Looking at the Full Picture: Utilizing Topic Modeling to Determine Disease-Associated Microbiome Communities.
The microbiome is a complex micro-ecosystem that provides the host with pathogen defense, food metabolism, and other vital processes. Alterations of the microbiome (dysbiosis) have been linked with a number of diseases such as cancers, multiple sclerosis (MS), Alzheimer's disease, etc. Generally, differential abundance testing between the healthy and patient groups is performed to identify important bacteria (enriched or depleted in one group). However, simply providing a singular species of bacteria to an individual lacking that species for health improvement has not been as successful as fecal matter transplant (FMT) therapy. Interestingly, FMT therapy transfers the entire gut microbiome of a healthy (or mixture of) individual to an individual with a disease. FMTs do, however, have limited success, possibly due to concerns that not all bacteria in the community may be responsible for the healthy phenotype. Therefore, it is important to identify the community of microorganisms linked to the health as well as the disease state of the host. Here we applied topic modeling, a natural language processing tool, to assess latent interactions occurring among microbes; thus, providing a representation of the community of bacteria relevant to healthy vs. disease state. Specifically, we utilized our previously published data that studied the gut microbiome of patients with relapsing-remitting MS (RRMS), a neurodegenerative autoimmune disease that has been linked to a variety of factors, including a dysbiotic gut microbiome. With topic modeling we identified communities of bacteria associated with RRMS, including genera previously discovered, but also other taxa that would have been overlooked simply with differential abundance testing. Our work shows that topic modeling can be a useful tool for analyzing the microbiome in dysbiosis and that it could be considered along with the commonly utilized differential abundance tests to better understand the role of the gut microbiome in health and disease.


Application of photogrammetry for analysis of occlusal contacts.
The conventional 2D-analysis methods for occlusal contacts provided limited information on tooth morphology. This present study aims to detect 3D positional information of occlusal contacts from 2D-photos via photogrammetry. We propose an image processing solution for analysis of occlusal contacts and facets via the black silicone method and a photogrammetric technique. The occlusal facets were reconstructed from a 2D-photograph data-set of inter-occlusal records into a 3D image via photogrammetry. The configuration of the occlusal surface was reproduced with polygons. In addition, the textures of the occlusal contacts were mapped to each polygon. DIFFERENCE FROM CONVENTIONAL METHODS: Constructing occlusal facets with 3D polygons from 2D-photos with photogrammetry was a defining characteristic of this image processing technique. It allowed us to better observe findings of the black silicone method. Compared with conventional 3D analysis using a 3D scanner, our 3D models did not reproduce the detail of the anatomical configuration. However, by merging the findings of the inter-occlusal record, the deformation of mandible and the displacement of periodontal ligaments under occlusal force were reflected in our model. EFFECT OR PERFORMANCE: Through the use of polygons in the conversion of 2D images to 3D images, we were able to define the relation between the location and direction of the occlusal contacts and facets, which was difficult to detect via conventional methods. Through our method of making a 3D polygon model, the findings of inter-occlusal records which reflected the jaw/teeth behavior under occlusal force could be observed 3-dimensionally.


Comparative microangiographic and histologic studies of the embryonal development of intracerebral capillaries.
In 69 embryos and fetuses of cattle and pigs with an age of gestation of 4 weeks to 4 months the development of intracerebral capillaries was studied comparatively by microangiography and controlled by histologic slices. The first invasion of blood vessels into the wall of the neural tube takes place in the brain stem and colliculus ganglionaris at an age of gestation of 4 weeks. After that, specific and different angioarchitectonic patterns of capillary development can be demonstrated within the telencephalon, basal ganglia, and brain stem. The telencephalic vessels show concentrically arranged areas of ramification which interrupt their longitudinal course towards the ventricular cavity. The branchings are related topographically to the projection fibers from the internal capsule and to the subependymal matrix layer. In the basal ganglia, the developing internal capsule interrupts the blood supply of the caudate nucleus from the periphery, and a new central system is established mainly running radially towards the ventricular canal. Thus, it could be shown in consecutive stages of cerebral development that the angioarchitectonic pattern of a certain embryonal stage and brain area depends on the histologic structure of the neural tissue and its specific metabolic demands.


Nurse practitioner-based models of specialist palliative care at home: sustainability and evaluation of feasibility.
Patients with serious medical problems who live at home may not be able to access specialist-level palliative care when the need develops. Nurse practitioner (NP)-based models may be able to increase the availability of specialist care in the community. The aim of this study was to evaluate the financial sustainability and feasibility of two NP-based models in an urban setting. In one model, an NP was linked with a social worker (SW) to create a new palliative home care team (PHCT-NP-SW), which would provide consultation and direct care to referred homebound elderly patients with advanced illnesses. In a second model, an NP was assigned to a hospice program (Hospice-NP) for the purpose of enhancing the reach and impact of a home care team. The revenue generated by each model was compared with direct costs; the PHCT-NP-SW model also was evaluated for its feasibility and impact on patient-level outcomes. Over a two-year period, the NP in the PHCT-NP-SW model made 350 visits and followed 114 patients at home. Annualized revenue through reimbursement from patient billing offset less than 50% of the NP's salary costs. In contrast, the Hospice-NP model led to a 360% increment in hospice referrals, yielding sufficient new revenue to support this position indefinitely after only seven months. The PHCT-NP-SW model provided numerous interventions that yielded a significant decline in symptom distress during the initial two weeks after referral (P=0.003), 100% compliance with advance care planning, 21% admission rate to hospice, access to other community services, and crisis management. Nonetheless, lack of funding led to closure of this model after the two years. This experience suggests that a PHCT-NP-SW model is not sustainable in this urban environment through reimbursement-based revenue, whereas a Hospice-NP model for hospice can be sustainable based on the growth of hospice census. The PHCT-NP-SW model appears to offer benefits, and additional efforts are needed to establish the funding mechanisms to sustain such programs, create mixed models of hospice and nonhospice funding, or provide a basis for sustainability through cost reduction.


Effects of tobacco smoking on the Hoffmann reflex.
Ten normal adult tobacco smoking volunteers 21 to 32 years of age were the subjects of this study. They were asked not to smoke for 12 hours prior to testing. The Hoffmann (H) reflex and its recovery cycle were measured before and just after smoking (on different days) one nonfiltered, zero, low (0.27 mg), or high (2.16 mg) nicotine tobacco cigarette. After smoking the nicotine-containing cigarettes, the subjects showed a reduction of the H reflex recovery cycle. Individual differences were marked. Nevertheless, the data obtained are consistent with evidence in animals that nicotine and tobacco smoke stimulate Renshaw inhibitory neurons in the spinal cord, either directly or indirectly. This technique provides another objective measure of the effects of tobacco smoking in human volunteers.


Iodoacetic acid, but not sodium iodate, creates an inducible swine model of photoreceptor damage.
Our purpose was to find a method to create a large animal model of inducible photoreceptor damage. To this end, we tested in domestic swine the efficacy of two chemical toxins, known to create photoreceptor damage in other species: Iodoacetic Acid (IAA) and Sodium Iodate (NaIO(3)). Intravenous (IV) administration of NaIO(3) up to 90 mg/kg had no effect on retinal function and 110 mg/kg was lethal. IV administration of IAA (5-20 mg/kg) produced concentration-dependent changes in visual function as measured by full-field and multi-focal electroretinograms (ffERG and mfERG), and 30 mg/kg IAA was lethal. The IAA-induced effects measured at two weeks were stable through eight weeks post-injection, the last time point investigated. IAA at 7.5, 10, and 12 mg/kg produce a concentration-dependent reduction in both ffERG b-wave and mfERG N1-P1 amplitudes compared to baseline at all post-injection times. Comparisons of dark- and light-adapted ffERG b-wave amplitudes show a more significant loss of rod relative to cone function. The fundus of swine treated with ≥10 mg/kg IAA was abnormal with thinner retinal vessels and pale optic discs, and we found no evidence of bone spicule formation. Histological evaluations show concentration-dependent outer retinal damage that correlates with functional changes. We conclude that NaIO(3,) is not an effective toxin in swine. In contrast, IAA can be used to create a rapidly inducible, selective, stable and concentration-dependent model of photoreceptor damage in swine retina. Because of these attributes this large animal model of controlled photoreceptor damage should be useful in the investigation of treatments to replace damaged photoreceptors.


Physical proximity of chromatin to nuclear pores prevents harmful R loop accumulation contributing to maintain genome stability.
During transcription, the mRNA may hybridize with DNA, forming an R loop, which can be physiological or pathological, constituting in this case a source of genomic instability. To understand the mechanism by which eukaryotic cells prevent harmful R loops, we used human activation-induced cytidine deaminase (AID) to identify genes preventing R loops. A screening of 400 Saccharomyces cerevisiae selected strains deleted in nuclear genes revealed that cells lacking the Mlp1/2 nuclear basket proteins show AID-dependent genomic instability and replication defects that were suppressed by RNase H1 overexpression. Importantly, DNA-RNA hybrids accumulated at transcribed genes in mlp1/2 mutants, indicating that Mlp1/2 prevents R loops. Consistent with the Mlp1/2 role in gene gating to nuclear pores, artificial tethering to the nuclear periphery of a transcribed locus suppressed R loops in mlp1∆ cells. The same occurred in THO-deficient hpr1∆ cells. We conclude that proximity of transcribed chromatin to the nuclear pore helps restrain pathological R loops.


Salvage of upper arm access grafts by extension to the infraclavicular axillary vein.
A technique has been described to salvage upper arm graft fistulas using expanded polytetrafluoroethylene grafts by subcutaneous extension to the infraclavicular axillary vein. The axillary vein is exposed through an infraclavicular incision near the lateral end of the clavicle by splitting the pectoralis major muscle and by dividing or retracting the pectoralis minor muscle medially. A new segment of polytetrafluoroethylene graft is anastomosed to the axillary vein, and then to the old graft segment. This technique was employed in six patients over a 12 month period, with a 24 month graft patency rate of 84 percent. The advantage over a new access graft is immediate hemodialysis through a puncture of the preserved arterial limb of the polytetrafluoroethylene graft.


