumed, and the importance of keeping the perioperative team members informed and safe. It also illustrates how facing the challenges caused by the pandemic helped to solidify the merger of the two health care organizations.

The US Medical Licensing Examination (USMLE) Step 1 exam has proven a difficult stressor for medical students during their training, even with the advent of pass-fail scoring. The preparation period before the exam places students at high risk for burnout and depression, leading to impaired exam performance and other serious consequences including suicide. Many medical schools already provide academic support for students during USMLE Step 1 preparation, yet to date, there are no published programs specifically geared towards mental health support during this time.Students from the Larner College of Medicine at the University of Vermont developed the "Step-Siblings" program to partner pre-clinical level students preparing for Step 1 (Little Sibs) with clinical-level students (Big Sibs) in an effort to promote near-peer mentorship and support for those studying. Big Sibs were trained to offer emotional support and wellness advice, but specifically not to provide academic counselling. The pilot program was evaluated by student surveys.Our program successfully paired Little Sibs (This student-driven mentorship model is simple to implement, easily generalizable to other medical schools and other board exams, and bears the lasting benefit of combatting the stress and burnout so prevalent in medical education.The online version contains supplementary material available at 10.1007/s40670-022-01571-4.

PURPOSE Pembrolizumab, a programmed death 1 inhibitor, demonstrated promising single-agent activity in untreated patients with various cancer types. The phase II KEYNOTE-427 study evaluated efficacy and safety of single-agent pembrolizumab in treatment-naive patients with advanced clear cell renal cell carcinoma (ccRCC; cohort A) and advanced non-ccRCC (cohort B). Results of cohort A are reported. METHODS In this open-label, single-arm phase II study, patients with advanced ccRCC received pembrolizumab 200 mg every 3 weeks for ≤ 24 months. The primary end point was objective response rate by RECIST, version 1.1. RESULTS In the total population (N = 110), median time from enrollment to data cutoff was 35.9 (range, 29.5-40.3) months. Objective response rate was 36.4% with four (3.6%) complete responses and 36 (32.7%) partial responses; disease control rate was 58.2% (95% CI, 48.4 to 67.5). Most patients (68.2%) had a decrease in target lesions, including 30.9% with a reduction ≥ 60%. Median duration of response was 18.9 (range, 2.3-37.6+) months; 64.1% of responders had a response ≥ 12 months (Kaplan-Meier). Median progression-free survival was 7.1 months (95% CI, 5.6 to 11.0). Median overall survival was not reached; 12-month and 24-month overall survival rates were 88.2% and 70.8%, respectively. Durable responses were observed across all International Metastatic RCC Database Consortium categories. Grade 3-5 treatment-related adverse events were reported in 30.0% of patients, of which colitis and diarrhea were most frequent. CONCLUSION Single-agent pembrolizumab showed promising antitumor activity as a first-line treatment in patients with advanced ccRCC, with durable responses across International Metastatic RCC Database Consortium categories. Safety and tolerability profile of pembrolizumab monotherapy was comparable to what has been previously described in other tumor types.

5069 Background: KEYNOTE-427 (NCT02853344), an open-label, single-arm, phase 2 study, showed clinical activity of first-line pembro monotherapy in patients (pts) with ccRCC (cohort A). Previous studies in RCC and immune-oncology suggest depth of response may correlate with long-term benefit. Association between depth of response and OS, along with updated efficacy and safety for cohort A of KEYNOTE-427, are presented. Methods: Pts with histologically confirmed ccRCC, measurable disease (RECIST v1.1), and no prior systemic therapy received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points: ORR (primary), DOR, and PFS (RECIST v1.1); OS, and safety. Association between depth of response (maximum reduction from baseline in the sum of target lesions) and OS was evaluated using Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: 110 pts enrolled; median time from enrollment to data cutoff was 23.1 (range, 16.7-27.5) mo. Overall, 38.2% of pts had favorable and 61.2% had intermediate/poor IMDC risk. ORR was 36.4% (95% CI, 27.4-46.1; 3 CRs, 37 PRs); median (range) DOR was not reached (2.3-23.5+ mo); 64.0% had a DOR ≥12 mo. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached; 18-mo PFS and OS rates were 26.6% and 80.0%, respectively. 69.1% had some reduction in target lesions. Pts with > 60% reduction in target lesions had a greater probability of survival than pts with a ≤60% reduction (Table). ORR observed in IMDC favorable and intermediate/poor risk was 31.0% and 39.7%, respectively; 18-mo OS rate was 95.2% for favorable and 70.5% for intermediate/poor IMDC risk. Treatment-related AEs (TRAEs) occurred in 81.8% of pts, primarily fatigue (29.1%) and pruritus (28.2%). Grade ≥3 TRAEs occurred in 29.1% of pts; 1 pt died of treatment-related pneumonitis. Conclusions: First-line pembro monotherapy was tolerable and showed promising antitumor activity in advanced ccRCC. In general, pts who had greater reductions in target lesions demonstrated a trend toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]

