Nontraumatic bladder rupture is a rare cause of abdominal pain. We presented a case of spontaneous bladder rupture following acute cystits.

Aim: To quantify the utility of the rate-adjusted area under the concentration curve method in increasing the probability of a correct and conclusive outcome of a bioequivalence (BE) trial for highly variable drugs when clearance (CL) varies more than volume of distribution (V). Methods. Data from a large population of subjects were generated with variability in CL and V parameters and used to simulate a two-period, crossover BE trial. The 90% confidence interval for formulation comparison was determined following BE assessment using the area under the concentration curve (AUC) ratio test, and the proposed rate-adjusted AUC ratio method. An outcome of bioequivalent, non-bioequivalent or inconclusive was then assigned in relation to predefined BE limits. Results: We illustrate the utility of the rate-adjusted AUC method for BE testing when CL varies more than V. The approach is expected to enhance the probability of correctly assigning BE or non-BE and to increase study power to further reduce the risk of an inconclusive trial. Conclusions: The rate-adjusted AUC method represents a simple and readily applicable approach to enhance the BE assessment of drug products when CL varies more than V.

Brittle cornea syndrome (BCS) is a rare autosomal recessive disorder characterized by corneal thinning and fragility, leading to corneal rupture, the main hallmark of this disorder. Non-ocular symptoms include hearing loss, but also signs of connective tissue fragility, placing it in the Ehlers-Danlos syndrome (EDS) spectrum. It is caused by biallelic pathogenic variants in ZNF469 or PRDM5, which presumably encode transcription factors for extracellular matrix components. We report the clinical and molecular features of nine novel BCS families, four of which harbor variants in ZNF469 and five in PRDM5. We also performed a genotype and phenotype-oriented literature overview of all (N=85) reported patients with ZNF469 (N=53) and PRDM5 (N=32) variants. Musculoskeletal findings may be the mean reason for referral, and often raise suspicion of another heritable connective tissue disorder such as kyphoscoliotic EDS, osteogenesis imperfecta or Marfan syndrome, especially when corneal rupture has not yet occurred. Our findings highlight the multisystemic nature of BCS and validate its inclusion in the EDS classification. Importantly, gene panels for heritable connective tissue disorders should include ZNF469 and PRDM5 to allow for timely diagnosis and appropriate preventive measures for this rare condition.

Aims To evaluate the effect of pre-RIRS ESWL on the efficiency and safety of RIRS in the treatment of proximal ureter stones. Methods The patients in the study population were divided into 2 groups. Group-1 was composed of patients who had undergone ESWL for proximal ureter stones before RIRS, and Group-2 was composed of patients who directly underwent RIRS without any prior ESWL. The clinical and demographic properties of the patients were analysed in the RIRSearch database. The operative outcomes, peroperative complications, postoperative complications, hospitalization time and the stone-free rates were compared between the groups. Results There were 56 patients in Group-1 and 95 patients in Group-2. The demographic and clinical properties were similar between the groups. The stone-free rates, peroperative complications and postoperative complications were also similar between the groups; however, the fluoroscopy time was significantly higher in Group-1 (p=.043). The cut-off duration of 10 weeks between ESWL and RIRS had reasonable/favourable discriminating ability, with a 51% sensitivity and 88% specificity rate for stone-free status. Conclusion Performing ESWL on the proximal ureter stones before RIRS did not change the efficacy and safety of RIRS. The time between the patient’s last ESWL session and RIRS had a predictive value for stone-free status, but did not have any effect on complications.