[Resumption of anticoagulant therapy after major bleeding and the risk of negative events in patients with atrial fibrillation (based on REGistry of Long-term AnTithrombotic TherApy-2 - REGATA)].
It is necessary to strive to resume anticoagulants for patients with atrial fibrillation who have a high risk of thrombosis after the development of large bleeding. Due to the fact that death in these patients is caused not by a recurrence of fatal bleeding, but by the development of stroke in case of refusal of anticoagulant therapy. To evaluate the effect of the resumption of anticoagulant therapy on the risk of recurrence of major bleeding, thrombosis and death in patients with atrial fibrillation who have suffered major bleeding. To evaluate the frequency of bleeding, thrombosis and death in patients with atrial fibrillation after major bleeding according to prospective follow-up data for one year. The recurrence rate of major bleeding after the resumption of therapy was 21.7% per year. The frequency of fatal bleeding was 2.2%. In the anticoagulant withdrawal group, the incidence of thrombotic complications (ischemic stroke and myocardial infarction) was significantly higher compared to patients who resumed therapy. The frequency of death from all causes was significantly higher in the group of patients who did not resume anticoagulant therapy. Half of the deaths were due to cardiovascular causes. The presence of more than 5 points of the Charlson Comorbidity Index was a predictor of the development of the sum of all adverse events. The resumption of anticoagulant therapy after the development of major bleeding in patients with atrial fibrillation reduces the risk of thrombosis and death at a cost, while increasing the risk of recurrence of non-fatal bleeding.


Using a combination therapy to combat scalp necrosis: a case report.
Chronic nonhealing wounds are very expensive to treat and debilitating, and they reduce health-related quality of life. Scalp necrosis is very rare due to its rich vascularity. However, any post-traumatic wounds with secondary infection can lead to scalp necrosis. We report a case of a 77-year-old Azerbaijani man with a history of diabetes who had a car accident and sustained a scalp wound. He underwent reconstructive surgery for the scalp wound. The wound became infected, and scalp necrosis developed following the surgery. There was no progress in wound healing in spite of conventional wound therapy. We combined maggot debridement therapy with negative-pressure wound therapy and amniotic membrane grafting for 7 months. Necrotic tissues began to be eliminated after the second use of larva therapy, and the wound became free of necrotic tissues with clear increase of granulated tissues after four treatments with maggot debridement therapy. Then, we applied negative-pressure wound therapy and amniotic membrane grafting to accelerate wound healing and improve wound closure. The patient's scalp wound recovered well, and he was discharged to home in good condition. Medical and wound care teams can benefit from this combination therapy when dealing with nonhealing necrotic wounds.


Amygdaloid projections to ventromedial striatal subterritories in the primate.
The ventral striatum is the part of the striatum associated with reward and goal-directed behaviors, which are mediated in part by inputs from the amygdala. The ventral striatum is divided into 'shell' and 'core' subterritories which have different connectional, histochemical and pharmacological properties. Behavioral studies also indicate that subterritories of the ventral striatum are differentially involved in specific goal-directed behaviors. The amygdala is a heterogeneous structure which has multiple nuclei involved in processing emotional information. While the existence of an amygdalostriatal pathway has long been established, the relationship between amygdaloid afferents and specific subterritories of the ventral striatum is not known. In this study we operationally defined the ventromedial striatum as the region receiving cortical inputs primarily from the orbital and medial prefrontal cortex. We placed retrograde tracer injections into subregions of the ventromedial striatum of macaques monkeys to determine the relative contribution of specific amygdaloid inputs to each region. Calbindin-D28k immunostaining was used to further define the shell subterritory of the ventromedial striatum. Based on these definitions, the amygdala innervates the entire ventromedial striatum, and has few to no inputs to the central striatum. The basal and accessory basal nuclei are the major source of input to the ventromedial striatum, innervating both the shell and ventromedial striatum outside the shell. However, a restricted portion of the dorsomedial shell receives few basal nucleus inputs. Afferent inputs from the basal nucleus subdivisions are arranged such that the parvicellular subdivision projects mainly to the ventral shell and core, and the magnocellular subdivision targets the ventral shell and ventromedial putamen. In contrast, the intermediate subdivision of the basal nucleus projects broadly across the ventromedial striatum avoiding only the dorsomedial shell. The shell has a specific set of connections derived from the medial part of the central nucleus and periamygdaloid cortex. Within the shell, the dorsomedial region is distinguished by additional inputs from the medial nucleus. The ventromedial caudate nucleus forms a unique transition zone with the shell, based on inputs from the periamygdaloid cortex. Together, these results indicate that subterritories of the ventromedial striatum are differentially modulated by amygdaloid nuclei which play roles in processing olfactory, visual/gustatory, multimodal sensory, and 'drive'-related stimuli.


Clinical relevance and inter-test reliability of anti-infliximab antibodies and infliximab trough levels in patients with inflammatory bowel disease.
Treatment with infliximab is a common option for inflammatory bowel disease (IBD) patients. Therapeutic drug monitoring could improve treatment management. To test inter-test reliability of two commercially available diagnostic kits for infliximab trough levels and infliximab antibodies, and their association with treatment outcomes. 86 IBD outpatients on infliximab maintenance treatment were enrolled in a prospective cross-sectional study, 115 samples were available for inter-test reliability. Inter-test agreement was good both for trough levels (concordance correlation coefficient 0.78, weighted κ 0.60, Sperman's ρ 0.937) and for infliximab antibodies (weighted κ 0.79) measurement, when comparing Promonitor and ImmunDiagnostik kits. According to manufacturers' cut-off values, trough levels were classified as undetectable (17%), low (21%) or in range (63%). The only significant associations were: mucosal healing (p=0.026; OR 6.50), infliximab antibody status (p=0.0015; OR 0.031) and adverse events (p=0.009; OR 0.115). Higher trough levels were observed among patients on concomitant steroid/immunosuppressive therapy and among patients with dose-intensification. Infliximab antibodies were significantly associated to treatment-related adverse events (p=0.0003, OR 30.42), and to lower trough levels, but not to other clinical variables. The two tests performed equally well. Infliximab antibodies were associated to adverse events, while trough levels were not associated to treatment outcomes.


Chronic bronchitis, cigarette smoking, and the subsequent onset of depression and anxiety: results from a prospective population-based cohort study.
The authors used data from a prospective, population-based cohort study to examine: (a) whether the presence of chronic bronchitis predicts the subsequent onset of depression or anxiety, and (b) if the incidence of depressed or anxious cases was different for smokers compared with nonsmokers. For studying the relation between chronic bronchitis and anxiety or depression, we used data from respectively 4468 and 4520 respondents. The number of incident anxious (19.1%, n = 17) and depressed (14.0%, n = 13) cases was highest in employees with chronic bronchitis compared with employees without respiratory complaints (4.3%, n = 189 and 3.3%, n = 145, respectively). The presence of chronic bronchitis was associated with a significant increase in anxious and depressed cases (odds ratio (OR) for anxiety = 5.09, 95% confidence interval (CI) 2.91, 8.89; OR for depression = 4.38, 95% CI 2.35, 8.16). The incidence of anxiety as well as depression was strongest in the smokers group (OR for anxiety = 8.94, 95% CI 4.08, 19.59; OR for depression = 7.56, 95% CI 3.37, 16.96). This prospective study shows significantly higher levels of anxiety as well as depression in employees with chronic bronchitis. Results also seem to indicate that smoking cigarettes modifies this association, resulting in an increased risk of depression and anxiety in employees with chronic bronchitis who smoke.


In vitro cell models merging circadian rhythms and brain waves for personalized neuromedicine.
New evidence is emerging about the dynamics of interaction between circadian rhythms and brain waves, whose coordination occurs through the entrainment process. The so-called "oscillopathies" or dysfunctions in synchronization of neuronal oscillation in key brain networks lead to the onset of neurodegenerative diseases. A typical example of alteration is insomnia, a risk factor for the oscillopathies, increasingly widespread worldwide. Recently, synchronization of circadian rhythms in cell cultures has allowed an improvement in the physiological relevance of responses to stimuli. Furthermore, brain organoids and neurons cultured in microfluidic systems are the latest frontiers for in vitro reproduction of rhythmic electrical signals. In this review, the combination of these in vitro experimental approaches is proposed as suitable for a more direct investigation on the common mechanisms and neurophysiological substrates underlying brain waves and circadian oscillations, and useful to evaluate the effects of "oscillotherapeutic" drugs for personalized neuromedicine.


Systems biology in malaria research.
A recent publication of genome and expression analyses of the murine parasites Plasmodium chabaudi chabaudi and Plasmodium berghei presents the state of the art in Plasmodium systems biology. By integrating genomics, transcriptomics and proteomics, the authors can classify and annotate genes by their expression profiles and can even detect evidence of posttranscriptional gene silencing in the murine malaria species.


Office-Based Blue Laser Therapy for Vocal Fold Leukoplakia: A Preliminary Report of 12 Cases.
To report the efficacy of office-based blue laser therapy for vocal fold leukoplakia. A retrospective case series. A tertiary care center. A retrospective chart review of patients with vocal fold leukoplakia who underwent office-based blue laser therapy between July 2019 and October 2022 was conducted. The video recordings of their laryngeal examination and their voice evaluation were analyzed before and after surgical intervention. A total of 10 patients, eight with unilateral disease and 2 with bilateral disease, were included in this study. In total, 12 vocal folds with leukoplakia were treated. Nine had a single session and 3 had 2 sessions due to incomplete regression of the lesion after the first laser therapy session. Following treatment, 9 regressed completely (75%) and 3 regressed partially (25%). The mean Voice Handicap Index-10 (VHI-10) score decreased significantly from 15.4 ± 12.9 preoperatively to 3.8 ± 2.86 after surgery (p = .023). There was a statistically significant decrease in the means of grade, roughness, breathiness, asthenia, and strain (p < .05). There was also a statistically significant decrease in the jitter and shimmer percent (p = .008 and p = .048, respectively) and a significant increase in the maximum phonation time from 9.63 ± 3.83 to 13.54 ± 5.92 seconds (p = .039). This preliminary study indicates that office-based blue laser therapy is an effective treatment modality for vocal fold leukoplakia.


Protomer selectivity of type II RAF inhibitors within the RAS/RAF complex.
RAF dimer inhibitors offer therapeutic potential in RAF- and RAS-driven cancers. The utility of such drugs is predicated on their capacity to occupy both RAF protomers in the RAS-RAF signaling complex. Here we describe a method to conditionally quantify drug-target occupancy at selected RAF protomers within an active RAS-RAF complex in cells. RAF target engagement can be measured in the presence or absence of any mutant KRAS allele, enabling the high-affinity state of RAF dimer inhibitors to be quantified in the cellular milieu. The intracellular protomer selectivity of clinical-stage type II RAF inhibitors revealed that ARAF protomer engagement, but not engagement of BRAF or CRAF, is commensurate with inhibition of MAPK signaling in various mutant RAS cell lines. Our results support a fundamental role for ARAF in mutant RAS signaling and reveal poor ARAF protomer vulnerability for a cohort of RAF inhibitors undergoing clinical evaluation.