We describe the principles of using orientation-independent differential interference contrast (OI-DIC) microscopy for mapping optical path length (OPL). Computation of the scalar two-dimensional OPL map is based on an experimentally received map of the OPL gradient vector field. Two methods of contrast enhancement for the OPL image, which reveal hardly visible structures and organelles, are presented. The results obtained can be used for reconstruction of a volume image. We have confirmed that a standard research grade light microscope equipped with the OI-DIC and 100 × / 1.3 NA objective lens, which was not specially selected for minimum wavefront and polarization aberrations, provides OPL noise level of ? 0.5 ?? nm and lateral resolution if ? 300 ?? nm at a wavelength of 546 nm. The new technology is the next step in the development of the DIC microscopy. It can replace standard DIC prisms on existing commercial microscope systems without modification. This will allow biological researchers that already have microscopy setups to expand the performance of their systems.

X-ray Talbot moire interferometers can now simultaneously generate two differential phase images of a specimen. The conventional approach to integrating differential phase is unstable and often leads to images with loss of visible detail. We propose a new reconstruction method based on the inverse Riesz transform. The Riesz approach is stable and the final image retains visibility of high resolution detail without directional bias. The outline Riesz theory is developed and an experimentally acquired X-ray differential phase data set is presented for qualitative visual appraisal. The inverse Riesz phase image is compared with two alternatives: the integrated (quantitative) phase and the modulus of the gradient of the phase. The inverse Riesz transform has the computational advantages of a unitary linear operator, and is implemented directly as a complex multiplication in the Fourier domain also known as the spiral phase transform.

To describe a severe phenotype of Meesmann's epithelial corneal dystrophy (MECD) and to determine the underlying molecular cause.We identified a 30-member family affected by MECD and examined 11 of the 14 affected individuals. Excised corneal tissue from one affected individual was examined histologically. We used PCR and direct sequencing to identify mutation of the coding regions of the KRT3 and KRT12 genes.Cases had an unusually severe phenotype with large numbers of intraepithelial cysts present from infancy and they developed subepithelial fibrosis in the second to third decade. In some individuals, the cornea became superficially vascularized, a change accompanied by the loss of clinically obvious epithelial cysts. Visual loss from amblyopia or corneal opacity was common and four individuals were visually impaired (≤6/24 bilaterally) and one was blind (6/60 bilaterally). In all affected family members, there was a heterozygous missense mutation c. 395TC (p. L132P) in exon 1 of the KRT12 gene, which codes for the helix-initiation motif of the K12 polypeptide. This sequence change was not found in unaffected family members or in 100 unaffected controls.The Leu132Pro missense mutation is within the helix-initiation motif of the keratin and is predicted to result in a significant structural change of the K12 protein. The clinical effects are markedly more severe than the phenotype usually associated with the Arg135Thr mutation within this motif, most frequently seen in European patients with MECD.

BACKGROUND: Activating mutations in serine-threonine protein kinase B-RAF (BRAF) are found in 50% of patients with advanced melanoma. Selective BRAF-inhibitor therapy improves survival, as compared with chemotherapy, but responses are often short-lived. In previous trials, MEK inhibition appeared to be promising in this population. METHODS: In this phase 3 open-label trial, we randomly assigned 322 patients who had metastatic melanoma with a V600E or V600K BRAF mutation to receive either trametinib, an oral selective MEK inhibitor, or chemotherapy in a 2:1 ratio. Patients received trametinib (2 mg orally) once daily or intravenous dacarbazine (1000 mg per square meter of body-surface area) or paclitaxel (175 mg per square meter) every 3 weeks. Patients in the chemotherapy group who had disease progression were permitted to cross over to receive trametinib. Progression-free survival was the primary end point, and overall survival was a secondary end point. RESULTS: Median progression-free survival was 4.8 months in the trametinib group and 1.5 months in the chemotherapy group (hazard ratio for disease progression or death in the trametinib group, 0.45; 95% confidence interval [CI], 0.33 to 0.63; P