Background: There is limited evidence of the relationship between peripheral blood eosinophilia and clinical remission of acute exacerbations of chronic obstructive pulmonary disease (AECOPD) at different ages, especially in elderly patients, which was the objective of the present study. Methods: This retrospective study stratified patients by age (>65 or ≤65 years) and analyzed the relationship between blood eosinophilia (≥2% or <2%) and AECOPD clinical remission at observing time points of 7, 10, 14, 21, and 28 days. Results: Of 703 AECOPD cases analyzed, 616 were elderly (>65 years), 272 of whom had eosinophilic exacerbations. There were statistically significant differences in leukocyte count, high-sensitivity C-reactive protein levels (hs-CRP), and overall and daily hospital costs between eosinophilic and non-eosinophilic AECOPD patients (p<0.05, respectively). In the overall analysis, eosinophilic exacerbation was significantly associated with a higher remission rate at 7 (hazard ratio [HR]=1.457 [1.072, 1.982]), 10 (HR=1.316 [1.108, 1.562]), 14 (HR=1.334 [1.102, 1.615]), 21 (HR=1.326 [1.125, 1.562]), and 28 days (HR=1.254[1.078, 1.459]). The subgroup analysis showed that eosinophilic exacerbation yielded better clinical remission than non-eosinophilic exacerbation in elderly patients (>65 years old) at 7 (HR=1.521 [1.084, 2.136]), 10 (HR=1.319 [1.096, 1.588]), 14 (HR=1.374 [1.118, 1.689]), 21 (HR=1.326 [1.112, 1.582]), and 28 days (HR=1.234 [1.049, 1.451]), while no differences were observed in middle-aged patients (between 45 and 65 years) at all time points (all p>0.05). Conclusion: The eosinophilic phenotype was associated with better clinical remission at 7, 10, 14, 21, and 28 days among elderly but not in middle-aged patients with AECOPD.

Background: Understanding the association between water consumption and mortality is important for guiding consumers and prioritizing dietary guidelines to reduce the risk. Therefore, in the current study, we conducted a systematic review and dose-response meta-analysis of prospective cohort studies to summarize the association between total water and drinking intake and risk of mortality from all causes and CVD. Method: A comprehensive search was performed on PubMed/Medline, Scopus, and ISI Web of Science up to February 2020. The random effects model was used to calculate pooled effect size (EFs) and 95% confidence interval. Result: Seven prospective cohort studies with a total of 116816 reporting 14754 cases of all-cause mortality and 7611 of CVD mortality, were included in the present meta-analysis. No significant association was found between drinking water intake and all-cause mortality (EFs: 0.82; 95% CI: 0.63-1.08, P=0.65) and CVD mortality (EFs: 0.82; 95% CI: 0.63-1.08, P= 0.16). Total water intake was not associated with all-cause mortality (EFs: 0.95; 95% CI: 0.83-1.09, P=0.47). However, indicating a significant inverse association between total water intake and risk of CVD mortality (EFs: 0.84; 95% CI: 0.77-0.93, P<0.001). Linear dose-response meta-analysis revealed a significant inverse association between total water intake and all-cause mortality by an additional one cup per day (Pooled ES: 0.98; 95% CI: 0.97-0.99, P= 0.001). Furthermore, each additional cup of total water intake per day was associated with a 3% lower risk of death from CVD (Pooled ES: 0.97; 95% CI: 0.96-0.98, P<0.001). Conclusion: High consumption of total water is associated with a lower risk of CVD mortality. However total water intake was not associated with an increased risk of all-cause mortality.

A document by Mainak Dutta. Click on the document to view its contents.

Exposure of Chinese hamster ovary cells (CHO) to highly concentrated feed solution during fed-batch cultivation is known to result in an unphysiological osmolality increase (>300 mOsm/kg), affecting cell physiology and morphology. Extending previous observation on osmotic adaptation, the present study investigates for the first time potential effects of hyperosmolality on CHO cells on both population and single-cell level. We intentionally exposed CHO cells to hyperosmolality of up to 545 mOsm/kg during fed-batch cultivation. Contrarily to an expected osmosis effect promoting cell shrinkage, hyperosmolality-exposed CHO cells showed a nearly triplicated volume accompanied by ablation of proliferation. On the molecular level, we observed a strong hyperosmolality-dependent increase in mitochondrial activity in CHO cells compared to control. The companion article “Hyperosmolality in CHO Culture: Effects on Proteome” provides a proteome-based insight into the effects of hyperosmolality on mitochondria. In contrast to mitochondrial activity, hyperosmolality-dependent proliferation arrest of CHO cells was not accompanied by DNA accumulation or caspase-3/7-mediated apoptosis. Notably, we demonstrate for the first time a formation of up to eight multiple, small nuclei in single hyperosmolality-stressed CHO cells. The here presented observations reveal unknown hyperosmolality-dependent morphological changes and support existing data on the osmotic response in mammalian cells.