Angiotensin and sodium balance: their role in chronic two-kidney Goldblatt hypertension.
The purpose of this study was twofold: 1) to determine whether the failure of rats with chronic renovascular hypertension to respond to the angiotensin II antagonist (AIIA) with a decrease in mean blood pressure (BP) was dur to the agonistic effect of the antagonist; and, 2) if this was not the case, to examine whether a positive sodium balance impaired the reversal of the hypertension, after unclamping, in the rats that did not respond to angiotensin inhibitors. For this purpose, rats with chronic, two-kidney Goldblatt hypertension (one renal artery clamped and contralateral untouched) were tested for their BP response to the AIIA (1-Sar-8-Ala-angiotensin II) and to the converting enzyme inhibitor (CEI) SQ20,881, which is devoid of agonistic effect. Approximately 50% of the rats responded to both inhibitors either with no change or with a decrease in BP of less than 20 mm Hg (nonresponders). The other 50% had a decrease in BP of 20 mm Hg or greater (responders). The decrease in BP produced by the AIIA and the CEI correlated significantly (r = 0.76). Nonresponders to both inhibitors were unclamped or sham unclamped. A positive sodium balance was produced before surgery by injecting either 400 or 1000 microEq of sodium and was maintained for 12 hours. Direct BP significantly decreased 12 hours after surgery in the unclamped rats despite a continuous positive sodium balance. In the sham unclamped rats, BP did not change. These data indicate that the failure to respond to the AIIA is not due to the agonistic effect of this peptide. Furthermore, these data suggest that a positive sodium balance is not a major pathogenetic factor in maintaining the high BP in the nonresponder rats, since a positive sodium balance failed to maintain the hypertension after unclamping.


Psychiatric consultations and ethics consultations. similarities and differences.
Although consultation-liaison psychiatry and clinical ethics both developed largely in response to the problems engendered by the new medical technology and the dilution of the traditional doctor-patient relationship, they represent distinct fields that rely on different, but overlapping, domains of expertise. To be effective, ethics consultants often need to augment their own background with psychiatric knowledge and skills. Consultation-liaison psychiatrists are well prepared to contribute to clinical ethics but cannot serve effectively as ethics consultants without additional education and training. Several case examples are presented to elucidate these points and to illustrate the similarities and differences between psychiatric consultations and ethics consultations.


Port-access cardiac surgery with cardiopulmonary bypass and cardioplegic arrest.
In the past decade, laparoscopic and thoracoscopiC technology have significantly and irreversibly altered the approach to many general and thoracic surgical diseases. With advances in laparoscopy and thoracoscopy, the concept of a minimally invasive approach to cardiac surgery has been realized.


Designing Empathic Virtual Agents: Manipulating Animation, Voice, Rendering, and Empathy to Create Persuasive Agents.
Designers of virtual agents have a combinatorically large space of choices for the look and behavior of their characters. We conducted two between-subjects studies to explore the systematic manipulation of animation quality, speech quality, rendering style, and simulated empathy, and its impact on perceptions of virtual agents in terms of naturalness, engagement, trust, credibility, and persuasion within a health counseling domain. In the first study, animation was varied between manually created, procedural, or no animations; voice quality was varied between recorded audio and synthetic speech; and rendering style was varied between realistic and toon-shaded. In the second study, simulated empathy of the agent was varied between no empathy, verbal-only empathic responses, and full empathy involving verbal, facial, and immediacy feedback. Results show that natural animations and recorded voice are more appropriate for the agent's general acceptance, trust, credibility, and appropriateness for the task. However, for a brief health counseling task, animation might actually be distracting from the persuasive message, with the highest levels of persuasion found when the amount of agent animation is minimized. Further, consistent and high levels of empathy improve agent perception but may interfere with forming a trusting bond with the agent.


[Physical complaints, emotional stress and locus of control in the course of orthopaedic rehabilitation].
Based on the biopsychosocial model, the present paper investigates the interactions between physical complaints and psychological parameters under the terms of a rehabilitation procedure. In 309 participants of orthopaedic rehabilitation, the course of physical complaints (GBB-24), emotional stress (HADS-D) and locus of control (KU-WS) were recorded using a pre-post design. Additionally, the impact of the factors gender, age and level of chronicity as well as the interactions between the variables were analysed. Compared to the general population, the rehabilitation participants had significantly higher levels of fatigue, limb pain and pressure caused by complaints as well as anxiety and depression. Definite changes under the terms of rehabilitation were found for all single parameters of physical complaints and emotional stress; however, the scales with initially significantly increased values did not reach the levels of the general population. The reduction of physical complaints was significantly correlated with the reduction of emotional stress. The relationship between physical complaints and locus of control was much lower. The present paper confirms the strong interaction between biological and psychological factors under the terms of a rehabilitation process.


Hyperhomocysteinemia induces liver injury in rat: Protective effect of folic acid supplementation.
Hyperhomocysteinemia, a condition of elevated blood homocysteine level, is an independent risk factor for cardiovascular diseases. Hyperhomocysteinemia is also found in patients with liver diseases. However, the direct effect of homocysteine on liver injury is not well known. Folic acid supplementation is a promising approach for improving endothelial function in patients with hyperhomocysteinemia. The aim of this study was to investigate the direct effect of hyperhomocysteinemia on liver injury and whether folic acid could offer any protective effect to the liver. Hyperhomocysteinemia was induced in rats fed a high-methionine diet for 4 weeks. There was a significant increase in the serum aspartate aminotransferase and alanine aminotransferase activities reflecting liver injury in hyperhomocysteinemic rats. Hepatic NAD(P)H oxidase was activated during hyperhomocysteinemia leading to increased superoxide anion production and peroxynitrite formation in the liver. As a consequence, the level of lipid peroxides was significantly elevated in livers of hyperhomocysteinemic rats. Folic acid supplementation effectively inhibited NAD(P)H oxidase-mediated superoxide anion production leading to reduced lipid peroxidation in the liver. Folic acid supplementation also alleviated hyperhomocysteinemia-induced liver injury. These results suggest that hyperhomocysteinemia can cause liver injury and supplementation of folic acid offers a hepatoprotective effect.


Impact of female age and nulligravidity on fecundity in an older reproductive age cohort.
To provide female age-related estimates of fecundity and incidence of infertility by history of prior pregnancy among women 30-44 years of age. Prospective, time-to-pregnancy cohort study. Not applicable. Women, between 30 and 44 years of age, attempting to conceive for ≤3 months, and no known history of infertility, polycystic ovarian syndrome (PCOS), or endometriosis. Not applicable. Fecundability and incidence of infertility. Compared to women aged 30-31 years, fecundability was reduced by 14% in women 34-35 years of age (fecundability ratio [FR] 0.86, 95% confidence interval [CI] 0.68-1.08), 19% in women 36-37 years of age (FR 0.81, 95% CI 0.60-1.08, 30% in women 38-39 years of age (FR 0.70, 95% CI 0.48-1.01), 53% in women 40-41 years of age (FR 0.47, 95% CI 0.28-0.78), and 59% in women 42-44 years of age (FR 0.39, 95% CI 0.16-0.93). Fecundability did not differ between women aged 30-31 years and 32-33 years. In general, fecundability and cumulative probability of pregnancy was lower for women who had never had a prior pregnancy. Women experience a significant reduction in fecundity and increase in the probability of infertility in their late thirties. At any age >30 years, women who have never conceived have a lower probability of achieving a pregnancy. NCT01028365.


The Transition of Pediatric Tracheobronchial Foreign Body Cases in the Past 36 Years: A Retrospective Single-Center Study in Japan.
Tracheobronchial foreign bodies (TFBs) are pediatric airway emergencies frequently seen. We aimed to examine the changes in the clinical characteristics of pediatric TFB patients in a single institution within the past 36 years. We retrospectively reviewed the data of 85 patients aged 0-10 years with TFBs lodged in the trachea or bronchus admitted at the Department of Otolaryngology-Head and Neck Surgery at Tohoku University Hospital between 1986 and 2021. We also compared the characteristics, diagnostic methods, and treatments of the previous 64 cases (1986-2005) with those of the recent 21 cases (2006-2021). The number of TFB patients decreased later in this study (3.2 vs. 1.3 patients per year). The proportion of TFB patients aged > 3 years was significantly higher in the later period (6.3% vs. 23.8%, p = 0.038). Peanut was the most common cause of TFBs in both periods, and the overall incidence of peanut aspiration significantly decreased in the later period (68.8% vs. 38.1%, p = 0.019). No patient had an undetected TFB for more than 1 month after the onset of symptoms in the later period. Foreign body extraction using rigid bronchoscopy was performed in all patients earlier, whereas flexible bronchoscopy was used in 14.3% later. Our study revealed a recent trend in the clinical characteristics of pediatric TFB patients in a single institution in Northeast Japan. The prevention and treatment of pediatric TFBs should be considered following the recent trends.


Predictors and prognoses of new onset post-stroke anxiety at one year in black Africans.
There is relatively limited information on the risk factors and outcome of new onset Poststroke Anxiety (PSA) in Low- and Middle-Income Countries. We estimated incidence, cumulative incidence, risk factors and outcome of new onset anxiety in the first year of stroke among African stroke survivors. We analyzed the dataset of a completed clinical trial comprising patients enrolled to test an intervention designed to improve one-year blood pressure control among recent (≤ one month) stroke survivors in Nigeria. Anxiety was measured using the Hospital Anxiety and Depression Scale. Outcomes were assessed using the modified Rankin Scale (mRS), Community screening instrument for dementia (CSID) and Health Related Quality of Life in Stroke Patients (HRQOLISP-26). Among 322 stroke survivors who were free of anxiety at baseline, we found a one-year cumulative incidence of 34% (95% CI = 28.6-39.3). Rates were 36.2% (95% CI =29.6-42.7) for men and 29.2% (95% CI =19.9-38.3) for women. In multivariate Cox regression analyses, haemorrhagic stroke type was associated with higher risk of new onset PSA (Hazard Ratio=1.52, 95% CI =1.01-2.29). New onset PSA was independently associated with cognitive [(mean difference (MD) in CSID scores=1.1, 95% C.I=0.2, 1.9)] and motor decline (MD in mRS scores= -0.2, 95% C.I= -0.4, -0.02), as well as poorer quality of life overtime (MD in total HRQOLISP-26 scores=3.6, 95% C.I=1.0, 6.2). One in 3 stroke survivors in Nigeria had PSA at one year. Clinicians in SSA should pay special attention to survivors of haemorrhagic stroke as they are at higher risk of incident anxiety and therefore its consequences.