Renal cell carcinoma (RCC) accounts for approximately 3% of all cancers and is refractory to cytotoxic chemotherapy – immunotherapy has until recently been the standard of care for advanced disease. Randomised trials reported in the last 5 years have demonstrated that a number of agents including the monoclonal antibody, bevacizumab, and the kinase inhibitors – sorafenib sunitinib, temsirolimus and everolimus – are active in advanced RCC. Bevacizumab is directed against the vascular endothelial growth factor (VEGF), a key mediator of angiogenesis, whilst sorafenib and sunitinib inhibit a number of targets including the VEGF and platelet-derived growth factor (PDGFR) receptor tyrosine kinases. Temsirolimus and everolimus inhibit the intracellular mammalian target of rapamycin (mTOR) kinase. Sunitinib and temsirolimus have demonstrated efficacy in comparison with immunotherapy in the first-line setting in patients with favourable and poor prognosis advanced disease respectively. In the second-line setting, everolimus has shown benefit over placebo in patients who progress following treatment with a VEGF receptor tyrosine kinase inhibitor and sorafenib has demonstrated efficacy in comparison with placebo in patients with immunotherapy-refractory disease. We review here recent clinical trial data and discuss future developments in the systemic treatment of RCC including combination and sequential therapy, adjuvant therapy, the role of biomarkers and the prospects for the development of rational mechanism-directed therapy in this disease.

The effect of numerical aperture on the fringe spacing in interferometry is analyzed by the use of wave optics. The results are compared with published experimental results, and the influence of apodization of the wave front is discussed. The effects of central obscuration and surface tilt are also considered.

As alpha-melanocyte-stimulating hormone (alpha-MSH) is released by immunocompetent cells and has potent immunosuppressive properties, it was determined whether human dendritic cells (DCs) express the receptor for this hormone. Reverse transcription-polymerase chain reaction detected messenger RNA specific for all of the known melanocortin receptors in DCs. Mixed lymphocyte reactions also revealed that treatment with [Nle(4), DPhe(7)]-alpha-MSH (NDP-MSH), a potent alpha-MSH analogue, significantly reduced the ability of DCs to stimulate allogeneic T cells. The expression of various cell surface adhesion, maturation and costimulatory molecules on DCs was also investigated. Although treatment with NDP-MSH did not alter the expression of CD83 and major histocompatibility complex class I and II, the surface expression of CD86 (B7.2), intercellular adhesion molecule (ICAM-1/CD54) and CD1a was reduced. In summary, our data indicate that NDP-MSH inhibits the functional activity of DCs, possibly by down-regulating antigen-presenting and adhesion molecules and that these events may be mediated via the extracellular signal-regulated kinase 1 and 2 pathway.

Summary: Dihydropyridine calcium antagonists are candidate anticonvulsants, but little is known of their penetration into brain. Nifedipine (NFD) and nimodipine (NMD) pharmacokinetics were compared in mouse blood and brain, and their activity against pentylenetetrazol (PTZ) was assessed. After intraperitoneal (i.p.) injection, both dihydropyridines achieved peak blood and brain concentrations in 5 min. Estimated blood and brain elimination half-lives (t1/2) of NMD (16.7 and 22.4 min) were slightly longer than those of NFD (11.2 and 14.7 min). Brain and blood concentrations correlated with both NFD (r = 0.701, p < 0.001) and NMD (r = 0.572, p < 0.001). Injection of the dihydropyridines as a suspension (Tween 80) did not alter brain penetration, although systemic absorption was more erratic. NFD (p < 0.001), NMD (p < 0.021, and carbamazepine (CBZ, p < 0.001) i.p. inhibited PTZ-induced seizures. Brain concentrations of PTZ were not altered by NFD pretreatment. Combining NFD and CBZ was less effective than giving NFD alone (p < 0.005). NFD (p < 0.002) and NMD (p < 0.001) inhibited PTZ seizures after 2-week oral dosing, but low dosing was more effective than high dosing (p < 0.002). NFD and NMD cross the blood-brain barrier (BBB) in mice and inhibit PTZ seizures. A possible therapeutic window was identified, and NFD and CBZ were less effective in combination than singly. A pharmacodynamic interaction may exist, inhibiting effective use of dihydropyridines as adjunctive therapy in epileptic patients. RESUME Les antagonistes calciques dihydropyridiniques sont des anticonvulsivants potentiels, mais on sait peut de choses sur leur penetration das le cerveau. Les pharmacocinetiques de la nifedipine (NFD) et de la nimodipine (NMD) ont ete comparees dansle sang et dans le cerveau de souris, et leur activite contre lescrises induites par pentylenetetrazol (PTZ) a eteevaluee. Apres injection intraperitoneale (i.p.), les deux dihydropyridines ont presente un pic sanguin et cerebral en moins de cinq minutes. Les demi-vies d'elimination evaluees au niveau du sang et ducerveau etaient de 16.7 et 22.4 minutes respectivement pour la NMD; elles etaient legerement plus longues que celles de la NFD(11.2 et 14.7 rnin). Les concentrations sanguines et cerebrales etaient correlees pour la NFD (r = 0.701, p < 0.001) et pour laNMD (r = 0.572, p < 0.001). L'injection de ces dihydropyridinesen suspension n'a pas modifie la penetration cerebrale; en revanche I'absorption systemique etait plus variable. Les crisesinduites par PTZ ont ete inhibees par administration i.p. de NFD(p < 0.001), de NMD (p < 0.02) et de carbamazepine (CBZ, p

