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Little is known about the impact of standardized imaging surveillance on anxiety levels and well-being of patients after endovascular aortic aneurysm repair (EVAR). We hypothesize that patient anxiety levels increase just before receiving the imaging results compared with standard anxiety levels. Methods: Prospective cohort study from November 2018 to May 2020 including post-EVAR patients visiting the outpatient clinics of 4 Dutch hospitals for imaging follow-up. The Patient-Reported Outcomes Measurement Information System (PROMIS) was used. Patients completed the PROMIS Anxiety v1.0 Short Form (SF) 4a, PROMIS-Global Health Scale v1.2, and PROMIS-Physical Function v1.2 SF8b at 2 time points: prior to the result of the imaging study (T1: pre-visit) and 6–8 months later (T2: reference measurement). Mean T-scores at T1 were compared to T2, and T2 to the general 65+ Dutch population. Results: Altogether 342 invited patients were eligible, 214 completed the first questionnaire, 189 returned 2 completed questionnaires and 128 patients did not participate. Out of 214 respondents, 195 were male (91.1%) and the mean (standard deviation) age was 75.2 (7.0) years. There were no significant differences between T1 and T2 in anxiety levels (0.48; 95% confidence interval[CI] -0.42–1.38), global mental health (0.27; 95% CI -0.79–0.84), global physical health (0.10; 95% CI -0.38–1.18) and physical function (0.53; 95% CI -0.26–1.32). Compared with the 65+ Dutch population, at T2 patients experienced more anxiety (3.8; 95% CI 2.96–5.54), had worse global physical health (-3.2; 95% CI -4.38 – -2.02) and physical function (-2.4; 95% CI -4.00 – -0.80). Global mental health was similar (-1.0; 95% CI -2.21 – 0.21). Conclusions: Post-EVAR patients do not experience more anxiety just before receiving surveillance imaging results than outside this period, but do suffer from more anxiety and worse physical outcomes than the 65+ Dutch population.

Presence of PBDEs tested in 127 liver samples from Atlantic Cod (Gadus morhua) and Turbot (Scophthalmus Maximus) and 80 adult participants from two rural Newfoundland communities. Seafood consumption was measured through a validated seafood consumption questionnaire. PBDEs (-28, -47, -99, -156, and -209) were found in all fish liver samples, and PBB-153 and PBDEs-28, -47, -99, -100, -153 were identified as the most prominent congeners from the participants' serum samples. Cod was the most frequently consumed species in the seafood consumption survey. PBB-153 was higher amongst older ( 50 years age) participants (p 0.0001), however, no PBDE congeners were significantly different by age. PBB-153 (p = 0.001), PBDE-153 (p = 0.006), and

The two polarities model (TPM) of personality organizes psychological assessment and psychotherapy and connects to personality disorder diagnosis using the DSM-5 Alternative Model for Personality Disorders (AMPD). The authors developed scales assessing the TPM from an existing self-report measure for level of personality functioning (LPF), a core component of the AMPD. Iterative content analyses of the LPF measure yielded scales for Autonomy and Communion corresponding to dimensions of the TPM. The scales were refined via internal consistency analyses using a measure of psychological attachment and studied in development and validation samples. Associations with relevant external criteria were explored in a series of multiple regressions. The new content-based LPF scales were illustrated with a case vignette. Although the new Autonomy/Communion scales await further validation prior to clinical use, initial evidence suggests that they may bridge the nomological nets of the TPM and AMPD and potentially offer clinical utility in assessment and treatment planning.

Kidney fibrosis is marked by excessive extracellular matrix deposition during disease progression. Unfortunately, existing kidney function parameters do not predict the extent of kidney fibrosis. Moreover, the traditional histology methods for the assessment of kidney fibrosis require liquid and imaging biomarkers as well as needle-based biopsies, which are invasive and often associated with kidney injury. The repetitive analyses required to monitor the disease progression are therefore difficult. Hence, there is an unmet medical need for non-invasive and informative diagnostic approaches to monitor kidney fibrosis during the progression of chronic kidney disease. Here, we summarize the modern advances in diagnostic imaging techniques that have shown promise for non-invasive estimation of kidney fibrosis in pre-clinical and clinical studies.