Incidence of antipsychotic use in relation to diagnosis of Alzheimer's disease among community-dwelling persons.
Behavioural and psychological symptoms of dementia are frequently treated with antipsychotics. To determine the incidence of antipsychotic use in relation to diagnosis of Alzheimer's disease. Cohort of all community-dwellers in Finland diagnosed with Alzheimer's disease in 2005 and matched controls. All antipsychotics dispensed between 1995 and 2009 were extracted from the Finnish National Prescription Register. Altogether 1996/6087 (32.8%) persons with Alzheimer's disease initiated antipsychotic use. The incidence of antipsychotic use was fivefold among persons with Alzheimer's disease compared with controls, started to increase 2-3 years before diagnosis and was highest during the first 6 months after diagnosis. A distinct increase in antipsychotic initiations occurs in the same time window as Alzheimer's disease diagnosis.


An increased frequency of structural chromosome aberrations in persons present in the vicinity of Chernobyl during and after the reactor accident. Is this effect caused by radiation exposure?
About a week after the reactor accident in Chernobyl, a number of German citizens returned to the Federal Republic of Germany from different places of residence in the U.S.S.R. Chromosome analyses of these individuals show a surprisingly significant increase in dicentric chromosomes in comparison to the laboratory control. Acentrics are nearly twice as frequent as dicentrics. Centric rings are also in evidence. Chromatid breaks do not significantly differ from the control with the exception of 1 place of residence. The frequency of aberrations is too high to be induced by absorbed doses calculated physically or by modelling techniques. So far, no explanation is available for the discrepancy-a factor of about 100-between calculated absorbed doses and the measured biological effect.


Multiplication of normal and virus-infected diploid cells cultivated on microcarriers.
In prelminary studies, growth of diploid cells (fetal calf buccal cells and chick embryo fibroblasts on dextran microcarriers was studied and compared to growth in monolayer. Growth coefficients obtained were always greater (by 2 fold) when microcarriers were used. Moreover, this technique had the advantage of reducing the number of manipulations and hence the risk of contamination. In two series of experiments, buccal epithelial cells were infected with vescicular stomatitis virus. Good virus multiplication was obtained.


Teletriage Pilot Study (Strategy for Unscheduled Teleconsultations): Results, Patient Acceptance and Satisfaction.
Non-urgent consultations to an Emergency Department (ED) contribute to overcrowding. Telecommunications represent a potential strategy to reduce some face-to-face consultations. To describe characteristics of patients who used the Teletriage Program during the pilot study, to explore safety and to report user acceptance and satisfaction. Cross-sectional study, including all adult patients affiliated to our health insurance attended to via this telemedicine service between January 18th and May 31st, 2019 (during pilot-study). Patients were followed-up for seven days to assess re-consultation to ED or unscheduled hospitalization. 276 effective consultations occurred, corresponding to 241 patients, with a mean of age of 50 years, 68% (189) were women. Chief complaints were related to clinical issues (70%) and remaining (30%) were administrative problems. Only four patients were suggested a referral or face-to-face assessment. Rate of re-consultation to the ED was 18% (51) at seven days of follow-up, and the rate of unscheduled hospitalization was <1% (2), both with good clinical evolution. Patient satisfaction was 72.73%, and regarding acceptability, 66.12% stated that without this channel they would have attended to a face-to-face consultation and 64.02% that they would do so if their needs remained unmet. Implementing this new communication channel could be a useful and safe strategy to reduce unnecessary non-urgent consultations to the ED.


Contribution of diet and other factors to the levels of selected polyfluorinated compounds: data from NHANES 2003-2008.
Contribution of diet and selected risk factors to the levels of four polyfluorinated compounds was evaluated. Data from National Health and Nutrition Examination Survey for the years 2003-2008 were used. Dietary factors accounted for 10.4% to 21.2% of the explained variation. Amount of milk consumed was found to be positively associated (p<0.01) with perfluorononanoic acid (PFNA) but negatively associated with perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) (p<0.01). Amount of meat and fish consumed was positively associated (p<0.01) with PFNA and PFOS. Amount of non-alcoholic beverages consumed was positively associated (p<0.01) with PFNA and PFOA. Levels of PFOS increased (p<0.01) with increase in the amount of alcoholic beverages consumed. Total amount of alcohol consumed was positively associated (p<0.01) with PFNA. Levels of both PFOA and PFOS decreased with increase in total amount of caffeine consumed. Total amount of fat consumed was negatively associated with PFNA and positively associated with PFOS. Total calories consumed were negatively associated with perfluorohexane sulfonate (PFHxS) and PFOS but positively associated with PFNA. New to this study, positive correlations (p<0.01) between serum cholesterol and PFNA, PFOA, and PFOS were found. Serum albumin levels were negatively correlated with PFHxS but positively correlated with PFOA and PFOS. Males had statistically significantly higher levels of all four PFCs as compared to females and Mexican Americans had the lowest levels of all four PFCs than other race/ethnic groups. Levels of all four PFCs increased with increase in family income. Body mass index was negatively correlated with PFNA but positively associated with PFOA. There was a statistically significant decrease in the levels of PFOS over survey years 2003-2008.


Clinical prediction of thrombectomy eligibility: A systematic review and 4-item decision tree.
A clinical large anterior vessel occlusion (LAVO)-prediction scale could reduce treatment delays by allocating intra-arterial thrombectomy (IAT)-eligible patients directly to a comprehensive stroke center. To subtract, validate and compare existing LAVO-prediction scales, and develop a straightforward decision support tool to assess IAT-eligibility. We performed a systematic literature search to identify LAVO-prediction scales. Performance was compared in a prospective, multicenter validation cohort of the Dutch acute Stroke study (DUST) by calculating area under the receiver operating curves (AUROC). With group lasso regression analysis, we constructed a prediction model, incorporating patient characteristics next to National Institutes of Health Stroke Scale (NIHSS) items. Finally, we developed a decision tree algorithm based on dichotomized NIHSS items. We identified seven LAVO-prediction scales. From DUST, 1316 patients (35.8% LAVO-rate) from 14 centers were available for validation. FAST-ED and RACE had the highest AUROC (both >0.81, p < 0.01 for comparison with other scales). Group lasso analysis revealed a LAVO-prediction model containing seven NIHSS items (AUROC 0.84). With the GACE (Gaze, facial Asymmetry, level of Consciousness, Extinction/inattention) decision tree, LAVO is predicted (AUROC 0.76) for 61% of patients with assessment of only two dichotomized NIHSS items, and for all patients with four items. External validation of seven LAVO-prediction scales showed AUROCs between 0.75 and 0.83. Most scales, however, appear too complex for Emergency Medical Services use with prehospital validation generally lacking. GACE is the first LAVO-prediction scale using a simple decision tree as such increasing feasibility, while maintaining high accuracy. Prehospital prospective validation is planned.


Sodium selective ion channel formation in living cell membranes by polyamidoamine dendrimer.
Polyamidoamine (PAMAM) dendrimers are highly charged hyperbranched protein-like polymers that are known to interact with cell membranes. In order to disclose the mechanisms of dendrimer-membrane interaction, we monitored the effect of PAMAM generation five (G5) dendrimer on the membrane permeability of living neuronal cells followed by exploring the underlying structural changes with infrared-visible sum frequency vibrational spectroscopy (SVFS), small angle X-ray scattering (SAXS) and transmission electron microscopy (TEM). G5 dendrimers were demonstrated to irreversibly increase the membrane permeability of neurons that could be blocked in low-[Na(+)], but not in low-[Ca(2+)] media suggesting the formation of specific Na(+) permeable channels. SFVS measurements on silica supported DPPG-DPPC bilayers suggested G5-specific trans-polarization of the membrane. SAXS data and freeze-fracture TEM imaging of self-organized DPPC vesicle systems demonstrated disruption of DPPC vesicle layers by G5 through polar interactions between G5 terminal amino groups and the anionic head groups of DPPC. We propose a nanoscale mechanism by which G5 incorporates into the membrane through multiple polar interactions that disrupt proximate membrane bilayer and shape a unique hydrophilic Na(+) ion permeable channel around the dendrimer. In addition, we tested whether these artificial Na(+) channels can be exploited as antibiotic tools. We showed that G5 quickly arrest the growth of resistant bacterial strains below 10μg/ml concentration, while they show no detrimental effect on red blood cell viability, offering the chance for the development of new generation anti-resistant antibiotics.


Polypoidal choroidal vasculopathy treatment options: A meta-analysis.
Combined treatment with intravitreal anti-vascular endothelial growth factor (anti-VEGF) and verteporfin photodynamic therapy (PDT) is widely used for patients with polypoidal choroidal vasculopathy (PCV), although clinical evidence regarding the therapeutic efficacy and safety of such treatment remains lacking. We performed a meta-analysis of previously reported studies comparing combination treatment, PDT monotherapy, and anti-VEGF monotherapy. Primary outcome measures included changes in best-corrected visual acuity (BCVA) and central retinal thickness (CRT). The proportion of patients with polyp regression was regarded as the secondary outcome measure. Twenty studies (three RCTs and 19 retrospective studies) involving 1,178 patients with PCV were selected. Significant differences in the proportion of patients with polyps were observed between the PDT and anti-VEGF monotherapy groups at 3 and ≥6 months (P < .00001; and P = .0001, respectively). Significantly greater reductions in CRT were observed in the anti-VEGF than in the PDT group at the 3-month follow-up (P = .04). Significantly greater improvements in BCVA were observed in the combined therapy group than in the PDT monotherapy group at 3, 6, 12, and 24 months (P = .03; P = .005; P = .02; and P < .00001, respectively). Combined treatment also resulted in significantly greater improvements in BCVA than monotherapy with anti-VEGF at 6 and 24 months (P = .001; P < .00001, respectively), and significantly greater polyp regression than that observed following anti-VEGF treatment at 3 and ≥6 months (P < .00001; P < .0001, respectively). Combined therapy involving anti-VEGF agents and PDT may be more effective in improving long-term outcomes for patients with PCV than monotherapy.