The movement of calcium into neurons may be the common denominator for the triggering and propagation of seizure activity. We report results of the first double-blind, placebo-controlled, crossover trial with the dihidropyridine calcium antagonist nifedipine (NFD) as adjuvant therapy in refractory epilepsy. Twenty-two students (12 male, 10 female, age 17-22 years) attending Lingfield Hospital School received NFD retard and matched placebo for 8 weeks in 2 doses (20 and 40 mg b.i.d. each for 4 weeks) with a washout period of 8 weeks between treatment phases. In the 20 students who completed the trial, fewer partial seizures (p less than 0.05) were documented during the first 2 weeks of NFD administration. Similarly, fewer seizure days (p less than 0.05) were reported in the first month of active treatment. This response was not sustained into the second month of the trial. Blind scoring of EEGs suggested a small improvement with NFD (p less than 0.05). More patients reported headache when receiving NFD (p less than 0.02) than placebo, but heart rate and erect and supine blood pressure remained unaffected. Mean maximum NFD concentrations were 13.1 +/- 10.4 ng/ml. A weak correlation was noted between total (p less than 0.05) and partial (p = 0.025) seizure numbers and NFD concentrations following 8 weeks of treatment. This study does not support important anticonvulsant efficacy for NFD as adjuvant therapy for refractory epilepsy at doses appropriate for the treatment of angina or hypertension. Further trials are recommended using higher doses of NFD in less severely affected patients.

Thirteen patients with newly diagnosed epilepsy performed a battery of psychomotor function tests before and during the first 12 weeks of carbamazepine (CBZ) therapy. Movement time (P less than 0.025), total choice reaction time (P less than 0.025), finger tapping rate (P less than 0.005) and number cancellation (P less than 0.05) were all significantly impaired after 1 week's treatment, but had returned to baseline by 4 weeks. Mean (+/- s.d.) serum CBZ concentrations and those of its active metabolite CBZ 10,11 epoxide (CBZ-E) were comparable at 1 (CBZ: 8.5 +/- 2.1 mg l-1, CBZ-E: 1.1 +/- 0.68 mg l-1) and 4 weeks (CBZ: 8.1 +/- 4.4 mg l-1, CBZ-E: 0.93 +/- 0.27 mg l-1). These results suggest the rapid development of tolerance to the acute deleterious psychomotor effects of CBZ.

Two new two dimensional (2-D) complex operators for estimating the energy and orientation of 2-D oriented patterns are proposed. The starting point for our work is a new 2-D extension of the Teager-Kaiser energy operator incorporating orientation estimation. The first new energy operator is based on partial derivatives and can be considered a local (point-based) estimator. Using a nonlocal (pseudo-differential) operator we derive a second and more general energy operator. A scale invariant nonlocal operator is derived from the recently proposed spiral phase quadrature (or Riesz) transform. The Teager-Kaiser energy operator and the phase congruency local energy are unified in a single equation for both 1-D and 2- D. Robust orientation estimation, important for isotropic demodulation of fringe patterns is demonstrated. Theoretical error analysis of the local operator is greatly simplified by a logarithmic formulation. Experimental results using the operators on noisy images are shown. In the presence of Gaussian additive noise both the local and nonlocal operators give improved performance when compared with a simple gradient based estimator.