Fatigue behaviour of HIPed and stress relieved Ti6Al4V alloy specimen’s produced by SLM was analysed (Rε = -1). The HIP process caused a microstructural transformation decreasing the hardness and monotonic properties that not allowed fatigue strength increase. A bilinear behaviour in the elastic strain-fatigue life curve was observed, because of Young´s modulus decrease during the cyclic elasto-plastic tests consequence of subgrains formation. The Smith-Watson-Topper and total strain energy density models showed a good concordance between predicted and experimental fatigue lives in notched samples.

Long-term experiments are important in evaluating ecosystem properties and processes that are slow to develop or require proper evaluation over an appropriately variable climate. We repurpose the wealth of data accessible through the forty-year-old Long-Term Ecological Research (LTER) network with a novel moving window algorithm and meta-analysis approach to ask if aspects of study taxa or environment alter the extent of research necessary to detect consistent results, or the proportion of spurious short-term trends. We found that experimental studies focused on plants, and those conducted in dynamic abiotic environments, were characterized by longer critical temporal thresholds and more spurious trends. Further, nearly half of the studies we investigated required 10 years or longer to reach a temporal threshold, and 4 studies (of 100) required longer than 20 years. We champion long-term data and argue that long-term experiments are more necessary than ever to understand, explain, and predict long-term trends.

We describe six teenagers presenting with fever and severe abdominal symptoms admitted with concerns for multisystem inflammatory syndrome in children (MIS-C). Laboratory evaluation revealed elevated markers of inflammation, lymphopenia, and increased d-dimers. Imaging studies revealed multifocal airspace disease and ground-glass opacities. SARS-CoV-2 PCR and serologies were negative. All patients reported a history of vaping, prompting E-cigarette, or vaping, product use-associated lung injury (EVALI) diagnosis. MIS-C has overlapping clinical and laboratory features highlighting the added challenge of diagnosing EVALI during the COVID-19 pandemic.

Aim: To develop clinical algorithms for the assessment and management of slow progress of labour. Population: Low-risk singleton, term, pregnant women in labour. Setting: Institutional births in low- and middle-income countries. Search Strategy: We systematically reviewed the literature on normal labour progression, and guidance on clinical management of abnormally slow progression from 1 December 2015 to 1 December 2020. Case scenarios: We developed two clinical algorithms: one for abnormally slow labour progression and arrest during first and one for second stage. Conclusions: Identifying abnormal progress of labour is often challenging. These algorithms may help to reduce misdiagnosis.

Background: There is variation in the reported incidence of levator avulsion (LA). Objective: Explore incidence of LA by mode of birth, imaging modality, timing of diagnosis and laterality of avulsion. Search strategy: We searched MEDLINE, EMBASE, CINAHL, AMED and MIDIRS with no language restriction from inception to April 2019. Study eligibility criteria: A study was included if LA was assessed by an imaging modality after the first vaginal birth or if only delivered by caesarean section. Case series and reports were not included. Data collection and analysis: RevMan v5.3 was used for the meta-analyses and SW SAS and STATISTICA packages for type and timing of imaging analyses. . Results: We included 37 primary non-randomized studies from 17 countries and involving 5594 women. Incidence of LA was 1%, 15%, 21%, 38.5% and 52% following caesarean, spontaneous, vacuum, spatula and forceps births respectively, with no differences by imaging modality. OR of LA following spontaneous birth vs. caesarean was 10.69. While the OR for LA following vacuum and forceps compared to the spontaneous birth were 1.66 and 6.32 respectively. LA was more likely to occur on the right side following spontaneous birth (p = 0.02) and unilaterally vs. bilaterally following spontaneous (P < .0001) and vacuum-assisted births (P = 0.0103) only. Incidence was higher if assessment was performed in the first 4 weeks postpartum. Conclusions: Forceps significantly increases incidence and severity of LA. Ultrasound and MRI are comparable diagnostic tools but early postpartum imaging may lead to over diagnosis of LA.