Characterization of a late gene, ORF75 from Bombyx mori nucleopolyhedrovirus.
Open reading frame 75 (Bm-p33) of Bombyx mori nucleopolyhedrovirus (BmNPV) is a homologue of Autographa californica multiple nucleopolyhedrovirus ORF92. The gene is conserved among all baculoviruses that have been completely sequenced to date and is considered to be a baculovirus core set gene. No amino acid mutation was found in Bm-p33 sequences among six BmNPV strains differing in geography, phenotype, or host. The Bm-p33 transcript can be detected as early as 12 h post infection (h p.i.) and remains detectable until 96 h p.i. The Bm-p33 protein was detected in cell lysates from 18 h p.i. through 96 h p.i., and no positive band could be detected in budded viruses (BVs) and occlusion-derived viruses (ODVs) by western blot using anti-Bm-p33 serum. Immunofluorescence microscopy indicated that Bm-p33 accumulated in the nuclear membrane and the intranuclear region, especially near the nuclear membrane of the virus-infected cells. Bm75 RNAi significantly decreased the mRNA level. However, no obvious effects on ODV formation and BV production in BmNPV-infected cells could be detected. Bm-p33 is a BmNPV late gene encoding a nonstructural protein which may function mainly in the nucleus of the infected cells.


Gender is a major factor explaining discrepancies in eye colour prediction based on HERC2/OCA2 genotype and the IrisPlex model.
In recent years, several studies have greatly increased our understanding of the genetic basis underlying human eye colour variation. A large percentage of the eye colour diversity present in humans can already be genetically explained, so much so that different DNA-based eye colour prediction models, such as IrisPlex, have been recently developed for forensic purposes. Though these models are already highly accurate, they are by no means perfect, with many genotype-phenotype discrepancies still remaining unresolved. In this work we have genotyped six SNPs associated with eye colour (IrisPlex) in 535 individuals from Spain, a Mediterranean population. Aside from different SNP frequencies in Spain compared to Northern Europe, the results for eye colour prediction are quite similar to other studies. However, we have found an association between gender and eye colour prediction. When comparing similar eye colour genetic profiles, females tend, as a whole, to have darker eyes than males (and, conversely, males lighter than females). These results are also corroborated by the revision and meta-analysis of data from previously published eye colour genetic studies in several Caucasian populations, which significantly support the fact that males are more likely to have blue eyes than females, while females tend to show higher frequencies of green and brown eyes than males. This significant gender difference would suggest that there is an as yet unidentified gender-related factor contributing to human eye colour variation.


PSA outcome following radical prostatectomy for patients with localized prostate cancer stratified by prostatectomy findings and the preoperative PSA level.
Algorithms have been developed to predict time to biochemical failure (BF) following radical prostatectomy (RP) for patients with clinically localized prostate cancer. The purpose of this study was to validate an algorithm based on prostatectomy findings and to evaluate whether the preoperative serum prostate specific antigen (PSA) enhances the predictive ability of the algorithm. Between 1988 and 2002, 2417 patients underwent RP for clinically localized prostate cancer at one of 2 large university hospitals. Patients were retrospectively stratified into 4 risk groups based upon prostatectomy grade, stage, and margin status, and were then dichotomized by the preoperative PSA level (cut point 10 ng/mL). Cox regression multivariable analyses were performed to evaluate the ability of the risk group and preoperative PSA level to predict time to BF (PSA more than 0.2 ng/mL) following RP. The preoperative PSA level (P < 0.0001) and risk group (P < 0.0001) were significant predictors of time to BF following RP. Estimates of the BF rates 7 years following RP were 13%, 30%, 51%, and 72% for groups 1-4, respectively (pairwise P values <or=0.0002). Further stratification within each risk group using the preoperative PSA level with a cut point at 10 ng/mL revealed BF rates of 8% versus 35%, 25% versus 54%, 31% versus 73%, and 63% versus 86% for risk groups 1-4, respectively (all P values <0.0001). An algorithm to predict BF based on prostatectomy findings has been validated, and the addition of the preoperative PSA level improved its ability to identify high risk patients who may benefit from entry into adjuvant treatment trials.


How safe is the light during ophthalmic diagnosis and surgery.
The light used when undertaking ophthalmic diagnosis or ophthalmic surgery can be hazardous and the need to address this from a clinical and practicable point of view is discussed. Not all patients are equally at risk. Age and health are risk factors that need to be taken into account, the aged eye being more at risk as is the eye with existing disease. The risk of photochemical damage to the retina is increased as a result of patients being examined with different ophthalmic instruments during a 24-h period. The ways in which the clinician needs to address these safety issues is discussed bearing in mind the guidelines that are being developed.


Elevated cardiac troponin I level in cases of thoracic nonaccidental trauma.
Injury patterns in nonaccidental trauma (NAT) often include injury to the chest. However, signs and symptoms of cardiac insult are often nonspecific and may be missed. Evaluation with serum cardiac troponin I (CTnI), a specific indicator of myocardial injury, could improve the comprehensive evaluation of patients with suspected NAT. The objective of this study was to describe the patient characteristics and results of CTnI testing in children with thoracic NAT. Children presenting to the emergency department were included if CTnI was obtained and they had at least one of the following: history of blunt trauma to the chest, bruising or abrasions to the chest, or fractures of the ribs, sternum, or clavicles. A serum CTnI level above 0.04 ng/mL was considered elevated. Ten patients (6 males) with an age range from 2 months to 4 years (mean [SD], 20 [20] months) were identified during the 17-month study period. All patients were evaluated with NAT. Cardiac troponin I level was elevated in 7 (70%) of 10 patients with levels between 2 and 50 times the upper limit of normal. This report is the first to document elevation of CTnI levels in cases of thoracic NAT. The elevation of the level of this specific biomarker may be indicative of sufficient chest trauma to result in the heart being injured, independent of the presence of cardiac decompensation or shock from other causes. Prospective evaluation of the forensic and clinical use of CTnI in this population is warranted.


Synthesis, Characterization and Biological Evaluation of Co(II), Cu(II), Ni(II) and Zn(II) Complexes With Cephradine.
Some Co(II), Cu(II), Ni(II) and Zn(II) complexes of antibacterial drug cephradine have been prepared and characterized by their physical, spectral and analytical data. Cephradine acts as bidentate and the complexes have compositions, [M(L)(2)X(2)] where [M = Co(II), Ni(II) and Zn(II), L = cephradine and X = Cl(2)] showing octahedral geometry, and [M(L)(2)] where [M = Cu(II), L = cephradine] showing square planar geometry. In order to evaluate the effect of metal ions upon chelation, eephradine and its complexes have been screened for their antibacterial activity against bacterial strains, Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa.


On the need of validating inpatient registers.
Register study. To design and implement a validation process to check the completeness of the Hospital Discharge Register (HDR) held by the Swedish National Board of Health and Welfare. Sweden. An accurate traumatic spinal cord injury prevalence group (n=495) was acquired from the Swedish Spinalis Clinic. A register control was performed on the group by raising three questions to check the validity of the HDR: Is an inpatient stay registered in association with the injury date? Is the reported first length of stay plausible, given the level and extent of injury? Are all the anticipated care and/or rehabilitation providers represented in the HDR? For 62% (of 413 cases) the first registered hospitalization date correlated with the injury date. For the other 38%, hospitalization was reported to start between 2 and 8651 days after injury. Considering the level and extent of injury, individuals were reported to have unrealistically short initial hospitalization. The prevalence group visited 42 different hospitals and 47 clinics. Five rehabilitation clinics, though, were not reported. The HDR is a valuable source when conducting epidemiological and health services research. However, using the register without any validation process could, as detected in the investigated diagnosis group, lead to a severe underestimation of the inpatient usage. The study showed that systematic errors could be detected by means of extensive knowledge of the diagnosis group.


Brain metastases.
Brain metastases are a common complication of cancer and alter patient management more than metastases at any other site of distant progression. Supportive therapies include steroids and antiseizure medications. Definitive treatments include radiation therapy, surgery, and chemotherapy. The optimal choice of treatment and overall prognosis largely depend on patient characteristics and the extent and distribution of disease. Delaying or decreasing neurologic cause of death and disability are important therapeutic goals for this population. While better definitive strategies are investigated, physicians must remember to optimize the use of supportive therapies to ameliorate symptoms and maintain quality of life.


Surface binding and catabolism of low-density lipoprotein by circulating lymphocytes from patients with abetalipoproteinaemia, with observations on sterol synthesis in lymphocytes from one patient.
Surface binding of low-density lipoprotein (LDL), degradation of LDL protein and sterol synthesis were investigated in freshly isolated lymphocytes from normal and abetalipoproteinamic human subjects. LDL binding as a function of LDL concentration showed no evidence of the presence of high-affinity binding sites in fresh lymphocytes from either group of subjects. The rate of degradation of LDL protein by lymphocytes from the patients was no greater than that from the normal subjects and, in the fresh lymphocytes of the one patient studied, sterol synthesis was not increased. We conclude that the formation of LDL receptors and the synthesis of sterol in circulating lymphocytes are largely suppressed and that in normal subjects this may be due to the presence of some plasma constituent other than LDL, possibly the apoE protein. This conclusion is discussed in relation to the possible contribution of LDL receptors to the degradation of LDL protein in vivo.


Effect of implantation of Augment(®) Bone Graft on serum concentrations of platelet-derived growth factors: a pharmacokinetic study.
Augment(®) Bone Graft is a bone graft substitute intended to be used as an alternative to autologous bone graft in the fusion of hindfoot and ankle joints. Augment(®) Bone Graft is a combination device comprised of beta-tricalcium phosphate (β-TCP) and recombinant human platelet-derived growth factor BB homodimer (rhPDGF-BB). This human pharmacokinetic study was undertaken to assess the effect of Augment(®) Bone Graft implantation on the serum concentration of platelet-derived growth factors (PDGFs). Under the terms of a Research Ethics Board-approved protocol, Augment(®) Bone Graft was implanted in patients (n = 7) undergoing hindfoot and ankle arthrodesis procedures requiring graft material. The control cohort of the study (n = 4) received autologous bone graft. The serum concentrations of PDGF isoforms AA, AB and BB in blood samples, obtained prior to and at ten time points (up to 7 days) after surgery, were measured using enzyme-linked immunosorbent assays (ELISA). The serum concentration of PDGF-BB did not vary significantly from baseline (median of the combined cohorts 3.89 ng/mL) throughout the course of the study. The serum concentrations of PDGF-AA, PDGF-AB and total PDGF did not deviate from their baseline values (medians of the combined cohorts were 2.87, 14.95 and 20.19 ng/mL for PDGF-AA, PDGF-AB and total PDGF, respectively) except for the last time point in which they were increased (medians for the combined cohorts were 4.71, 20.42 and 30.29 ng/mL for PDGF-AA, PDGF-AB and total PDGF, respectively). There were no differences between the two treatment groups with regard to changes in the serum concentrations of PDGF. None of the samples tested contained anti-PDGF-BB antibodies. Analysis of the data demonstrated that the serum concentrations of all three PDGF isoforms analysed were unaffected by implantation of Augment(®) Bone Graft.