Interaction with adenosine A1 receptors is a possible contributory mechanism to the anticonvulsant effects of carbamazepine (CBZ) and the dihydropyridine calcium antagonists. We measured the binding of [3H]cyclohexyladenosine to adenosine A1 receptors in mouse brain stem, cerebellum, and cortex after oral administration of nifedipine, nimodipine (NMD), and CBZ for 7 days and compared the results with binding in control mice. Equilibrium dissociation constant (Kd) and receptor numbers (Bmax) were calculated using Scatchard and saturation isotherm analyses. Mean Kds (SEM) in control brain stem, cerebellum, and cortex were 2.09 (0.31), 2.39 (0.2), and 3.12 (0.28) nM, respectively. Results of Bmax for the same areas were 188 (26), 280 (24), and 449 (54) fmol/mg protein. Nifedipine (p less than 0.005) and NMD (p less than 0.02) raised the Kd of A1 receptors only in the cerebellum, and CBZ increased cerebellar Bmax (p less than 0.05). These minor effects on A1 receptors in CF1 mice, when given in doses previously shown to have anticonvulsant properties in these animals, do not suggest that alteration in A1 receptor activity is an important mechanism for the anticonvulsant effects of these drugs.

In phase shifting interferometry, phase errors due to harmonic components of a fringe signal can be minimized by applying synchronous phase shifting algorithms with more than four samples. However, when the phase shift calibration is inaccurate, these algorithms cannot eliminate the effects of a non-sinusoidal waveform. It is shown that by taking a number of samples beyond one period of the fringe pattern, phase errors due to the harmonic components of the fringe signal can be eliminated, even when there exists a constant error in the phase shift interval. A general procedure for constructing phase shifting algorithms that eliminate these errors is derived. A seven-sample phase shifting algorithm is derived as an example, in which the effect of the second harmonic component can be eliminated in the presence of a constant error in the phase shift interval.

LBA8509 Background: Dacarbazine (D) and paclitaxel (P) have been used to treat MM pts with limited effect. The MM treatment landscape has recently changed with the approval of vemurafenib and ipilimumab in 2011, but secondary malignancies or other toxicities are of concerns. T is a reversible, highly selective allosteric inhibitor of MEK1/2 activation and kinase activity. In a PhII trial (NCT01037127), pts with BRAFV600E mutation MM had median PFS of 5.3 mos. This PhIII trial (NCT01245062) was conducted in pts with BRAFV600E/K mutant advanced or MM. Methods: Pts were randomized 2:1 to T (2mg QD) or C (D or P). Pts were stratified by baseline LDH level and prior C; pts in the C arm were allowed to crossover to receive T after confirmation of PD. Primary endpoint was PFS in pts with BRAFV600E mutation-positive MM and no prior brain mets; secondary endpoints were OS, ORR and safety in primary and ITT. PFS and OS were compared using a stratified log-rank test. The study was designed with ≥99% power and one-sided α = 0.025 to detect 57% reduction in the risk of PD or death in pts treated with T vs C. Results: Between Dec 2010 and Jul 2011, 322 pts were randomized to T (n=214) or C (n=108); 273 pts were BRAFV600E mutation-positive with no prior brain mets. HR for primary population for PFS by investigator was 0.44 (95% CI 0.31–0.64; pV600E/K mutant MM.

To determine the effects of short-duration treatments with 5-fluorouracil (5FU) and mitomycin-c (MMC) on "activated" and "nonactivated" ocular fibroblasts in collagen lattices.Activated and nonactivated ocular fibroblasts seeded in collagen lattices were exposed to single 5-minute treatments with 5FU (0.01 to 25 mg/ml) and MMC (0.01 to 1 mg/ml). The effects of these treatments on lattice contraction, cellularity, cellular viability, cellular structure, and actin distribution were investigated.Treatment with 5FU (0.01 to 25 mg/ml) or MMC (0.1 to 1 mg/ml) significantly inhibited (P0.001 and P0.0001, respectively) lattice contraction compared to water controls. The degree of inhibition was greater in lattices containing nonactivated cells than in those containing activated cells. Activated cell viability and cellularity, unlike their nonactivated counterparts, were not significantly affected (P0.0083) by treatment with 5FU at high concentrations (25 mg/ml). MMC treatment had significant effects on cell viability and cellularity (P0.0001). Treatment with 5FU and MMC also affected cellular structure and actin distribution compared to water controls.Single, short exposures to 5FU or MMC inhibit ocular fibroblast-mediated collagen contraction. MMC causes cell death and a decrease in cellularity at high concentrations. The results also indicate that collagen lattices seeded with activated and nonactivated fibroblasts are differentially affected by short-term exposures to 5FU or MMC. These findings may have important clinical implications regarding the concentrations of these agents used in the treatment of different patient groups.