Vector-borne diseases (VBDs) are embedded within complex socio-ecological systems. While research has traditionally focused on direct effects of VBDs on morbidity and mortality, it is increasingly clear that VBD impacts are much more pervasive, dynamically linked to feedbacks between environmental conditions, vector ecology, disease burden, and societal responses that drive transmission. VBDs have had profound influence on human history via mechanisms that include: (1) killing or debilitating large numbers of people, with direct demographic and population-level impacts; (2) differentially affecting populations based on prior history of disease exposure, immunity, and resistance; (3) being weaponized to promote or justify existing hierarchies of power, colonialism, racism, classism, and sexism; (4) catalyzing changes in ideas, institutions, infrastructure, technologies, and social practices in efforts to control disease outbreaks; and (5) changing human relationships with the land and environment. We use historical and archaeological evidence interpreted through an ecological lens to illustrate how four major VBDs have shaped society and culture: plague, malaria, yellow fever, and trypanosomiasis. By comparing across diseases, time periods, and geographies, this review highlights the enormous scope and variety of mechanisms by which VBDs have influenced human history from the age of early Homo sapiens to the modern context.

An 11 years-old male mixed-breed cat, with exclusively indoor life, presented 3 cough episodes after the owners tested positive by RT-PCR for SARS-CoV-2. The house is inhabited by 5 people (3 adults and 2 children), and 2 of the adults have shown mild symptoms associated with throat discomfort. The cat was vaccinated, had no history of any previous disease, and tested negative for Feline Coronavirus (FeCoV), Feline Immunodeficiency Virus (FIV) and Feline Leukemia Virus (FeLV). Rectal sample collected from the cat was positive for SARS-CoV-2 by RT-PCR. Viral genome sequences recovered from human and cat samples showed an average 99.4% sequence identity. This is the first report of genome sequences of SARS-CoV-2 recovered from a cat and its owner in Latin America.

COVID-19 and nuclear cardiology: Introducing the ‘’forward” virtual visit Angelidis G, Valotassiou V, Psimadas D, Georgoulias PNuclear Medicine Laboratory, University of Thessaly, Larissa, GreeceWe read with great interest the recent review article by Kaushik A, et al. concerning the potential role of digital health applications in the present pandemic situation [1]. As the authors noted, alternative tools are needed for the optimal management of cardiovascular patients, avoiding unnecessary visits to health care facilities. The severe acute respiratory syndrome – coronavirus – 2 (SARS-CoV-2) can invade the cardiovascular cells, potentially causing life-threatening cardiac impairment [2]. In particular, patients with pre-existing cardiovascular diseases are characterized by a higher risk of adverse cardiovascular events. Therefore, most of those referred for nuclear cardiology techniques are expected to be at higher risk of developing serious coronavirus disease 2019 (COVID-19) complications. However, the performance of the individually required diagnostic and follow-up procedures is important [3].Telemedicine applications have been used in public health emergencies, leading to several advantages in terms of safety and efficacy. In the field of nuclear cardiology, the initial evaluation of patients’ history and clinical features can take place remotely (‘’forward” virtual visit). This approach seems to be patient-centred (permitting an adequate case assessment) and conducive to self-quarantine (protecting patients, healthcare professionals, and the community from viral exposure). Importantly, possible clinical presentations of COVID-19 may be evaluated during the ‘’forward” virtual visit, as well as information regarding travel and exposure histories. Moreover, local epidemiological information may be used to adjust screening pattern, and special measures could be developed (such as isolation in dedicated ‘’hot” rooms) for patients with high-risk features. After the performance of the examination, telemedicine applications could be also used for the consultation with the patients.Telemedicine applications may contribute to a better adjustment of nuclear cardiology services under the current demanding circumstances. Of course, no telemedicine programme can be created overnight, but this approach may be of value not only during the next months but also after the end of COVID-19 pandemic [4]. For example, our nuclear medicine laboratory is located in central Greece providing services to inhabitants of mountain villages, and nearby small islands. Consequently, the use of telemedicine applications could aid our practice in the future as well, particularly during the winter months when travelling by car or sea travels may be extremely demanding.

Emicizumab is a prophylaxis for patients with severe haemophilia A with inhibitor. Despite the daily prophylaxis, coagulation states stay below normal value and cannot be assessed by standard hemostasis techniques. In our two patients, we use thrombin generation assay (endogenous thrombin potential (ETP) and Peak) to monitor the patient’s clotting status. Under emicizumab, it is needed to add by-passing agent such as FVIIa (Novoseven®) to avoid bleeding before surgery. By-passing agent dose was chosen with the help of thrombin generation assay and after collegial concertation.

Lorlatinib is an anaplastic lymphoma kinase tyrosine kinase inhibitor for the treatment of non-small-cell lung cancer. We report a case in which visual and auditory hallucinations developed while receiving lorlatinib.