Effects of an organophosphorous compound on cardiac rhythm and haemodynamics in anaesthetized and conscious beagle dogs.
Cardiac toxicity of S-(2-diisopropylaminoethyl)-O-ethylmethyl phosphonothiolate (VX) has been investigated in the dog. Conscious or open-chest anaesthetized animals were subcutaneously injected with VX (1.5, 3.0 or 6.0 micrograms/kg b.w.). Blood cholinesterase activity decreased to 60%, 20% and 18% respectively of initial values. Only in the 6.0 micrograms/kg-treated group, heart rate, arterial and left intraventricular pressures and contractility index slightly but significantly decreased. In some dogs, treated with either 3.0 micrograms/kg or 6.0 micrograms/kg b.w. of VX, the electrocardiogram was changed: the Q-T interval was lengthened and arrhythmias (atrioventricular blocks, ventricular premature complexes. 'Torsade de pointe') were observed. Plasma non-esterified fatty acid concentrations were identical in control and VX-poisoned dogs. This study shows that, besides the expected cardiac effects resulting from muscarinic stimulation, VX can affect ventricular function through a yet unknown mechanism.


Synthesis of 2-Aminoazoles from Thioesters via α-Heterosubstituted Ketones by Copper-Mediated Cross-Coupling.
Facile synthesis of a variety of α-heterosubstituted ketones under mild conditions was achieved by copper-mediated cross-coupling of thioesters with functionalized organostannanes. Application of this coupling methodology provided a concise pathway for the conversion of carboxylic acids to 2-aminoimidazoles, 2-aminothiazoles, and 2-aminooxazoles via thioesters in practical yields.


Single-locus and Haplotype Associations of GRIN2B Gene with Autism Spectrum Disorders and the Demographic and Clinical Characteristics of Patients in Guilan, Iran.
Autism spectrum disorders (ASDs) are described as generalized developmental disorders, with an average age of onset of 36 months. Genetic and environmental factors may contribute to this multifactorial disorder. The present study aimed to investigate the association of three GRIN2B polymorphisms, including rs1019385, rs1024893, and rs3764028, with ASDs. Based on the results, there was a significant difference regarding the genotype frequency of rs3764028 polymorphism between the control and case (ASD) groups (P = 0.027). According to the recessive model, this variant was associated with ASDs (P = 0.23). None of the eight haplotype models with frequencies above 0.5 showed significant differences between the case and control groups in terms of allelic frequency. The present results showed that the rs376028 variant was directly related to the phenotypic symptoms of ASDs.


An integrated microfluidic system for bovine DNA purification and digital PCR detection.
In this paper, we described an integrated modularized microfluidic system that contained two distinct functional modules, one for nucleic acids (NA) extraction and the other for digital PCR (dPCR), allowing for detecting the bovine DNA in ovine tissue.


Effect of organic zinc, manganese, copper, and selenium chelates on colostrum production and reproductive and lameness indices in adequately supplemented Holstein cows.
The current study aimed to investigate if different sources of supplemental zinc (Zn), manganese (Mn), copper (Cu), and selenium (Se) fed to dry and lactating dairy cows affect reproductive performance, lameness status, and colostrum production. The experiment was carried out on 60 multiparous non-lactating Holstein cows in a commercial dairy herd. The cows received randomly mineral mixtures in three treatment groups containing inorganic, 25% organic-75% inorganic, or 50% organic-50% inorganic forms of Zn, Mn, Cu, and Se starting from approximately 3 weeks prior to calving up to 90 days postpartum. Supplements were included in rations and fed twice a day. Reproductive parameters including days to first service, days to first estrus, service per conception, and conception rate were investigated. After parturition, colostrum production, composition, and immunoglobulin G(1) concentration were determined. Lameness, as an indicator of trace minerals deficiency, was evaluated in a five-score scale. The source of mineral supplement only numerically improved the assessed parameters excluding colostrum fat, protein, and ash percent. The organic form of supplements did not significantly affect reproductive performance, lameness score, or colostrum production.


Using stable lead isotopes to trace heavy metal contamination sources in sediments of Xiangjiang and Lishui Rivers in China.
Lead isotopes and heavy metal concentrations were measured in two sediment cores sampled in estuaries of Xiangjiang and Lishui Rivers in Hunan province, China. The presence of anthropogenic contribution was observed in both sediments, especially in Xiangjiang sediment. In the Xiangjiang sediment, the lower (206)Pb/(207)Pb and higher (208)Pb/(206)Pb ratio, than natural Pb isotope signature (1.198 and 2.075 for (206)Pb/(207)Pb and (208)Pb/(206)Pb, respectively), indicated a significant input of non-indigenous Pb with low (206)Pb/(207)Pb and high (208)Pb/(206)Pb. The corresponding concentrations of heavy metals (As, Cd, Zn, Mn and Pb) were much higher than natural values, suggesting the contaminations of heavy metals from extensive ore-mining activities in the region.


Midgut proteome of an argasid tick, Ornithodoros erraticus: a comparison between unfed and engorged females.
The argasid tick Ornithodoros erraticus is the vector of African swine fever virus and of several Borrelia species that cause human relapsing fever in the Iberian Peninsula. The tick midgut is part of the ectoparasite-host interface and expresses proteins that are vital for the survival of the tick. Midgut proteins are therefore potential targets for drug and/or vaccine design aimed at the development of new strategies for tick control. Thus, the aim of this work was the characterization of the proteome of the O. erraticus midgut before and after a blood meal trying to elucidate the induced changes upon blood feeding. Midgut tissues from unfed and engorged O. erraticus females were dissected and proteins were fractionated by centrifugation and SDS-PAGE, and the corresponding gel pieces analysed by LC-MS/MS. The identified proteins were classified according to their Protein Class and Molecular Function and the differences between fed and unfed specimens were analysed. Overall 555 tick proteins were identified: 414 in the midgut of the unfed specimens and 376 in the fed specimens, of which 235 were present in both groups. The proteins with catalytic, binding and structural functions were the most numerous and abundant, consistent with their role in the intracellular processing of the blood meal. The analysis of some groups of proteins putatively involved directly in blood meal digestion, including protein digestion (peptidase activity), iron metabolism, enzymes involved in oxidative stress and detoxification and membrane traffic and transport proteins, detected some differences between the fed and unfed ticks This work reports for the first time the collection and analysis of the midgut proteome of an argasid tick species and provides molecular information about the argasid machinery involved in blood digestion. This information represents a starting point for the identification and selection of new targets for the development of alternative control strategies.


Childhood esophageal achalasia: Case report from Afghanistan with literature review.
Esophageal achalasia is a motility disorder of the esophagus with unknown etiology characterized by the failure of lower esophageal sphincter relaxation. Diagnosis is made by barium esophagography, endoscopy, and esophageal manometery. Heller Esophagomyotomy along with Dor's fundoplication is the treatment of choice. Persisting undiagnosed cases may lead to malnutrition. We present a case of an 8-year-old child suffering from dysphagia and regurgitation. The child was misdiagnosed and maltreated for the suspicion of respiratory tract and gastrointestinal problems in the local clinics. During this time, he remained unresponsive to the mentioned treatments, and the local physician advised him to have an upper gastrointestinal (GI) endoscopy, which revealed esophageal achalasia (EA). On admission to our pediatric surgery ward, the patient had coexistent parotitis, which was treated conservatively. Following recovery, the patient was prepared for surgery and underwent esophageal myotomy along with Dor's fundoplication. Esophageal achalasia is rare in children, but poses major health challenges to children if left untreated. Symptomatic treatment may mask the actual picture of the problem and last for years. Following surgery and discharge from the hospital in a three-month follow-up interval of time, our patient exhibited full recovery, with gaining 4 kg weight. Respiratory and gastrointestinal conditions with similar signs and symptoms should always be considered in differential diagnosis of esophageal achalasia, especially where there is no direct access to a pediatric specialized complex. On-time evaluation and treatment will further prevent children from malnutrition in long-lasting undiagnosed patients.


Systematic Review on Rocuronium Continuous Infusion for Deep Neuromuscular Blockade.
Rocuronium is a muscle relaxant with increased use due to its binding relation with the reversal agent sugammadex. The purpose of this review entails the investigation of its use for the maintenance of Deep Neuromuscular Block (NMB) via continuous infusion. Based on PRISMA systematic search guidelines, databases included PubMed, ISI Web of Science, Cochrane Library and Google Scholar. This comprehensive search addresses surgical patients under deep muscle relaxation via continuous rocuronium infusion. The main indicators were the rocuronium administration, NMB monitoring approaches and effects in order to maintain the deep level of relaxation, as well as reversal time after a standard dose of sugammadex. Despite the variance in approaches found in the literature, findings show the overall maintenance of deep NMB requires approximately 0.758 mg.kg-1h-1 of rocuronium (according to the PTC target of 0-10, 0-5 and 1-2, mean estimates are 0.445, 0.65 and 0.833 mg.kg-1h-1 respectively), suggesting that a lower range and a smaller maximum of PTC response require higher amount of rocuronium for its maintenance. The standard dose of sugammadex (4 mg/kg), administered at the end of the surgery takes longer [2.85 (1.17) min] than when they are administered after moderate NMB recovery [1.68 (0.47) min]. Continuous infusion for deep NMB presents inherent advantages in terms of maintenance and stability of muscle relaxation. Monitoring and rocuronium administration approaches are fundamental and intrinsically connected to provide a stable and improved maintenance of deep NMB.


Multilocus genotyping of Giardia duodenalis isolates from calves in Oromia Special Zone, Central Ethiopia.
Giardia duodenalis is a widespread protozoan parasite that infects human and other mammals. Assessing the zoonotic transmission of the infection requires molecular characterization as there is considerable genetic variation within the species. This study was conducted to identify assemblages of Giardia duodenalis in dairy calves; and to assess the potential role of cattle isolates in zoonotic transmission in central Ethiopia. A total of 449 fecal samples were collected and screened using microscopy and PCR targeting the small-subunit (ssu) rRNA, triose phosphate isomerase (tpi), β-giardin (bg) and glutamate dehydrogenase (gdh) genes. The overall prevalence of Giardia duodenalis in dairy calves was found to be 9.6% (43/449). The prevalence of infection based on sex, age and breed difference was statistically not significant (p>0.05). Genotyping results revealed the presence of assemblage E and assemblage A (AI). The genotypic frequency reported was 95.3% (41/43) for assemblage E and 4.7% (2/43) for assemblage A. There was one mixed infection with assemblages AI and E. Sequence analyses showed the existence of 10 genotypes within assemblage E. One genotype that showed novel nucleotide substitution was identified at the ssu rRNA locus. The other 9 genotypes, 3 at each locus, were identified at the tpi, the bg and the gdh loci with two of the gdh genotypes were novel. Findings of the current study indicate the occurrence of the livestock-specific assemblage E and the potentially zoonotic assemblage A, with the former being more prevalent. Although the zoonotic assemblage was less prevalent, there is a possibility of zoonotic human infection as AI is reported from both animals and humans.