SUMMARY: To assess the value of onsite therapeutic drug monitoring at the epilepsy clinic, management decisions were recorded before and immediately after antiepileptic drug (AED) concentrations became available. In the first year of this prospective study, 632 [277 carbamazepine (CBZ), 170 phenytoin (PHT), 113 valproate (VPA), and 72 phenobarbital (PB)] assays were performed during 488 clinic attendances in 182 actively managed epileptic patients. The results of drug analysis led to alterations in management at 114 patient visits, i.e., 23% of those monitored. Dosage was increased in response to the circulating AED concentration in 12% of consultations and decreased in another 7.5%. Unsuspected poor compliance was uncovered in eight patients, and in three others an AED was added or discontinued on the basis of the assay result. The time of the next appointment was rearranged in 58 attendances. Only 50% of results were in the “therapeutic” ranges for the four major AEDs. Dosage was adjusted (50 up, 16 down) after 54% of low results. “Therapeutic” levels were followed by a change in AED dose (52 up, 31 down) in 26%. Only 29% of concentrations above the “therapeutic” range persuaded the doctor to alter the dosage regimen, and in 20% of these an increase in dose was recommended. On-site AED monitoring had an immediate impact on clinical decision-making in > 23% of consultations but in a form more subtle than the simple quest for a therapeutic result. RESUME Afin d‘evaluer l'interet d'une surveillance des taux de medicaments epileptiques lors d'une consultation epileptologique, les auteurs ont recueilli les decisions therapeutiques avant et immediatement apres la mise a leur disposition des dosages des antiepileptiques (AE). Pendant la premiere annee de ces etudes prospectives, un total de 632 dosages a ete realisea l'occasion de 448 consultations chez 182 patients epileptiques pris en charge de facon active (ont ete doses: 277 fois la carbamazepine, 170 fois la phenytoine, 113 fois le valproate, 72 fois le phenobarbital). Les resultats des dosages des medicaments ont abouti a des modifications du traitement lors de 114 consultations, c'est a dire 23%. La dose quotidienne a ete augmentee en raison des resultats des dosages des AE dans 12% des consultations, elle a ete diminuee dans 7.5%. Une mauvaise compliance a ete decouverte chez 8 patients, chez 3 patients un traitement AE a ete mis en route ou arrete sur la base des resultats des dosages. La date du rendezvous suivant a ete modifiee lors de 58 consultations. 50% seulement des resultats des dosages etaient dans les zones “therapeutiques” pour les 4 antiepileptiques majeurs etudies. La dose a ete ajustee (en augmentation pour 50, en diminution pour 16) apres 54% des resultats bas. L'obtention de taux “therapeutiques” a entraine par un changement de la dose lors de 26% des consultations (en augmentation pour 52, en diminution pour 31). 29% seulement des taux seriques se situant au-dessus de la zone “therapeutique” ont pu persuader le medecin de modifier le dosage quotidien, et dans 20% de ces cas la dose a ete augmentee. II apparait pour les auteurs que le dosage immediat des AE a un impact net sur la prise de decision clinique lors de plus de 23% des consultations, mais que ces modifications prennent un aspect plus subtil que la simple recherche d'un niveau sanguin “therapeutique.” RESUMEN Para determinar el valor de la monitorizacion de las medicaciones en una clinica de epilepsia se han anotado las decisiones del control antes e inmediatamente despues de que se obtuvieran las concentraciones de medicaciones antiepilepticas (AED). Durante el primer ano de este estudio prospectivo se realizaron un total de 632 ensayos (277 de Carbamacepina, 170 de Fenitoina, 113 de Valproato y 72 de Fenobarbital) durante 488 visitas a la clinica en 182 pacientes epilepticos activamente controlados. Los resultados de los analisis de la droga mostraron alteraciones en el manejo de 114 visitas de pacientes, es decir, 23% de todos los monitorizados. Las dosis se incrementaron, como resultado de las concentraciones de las AED circulantes, en 12% de las consultas y se redujeron en un 7.5%. Se descubrio un inesperado escaso cumplimiento con respecto a las tomas en 8 enfermos y en otros 3, se anadio o se interrumpio una AED segun los resultados del ensayo. La hora de la siguiente cita se reajusto en 58 asistentes. Solamente el 50% de los resultados estaban dentro del rango terapeutico para 4 de las AEDs mayores. La dosis se ajusto (50 hacia arriba y 16 hacia abajo) despues del 54% de resultados bajos. Los niveles terapeuticos se siguieron de un cambio en las dosis de AED (52 hacia arriba y 31 hacia abajo) en 26% de los casos. Solamente el 29% de las concentraciones por encima del rango terapeutico consiguieron persuadir al medico para alterar las dosis y el 20% de estos se recomendo un incremento de la misma. La monitorizacion de las AED en consulta produjo un impacto immediato en el proceso de decision clinica en mas del 23% de las consultas pero en una forma mas sutil que la simple busqueda de un resultado terapeutico.