Immunohistochemical analysis of transporters related to clearance of amyloid-β peptides through blood-cerebrospinal fluid barrier in human brain.
A large number of previous reports have focused on the transport of amyloid-β peptides through cerebral endothelial cells via the blood-brain barrier, while fewer reports have mentioned the transport through the choroid plexus epithelium via the blood-cerebrospinal fluid barrier. Concrete roles of these two pathways remain to be clarified. In this study, we immunohistochemically examined the expression of transporters/receptors that are supposed to be related to the clearance of amyloid-β peptides in the choroid plexus epithelium, the ventricular ependymal cells and the brain microvessels, using seven autopsied human brains. In the choroid plexus epithelium, immunoreactivity for low-density lipoprotein receptor (LDLR), LDLR-related protein 1 (LRP1), LRP2, formylpeptide receptor-like 1 (FPRL1), ATP-binding cassette (ABC) transporter-A1 (ABCA1), ABCC1 and ABCG4 was seen in 7 of 7 brains, while that for ABCB1, ABCG2, RAGE and CD36 was seen in 0-2 brains. In the ventricular ependymal cells, immunoreactivity for CD36, LDLR, LRP1, LRP2, FPRL1, ABCA1, ABCC1 and ABCG4 was seen in 6-7 brains, while that for ABCB1, ABCG2 and RAGE was seen in 0-1 brain. Immunoreactivity for insulin-degrading enzyme (IDE) was seen in three and four brains in the choroid plexus epithelium and the ventricular ependymal cells, respectively. In addition, immunoreactivity for LDLR, ABCB1 and ABCG2 was seen in over 40 % of the microvessels (all seven brains), and that for FPRL1, ABCA1, ABCC1 and RAGE was seen in over 5 % of the microvessels (4-6 brains), while that for CD36, IDE, LRP1, LRP2 and ABCG4 was seen in less than 5 % of the microvessels (0-2 brains). These findings may suggest that these multiple transporters/receptors and IDE expressed on the choroid plexus epithelium, ventricular ependymal cells and brain microvessels complementarily or cooperatively contribute to the clearance of amyloid-β peptides from the brain.


Superficial outside-flap shunt (SOS) is associated with a low incidence of postoperative DIEP flap venous congestion: A single-institution retrospective cross-sectional study.
Venous congestion burdens up to 15% of deep inferior epigastric artery perforator (DIEP) flap breast reconstructions. For these cases, venous augmentation by superficial outside shunt (SOS) is associated with 100% success in secondary salvage surgeries. Intraoperative venous augmentation using other techniques yields a 0.3% rate of return to theater due to venous congestion, but there is no evidence assessing the effectiveness of the SOS technique applied preventively. Comparing this preventive approach to data prior to its implementation, we expect to find a reduced number of venous congested flaps with reduced flap losses and revision surgeries. This retrospective cross-sectional study involved DIEP flap breast reconstructions performed between 2011 and 2020. The control group included patients receiving additional venous anastomosis as a secondary salvage procedure. The "preventive SOS group" included patients who received preventive SOS during the main surgery. Age, body mass index (BMI), pregnancies, perioperative treatments (neoadjuvant or adjuvant chemo or radiotherapy), follow-up complications (arterial ischemia, venous congestion, hematomas, partial/total flap loss), and revision surgeries (breast debridement, flap remodeling) were recorded and compared. Within 695 flaps performed, 397 flaps were included in the control group, and 298 flaps were included in the preventive SOS group. The groups were homogeneous for age (p = 0.418), BMI (p = 0.747), and flap weight (p = 0.064). Fifty-one flaps (12.8%) in the control group compared to zero (0.0%) in the preventive SOS group required return to theater (p < 0.001). We reported encouraging preliminary results for SOS to prevent DIEP flap venous congestion. These results must be validated prospectively.


Central venous catheter-related Rhodotorula rubra fungemia.
With the increased use of indwelling central venous catheters, increasing numbers of cases of Rhodotorula fungemia have been observed in patients with neoplasia and neutropenia. In most patients with catheter-related Rhodotorula fungemia, the condition has been treated with broadspectrum antibiotics. We report two cases of central venous catheter-related Rhodotorula rubra fungemia that occurred in patients with acute myeloblastic leukemia. Both patients were in a state of neutropenia. One patient was treated with amphotericin B and his central venous catheter was removed, but he died of Klebsiella pneumoniae bacteremia. The other patient was treated with amphotericin B and discharged, with a central venous catheter, after recovery from neutropenia. Although the management of catheter-related Rhodotorula fungemia infections remains controversial, resolution of the underlying disease is more important than catheter removal for recovery from Rhodotorula rubra fungemia.


Dermatitis herpetiformis and vitiligo: report of a case and review of the literature.
We describe the case of a 53-year-old woman presenting papulous and papulovesicular lesions that were highly pruritic, localized mostly in the achromic areas of vitiligo and symmetrically distributed on the elbows, the buttocks, the shoulders and the neck. The histopathological examination performed on the elbow's lesional skin showed the presence of neutrophils and fibrin microabscesses at the tips of dermal papillae, with a few eosinophils, and small separations between the dermis and epidermis just over the infiltrate. The overlying epidermis was uninjured. The performed tests detected IgA anti-endomysium, anti-thyrogloblin, anti-smooth muscle and anti-microsomal fraction autoantibodies; DIF showed the presence of IgA granular deposits at the dermo-epidermal junction, prevalently at the tips of dermal papillae. This is the tenth case reported of an association between dermatitis herpetiformis and vitiligo. Although the two disorders both have immunological pathogeneses, we think that the topographic coexistence of both disorders is coincidental.


Expression patterns of sex steroid receptors in developing mesonephros of the male mouse: three-dimensional analysis.
The androgen pathway via androgen receptor (AR) has received the most attention for development of male reproductive tracts. The estrogen pathway through estrogen receptor (ESR1) is also a major contributor to rete testis and efferent duct formation, but the role of progesterone via progesterone receptor (PGR) has largely been overlooked. Expression patterns of these receptors in the mesonephric tubules (MTs) and Wolffian duct (WD), which differentiate into the efferent ductules and epididymis, respectively, remain unclear because of the difficulty in distinguishing each region of the tracts. This study investigated AR, ESR1, and PGR expressions in the murine mesonephros using three-dimensional (3-D) reconstruction. The receptors were localized in serial paraffin sections of the mouse testis and mesonephros by immunohistochemistry on embryonic days (E) 12.5, 15.5, and 18.5. Specific regions of the developing MTs and WD were determined by 3-D reconstruction using Amira software. AR was found first in the specific portion of the MTs near the MT-rete junction at E12.5, and the epithelial expression showed increasing strength from cranial to the caudal regions. Epithelial expression of ESR1 was found in the cranial WD and MTs near the WD first at E15.5. PGR was weakly positive only in the MTs and cranial WD starting on E15.5. This 3-D analysis suggests that gonadal androgen acts first on the MTs near the MT-rete junction but that estrogen is the first to influence MTs near the WD, while potential PGR activity is delayed and limited to the epithelium.


Identification of liver-specific CD24+ invariant NK T cells with low granzyme B production and high proliferative capacity.
Invariant NK T (iNKT) cells are innate-like lymphocytes that can recognize the lipid Ag presented by MHC I like molecule CD1d. Distinct tissue distribution of iNKT cells subsets implies a contribution of these subsets to their related tissue regional immunity. iNKT cells are enriched in liver, an organ with unique immunological properties. Whether liver-specific iNKT cells exist and dedicate to the liver immunity remains elusive. Here, a liver-specific CD24+ iNKT subset is shown. Hepatic CD24+ iNKT cells show higher levels of proliferation, glucose metabolism, and mTOR activity comparing to CD24- iNKT cells. Although CD24+ iNKT cells and CD24- iNKT cells in the liver produce similar amounts of cytokines, the hepatic CD24+ iNKT cells exhibit lower granzyme B production. These liver-specific CD24+ iNKT cells are derived from thymus and differentiate into CD24+ iNKT in the liver microenvironment. Moreover, liver microenvironment induces the formation of CD24+ conventional T cells as well, and these cells exhibit higher proliferation ability but lower granzyme B production in comparison with CD24- T cells. The results propose that liver microenvironment might induce the generation of liver-specific iNKT subset that might play an important role in maintaining liver homeostasis.


Harnessing free radicals: formation and function of the tyrosyl radical in ribonucleotide reductase.
Ribonucleotide reductases (RNRs) are uniquely responsible for converting nucleotides to deoxynucleotides in all organisms. The cofactor of class-I RNRs comprises a di-iron cluster and a tyrosyl radical, and is essential for initiation of radical-dependent nucleotide reduction. Recently, much progress has been made in understanding the mechanism by which this cofactor is generated in vitro and in vivo, as well as the function of the tyrosyl radical in nucleotide reduction. The Escherichia coli RNR cofactor provides a paradigm for cofactors in other di-iron requiring or tyrosyl-radical-requiring proteins.


[Examination and assessment of time-variant human strain in motor car driving: real situation--simulation (author's transl)].
Time variant processes of activity, activation and strain of man are registrated during several hours of automobil driving (highway-autobahn) for different stress conditions and classified in terms of degrees of fatigue. By comparison with an assessment of strain in a simulated driving task with the same individuum and the same research-methods it is shown that the development of methods for measurement and assessment of time-variant human processes in laboratory experiments can be recommended, field-studies higher degrees of strain were found than under laboratory conditions.


The Potential of Psychedelics for End of Life and Palliative Care.
End of life and palliative care has improved in recent decades but the psychopharmacological options available to clinicians and patients in these contexts remain limited. In particular, psychological factors such as depression, existential distress, and well-being remain challenging to address with current medications. Here, we review recent research on the use of psychedelics in clinical settings with a particular focus on patients with life-threatening diagnoses. We propose that psychedelics may provide clinicians with an additional psychopharmacological treatment in the context of end of life and palliative care.