We propose a coherent mathematical model for human fingerprint images. Fingerprint structure is represented simply as a hologram - namely a phase modulated fringe pattern. The holographic form unifies analysis, classification, matching, compression, and synthesis of fingerprints in a self-consistent formalism. Hologram phase is at the heart of the method; a phase that uniquely decomposes into two parts via the Helmholtz decomposition theorem. Phase also circumvents the infinite frequency singularities that always occur at minutiae. Reliable analysis is possible using a recently discovered two-dimensional demodulator. The parsimony of this model is demonstrated by the reconstruction of a fingerprint image with an extreme compression factor of 239.

A new method of estimating the phase-shift between interferograms is introduced. The method is based on a recently introduced two-dimensional Fourier-Hilbert demodulation technique. Three or more interferogram frames in an arbitrary sequence are required. The first stage of the algorithm calculates frame differences to remove the fringe pattern offset; allowing increased fringe modulation. The second stage is spatial demodulation to estimate the analytic image for each frame difference. The third stage robustly estimates the inter-frame phase-shifts and then uses the generalised phase-shifting algorithm of Lai and Yatagai to extract the offset, the modulation and the phase exactly. Initial simulations of the method indicate that high accuracy phase estimates are obtainable even in the presence of closed or discontinuous fringe patterns.

A simple nonlinear (quadratic) filter is shown to demodulate bandpass sampled AM signals efficiently. The filter is based upon a discrete version of the recently introduced Teager-Kaiser energy operator, but also closely resembles a complex digital sampling demodulator. Such a filter can also be implemented in analogue circuitry.

A battery of psychometric tests was administered to 85 patients with epilepsy, of whom 26 were untreated, 40 received carbamazepine monotherapy and 19 took carbamazepine with another anticonvulsant. Carbamazepine alone had little effect on performance, but carbamazepine polypharmacy produced significant impairment. Increasing concentrations of carbamazepine (four tests) and its active metabolite, carbamazepine 10,11 epoxide (seven tests), correlated with decreasing performance in the monotherapy patients.

1. Eight healthy subjects took part in a balanced, double-blind, crossover comparison of conventional carbamazepine (Tegretol, Ciba-Geigy Ltd, CBZ-C) and a novel controlled-release formulation (Tegretol CR Divitabs, Ciba-Geigy Ltd; CBZ-CR). An initial single dose of either preparation was followed 1 week later by a 2 week course of 200 mg twice daily. 2. Following the single dose, CBZ-CR produced a concentration plateau from 6-56 h at 50-60% of the CBZ-CR peak. 3. After 2 weeks' treatment, CBZ daytime levels measured as area under the concentration-time curve over a dosage interval were 7% lower with CBZ-CR, but this difference was not statistically significant. 4. CBZ-CR showed less diurnal fluctuation (12%) of CBZ than CBZ-C (24%; P less than 0.025) with less rapid changes in concentration (P less than 0.02). 5. Diurnal fluctuation of free CBZ and of CBZ 10,11 epoxide, the active metabolite, did not differ significantly between the two preparations. 6. Auto-induction of CBZ metabolism resulted from the administration of both formulations. The mean elimination half-life was 23 h (CBZ-C) and 25 h (CBZ-CR) after dose 29 compared with a base-line value of 37 h (both P less than 0.02). Antipyrine metabolism was also induced to a similar extent in both legs of the study (P less than 0.01). 7. No significant alteration in psychomotor function was demonstrated with either preparation. 8. CBZ-CR fulfils the criteria for a controlled-release preparation with comparable apparent bioavailability to CBZ-C. Further pharmacokinetic and, more importantly, pharmacodynamic studies are required in epileptic patients to confirm a clinical advantage over the currently available formulation.

The 1976-1977 drought affected all levels of water use and management in Californiathe state, local agencies, and individual water users. All experienced difficulties in planning and in coping with the water shortages, and all were affected economically. As a water utility affected by the drought, the East Bay Municipal Utility Dist. (EBMUD) modified its operations and regulations in order to conserve water and to assure a continuing water supply. As background to EBMUD's water conservation program and its economic effects, a short description of the drought itself will be given here. A more complete discussion can be found in the February 1978 Journal.*

California's East Bay Munic. Utility Dist. (EBMUD), formed 50 years ago, serves a 286-sqmi area in Alameda and Contra Costa counties, including fifteen cities and fifteen unincorporated communities across the bay from San Francisco. The present population of the area is 1 093 000, with an average percapita consumption of 195 gpd. The principal source of water is the Mokelu ne River water shed, a 575-sqmi portion of the Sierra Nevada in Alpine, Amador, and Calaveras counties. Over the next five years, the district plans to average about $16 million annually in a substantial capital-improvement program. In recent years, EBMUD has integrated a new dimension environmental considerations into its programs, and there has been considerable progress from the first efforts to the present administration of the environmental-assessment process. EBMUD had always recognized the need for such "environmental" considerations as architecture and landscaping in its works, but formal requirements for environmental assessment have resulted in projects that are more compatible with their surroundings. Environmental assessment is now an integral part of EBMUD's planning-design-construction interrelationship.

Anyone attempting to comment at this time on the future of higher education for the next decade opens himself to challenge. Innovations wrought on the American campus in the Ig60's have been popularly received as evidence of instability and change in the higher education process. But events also suggest that higher education is daily becoming more widely recognized among the young as a stepping-stone to higher responsibility and multiplex rewards in the world of work. In spite of surface turmoil, certain undercurrents in higher education can be detected. Patterns of economic growth suggest many instructional programs that will be in demand in the I970'S. The present article reviews some manpower trends in brief and discusses the demand for selected college-trained professionals reflected in the nation's priority objectives for the decade ahead. A profound development of modern times has been the shift from property ownership to individual skill and effort as a primary title to income and wealth. The physician is replacing

Whether it be the plague or influenza, one thing we learn at the knee of our 'alma mater' is that diabetics are more likely to get it. The origins of this presumption are unclear. The decrease in mortality from sepsis and tuberculosis following the introduction of insulin has been well documented (Flynn, 1935) but in recent years there has been a tendency to presuppose an increased incidence of infection in diabetics and to search for an underlying cause. The complex problem of infection and diabetes mellitus requires critical reexamination and we have considered the following three questions: (1) Are diabetic patients more prone to infection? (2) Are infections more serious when they occur in diabetics? (3) Is there an explanation for positive answers to the first two questions?

Impairment of libido and sexual potency are commonly reported by male epileptic patients. This may be partly a consequence of medication. Circulating hormones were measured in 53 postpubertal male epileptic patients less than 45 years of age and in an age-matched control group (n = 40), consisting of 14 untreated epileptic patients and 26 unmedicated healthy subjects. A subgroup also underwent a combined gonadotrophin- and thyrotrophin-releasing hormone (LH-RH/TRH) pituitary stimulation test. Untreated patients did not differ from healthy subjects for any parameter, and their data were combined for comparison with the treated epileptic patients. Total testosterone (T), androstenedione, and basal follicle-stimulating hormone concentrations were similar in all patient groups. Patients receiving more than one drug had higher sex hormone binding globulin (SHBG) (p less than 0.01) and lower free T and dehydroepiandrosterone sulphate (DHAS) levels (both p less than 0.001) than controls. Carbamazepine (CBZ) monotherapy also reduced free T (p less than 0.05) and DHAS (p less than 0.001) and increased basal prolactin (p less than 0.01). In these two groups of patients, basal luteinising hormone (LH) was elevated (p less than 0.01), presumably as a pituitary response to increased T catabolism. There was a negative correlation between free T and circulating CBZ (r = -0.54, p less than 0.05) in the monotherapy patients. Phenytoin (PHT) was associated with a rise in SHBG (p less than 0.01) and a fall in DHAS (p less than 0.001). Basal LH was also elevated, but this just failed to reach statistical significance (p less than 0.1).(ABSTRACT TRUNCATED AT 250 WORDS)

Notes on method of preparing a terra cotta body, proportioning by volume and using unground material, and method of preparing body, proportioning with ground materials, using disc feeders, are given. Notes on checking laboratory work with these two methods and variation in shrinkage due to amount of water in the body are also considered.

La limitation de la mobilite des articulations des doigts et la contracture de Dupuytren sont tres nettement plus frequentes chez les diabetiques que chez les sujets normaux. Dans l'hypertension, la limitation des mouvements des doigts est un peu plus frequente que dans l'etat normal. Il se peut que la microangiopathie diabetique s'accompagne d'un vieillissement accelere