The role of prey nutritional status in governing protozoan nitrogen regeneration efficiency.
Laboratory experiments were conducted to study nitrogen (N) regeneration by the heterotrophic marine dinoflagellate Oxyrrhis marina when ingesting phytoplankton prey of two different species and of two alternative carbon:nitrogen (C:N) ratios. Experiments were conducted in the presence of L-methionine sulfoximine (MSX) which acts as a glutamine synthetase inhibitor. Utilisation by phytoplankton of N regenerated by protozoans and other organisms drives secondary production in marine food webs. However, the rapid utilisation of this N by phytoplankton has previously hampered accurate assessment of the efficiency of protozoan N regeneration. This phenomenon is particularly problematic when the phytoplankton are nutrient stressed and most likely to rapidly utilise N. The use of MSX prevented significant utilisation by phytoplankton of protozoan regenerated N. Hence, by removing the normal pathway of N cycling, we were able to determine the N regeneration efficiency (NRE) of the protozoan. The results suggested that predator NRE could be explained in terms of the relative CN stoichiometry of prey and predator. Using a mathematical model we demonstrated that changing the method used to simulate the NRE of the protozoan trophic level has the potential to markedly modify the predicted dynamics of the simulated microbial food web.


Automated image registration of gated cardiac single-photon emission computed tomography and magnetic resonance imaging.
To develop an automatic registration method for electrocardiogram-gated myocardial perfusion single-photon emission computed tomography (SPECT) and cardiac cine-magnetic resonance imaging (MRI). Paired myocardial perfusion SPECT (MPS) and MRI from 20 patients were considered. MR images were presegmented by heart localization based on detection of cardiac motion and optimal thresholding. A registration algorithm based on mutual information was subsequently applied to all time frames or a selected subset from both modalities. A preprocessing step significantly improved the accuracy of the registration when compared to automatic registration performed without preprocessing. Errors in translation parameters (T(x), T(y), T(z)) averaged (1.0 +/- 1.5, 1.1 +/- 1.3, 0.9 +/- 0.9) pixels with MRI segmentation and (4.6 +/- 3.2, 3.4 +/- 2.6, 3.0 +/- 3.4) pixels without MRI segmentation. Errors in rotation parameters (R(x), R(y), R(z)) averaged (5.4 +/- 2.9, 3.4 +/- 2.7, 4.5 +/- 3.6) degrees with MRI segmentation and (9.3 +/- 6.1, 4.8 +/- 4.3, 14.6 +/- 12.6) degrees without MRI segmentation. Error was calculated as the absolute difference between the expert manual and the automatic registration transformation. Automatic registration of gated MPS and cine MRI is possible with the use of a mutual information-based technique when MR images are presegmented. Cardiac motion can be used to isolate the left ventricle (LV) on the MR images automatically, and subsequently the segmented MR images can be coregistered with gated MPS.


Is ultrasound guidance necessary for transrectal prostate biopsy?
The relatively simultaneous development of spring-loaded biopsy devices and the proliferation of transrectal ultrasonography for transrectal guidance of biopsy needles have led to the general use of both technologies for transrectal prostate biopsy. This review was done because the incremental cost of ultrasonographic guidance is considerable and the marginal improvement of sensitivity over digital guidance alone is unknown. A total of 200 consecutive men underwent prostate biopsy with digital and ultrasound guidance. Biopsy sensitivity was superior for ultrasound guidance in all categories of tumors studied, with an overall sensitivity of 88% compared to 74% for digital guidance. Nevertheless, 12% of the tumors were detected with digital rectal examination guidance alone. These data suggest that the optimal method of prostate biopsy may include ultrasound and digital guidance.


Prenatal detection of Pai syndrome without cleft lip and palate: a case report.
Pai syndrome is a rarely encountered disease characterized by findings of median cleft lip, facial skin polyps, nasal mucosal polyps and midline central nervous system lipoma. We report a case with prenatal detection of a pericallosal lipoma and a skin tag on the forehead. After delivery, the diagnosis was confirmed as a case of Pai syndrome.


The acceptability of continuous cell lines: A personal & historical perspective.
In the 1950s, only primary cell cultures were acceptable for the production of human biological products. This position was challenged in the late 1960s by human diploid cells (HDCs), and again in the 1980s by continuous cell lines (CCLs). The history of the HDC controversy is reviewed and lessons from that era that are relevant to the use of CCLs are pointed out. It became apparent in the early days of recombinant DNA technology in the 1980s that CCLs were needed for the development of some products. CCL acceptability therefore became more urgent, and several attempts were made to reach a consensus on regulatory issues. In 1986, the World Health Organization convened a Study Group to review the safety issues related to products derived from CCLs. The Study Group made a clear recommendation to pursue CCLs in product development because of the demonstrated capability of modern manufacturing processes to cope with contaminants. Issues such as acceptable levels of cellular DNA in products and the relationship of purity to safety are discussed in the context of the need for regulatory authorities, industry, and the general biomedical community to cooperate in addressing problems in a rational scientific manner.


Correction: Plasma microRNAs biomarkers in mild cognitive impairment among patients with type 2 diabetes mellitus.
[This corrects the article DOI: 10.1371/journal.pone.0236453.].


Treatment of Latent Tuberculosis Infection-An Update.
Treatment of latent tuberculosis infection (LTBI) is an important component of TB control and elimination. LTBI treatment regimens include once-weekly isoniazid plus rifapentine for 3 months, daily rifampin for 4 months, daily isoniazid plus rifampin for 3-4 months, and daily isoniazid for 6-9 months. Isoniazid monotherapy is efficacious in preventing TB disease, but the rifampin- and rifapentine-containing regimens are shorter and have similar efficacy, adequate safety, and higher treatment completion rates. Novel vaccine strategies, host immunity-directed therapies and ultrashort antimicrobial regimens for TB prevention, such as daily isoniazid plus rifapentine for 1 month, are under evaluation.


Naloxone analogy and opioid overdose terminology preferences among rural caregivers: Differences by race.
Despite national and state policies aimed at increasing naloxone access via pharmacies, opioid overdose death rates rose during the COVID-19 pandemic, particularly among Blacks and American Indians (AIs) in rural areas. Caregivers, or third parties who can administer naloxone during an overdose event, are important individuals in the naloxone administration cascade, yet no studies have explored rural caregivers' opioid overdose terminology and naloxone analogy preferences or whether these preferences differ by race. To identify rural caregivers' overdose terminology and naloxone analogy preferences and determine whether preferences differ by race. A sample of 40 caregivers who lived with someone at high risk of overdose and used pharmacies in 4 largely rural states was recruited. Each caregiver completed a demographic survey and a 20- to 45-minute audio-recorded semi-structured interview that was transcribed, de-identified, and imported into a qualitative software package for thematic analysis by 2 independent coders using a codebook. Overdose terminology and naloxone analogy preferences were analyzed for differences by race. The sample was 57.5% white, 35% Black, and 7.5% AIs. Many participants (43%) preferred that pharmacists use the term "bad reaction" to refer to overdose events over the terms "accidental overdose" (37%) and "overdose" (20%). The majority of white and Black participants preferred "bad reaction" while AI participants preferred "accidental overdose." For naloxone analogies, "EpiPen" was most preferred (64%), regardless of race. "Fire extinguisher" (17%), "lifesaver" (9.5%), and other analogies (9.5%) were preferred by some white and Black participants but not AI participants. Our findings suggest that pharmacists should use the "bad reaction" term and "EpiPen" analogy when counseling rural caregivers about overdose and naloxone, respectively. Caregivers' preferences varied by race, suggesting that pharmacists may want to tailor the terminology and analogy they use when discussing naloxone with caregivers.


Liesegang rings in the setting of end-stage renal disease.
Liesegang rings are acellular, lamellar, concentric rings of organic or inorganic material naturally formed in both biologic and environmental systems. Description in human tissue is scarce. Liesegang rings have exclusively been identified in association with pathologic disease processes and thus are not typically considered in differential diagnosis. They are usually described with cystic or inflammatory lesions. Histologically, Liesegang rings show features that are also seen in sections of parasitic ova, larvae, psammoma bodies, and by radiology as calcifications in cystic diseases of the breast and kidney. We noted at autopsy of a 59-year-old diabetic woman multiple black "stones" in the renal medulla. Microscopic examination demonstrated these to contain Liesegang rings. Liesegang rings formation should be considered in the differential diagnosis of atypical appearing deposits in the kidneys and other tissues. They may play a role in the pathogenesis of kidney stones.


Cone-beam CT-derived relative stopping power map generation via deep learning for proton radiotherapy.
In intensity-modulated proton therapy (IMPT), protons are used to deliver highly conformal dose distributions, targeting tumors, and sparing organs-at-risk. However, due to uncertainties in both patient setup and relative stopping power (RSP) calculation, margins are added to the treatment volume during treatment planning, leading to higher doses to normal tissues. Cone-beam computed tomography (CBCT) images are taken daily before treatment; however, the poor image quality of CBCT limits the use of these images for online dose calculation. In this work, we use a deep-learning-based method to predict RSP maps from daily CBCT images, allowing for online dose calculation in a step toward adaptive radiation therapy. Twenty-three head-and-neck cancer patients were simulated using a Siemens TwinBeam dual-energy CT (DECT) scanner. Mixed-energy scans (equivalent to a 120 kVp single-energy CT scan) were converted to RSP maps for treatment planning. Cone-beam computed tomography images were taken on the first day of treatment, and the planning RSP maps were registered to these images. A deep learning network based on a cycle-GAN architecture, relying on a compound loss function designed for structural and contrast preservation, was then trained to create an RSP map from a CBCT image. Leave-one-out and holdout cross validations were used for evaluation, and mean absolute error (MAE), mean error (ME), peak signal-to-noise ratio (PSNR), and structural similarity (SSIM) were used to quantify the differences between the CT-based and CBCT-based RSP maps. The proposed method was compared to a deformable image registration-based method which was taken as the ground truth and two other deep learning methods. For one patient who underwent resimulation, the new planning RSP maps and CBCT images were used for further evaluation and validation. The CBCT-based RSP generation method was evaluated on 23 head-and-neck cancer patients. From leave-one-out testing, the MAE between CT-based and CBCT-based RSP was 0.06 ± 0.01 and the ME was -0.01 ± 0.01. The proposed method statistically outperformed the comparison DL methods in terms of MAE and ME when compared to the planning CT. In terms of dose comparison, the mean gamma passing rate at 3%/3 mm was 94% when three-dimensional (3D) gamma index was calculated per plan and 96% when gamma index was calculated per field. The proposed method provides sufficiently accurate RSP map generation from CBCT images, allowing for evaluation of daily dose based on CBCT and possibly allowing for CBCT-guided adaptive treatment planning for IMPT.