The epithelium lining airspaces of the human lung is maintained by regional stem cells including basal cells of pseudostratified airways and alveolar type 2 pneumocytes (AT2) of the alveolar gas-exchange region. Despite effective methods for long-term preservation of airway basal cells, methods for efficient preservation of functional epithelial cell types of the distal gas-exchange region are lacking. Here we detail a method for cryobanking of epithelial cells from either mouse or human lung tissue for preservation of their phenotypic and functional characteristics. Flow cytometric profiling, epithelial organoid-forming efficiency, and single cell transcriptomic analysis, were used to compare cells recovered from cryopreserved tissue with those of freshly dissociated tissue. Alveolar type 2 cells within single cell suspensions of enzymatically digested cryobanked distal lung tissue retained expression of the pan-epithelial marker CD326 and the AT2 cell surface antigen recognized by monoclonal antibody HTII-280, allowing antibody-mediated enrichment and downstream analysis. Isolated AT2 cells from cryobanked tissue were comparable with those of freshly dissociated tissue both in their single cell transcriptome and their capacity for in vitro organoid formation in 3D cultures. We conclude that the cryobanking method described herein allows long-term preservation of distal human lung tissue for downstream analysis of lung cell function and molecular phenotype, and is ideally suited for creation of an easily accessible tissue resource for the research community.

Objective: The aims of the present study were to examine the impact of type 2 endoleaks (T2EL) on overall survival and to determine the need for secondary intervention after endovascular aneurysm repair (EVAR). Methods: A multicentre retrospective cohort study in the Netherlands was conducted among patients with an infrarenal abdominal aortic aneurysm (AAA) who underwent EVAR between 2007 and 2012. The primary endpoint was overall survival for patients with (T2EL+) or without (T2EL-) a T2EL. Secondary endpoints were sac growth, AAA rupture, and secondary intervention. Kaplan–Meier survival and multivariable Cox regression analysis were used. Results: A total of 2 018 patients were included. The median follow up was 62.1 (range 0.1 – 146.2) months. No difference in overall survival was found between T2EL+ (n = 388) and T2EL- patients (n = 1630) (p =.54). The overall survival estimates at five and 10 years were 73.3%/69.4% and 45.9%/44.1% for T2EL+/T2EL- patients, respectively. Eighty-five of 388 (21.9%) T2EL+ patients underwent a secondary intervention. There was no difference in overall survival between T2EL+ patients who underwent a secondary intervention and those who were treated conservatively (p =.081). Sac growth was observed in 89 T2EL+ patients and 44/89 patients (49.4%) underwent a secondary intervention. In 41/44 cases (93.1%), sac growth was still observed after the intervention, but was left untreated. Aneurysm rupture occurred in 4/388 T2EL patients. In Cox regression analysis, higher age, ASA classification, and maximum iliac diameter were significantly associated with worse overall survival. Conclusion: No difference in overall survival was found between T2EL+ and T2EL- patients. Also, patients who underwent a secondary intervention did not have better survival compared with those who did not undergo a secondary intervention. This study reinforces the need for conservative treatment of an isolated T2EL and the importance of a prospective study to determine possible advantages of the intervention.

The examination of violence perpetrated by female offenders remains an understudied topic, as research typically focuses on male offender samples. As such, it remains unclear what personality characteristics may be associated with the perpetration of violence among female offenders. This study sought to examine the relationship between personality characteristics, as assessed by the MMPI-2-RF, and engagement in violence, within a sample of 228 incarcerated women. Results indicated that women serving time for a violent offense obtained higher mean scores on MMPI-2-RF scales related to underreporting, atypical thoughts/experiences, and paranoia. Women who obtained disciplinary reports for violence within the institution obtained higher mean scores on MMPI-2-RF scales related to behavior/externalizing dysfunction, overactivation, and aggression. Taken together, violence was most strongly associated with the MMPI-2-RF scales related to paranoia and atypical thoughts/experiences (e.g., THD, PSYC-r). This study provides new data on the viability of the MMPI-2-RF to provide critical insights into violent and aggression behavior in female inmates, an understudied population and demonstrate the instrument’s efficacy in assessing characteristics associated with violent behavior.

Intrarenal extracellular matrix production or kidney fibrosis is a prevalent feature of all forms of chronic kidney disease (CKD). The transforming growth factor-beta (TGFβ) is believed to be a major driver of extracellular matrix production. Nevertheless, anti-TGFβ therapies have consistently failed to reduce extracellular matrix production in CKD patients indicating the need for novel therapeutic strategies. We have previously shown that necroinflammation contributes to acute kidney injury. Here, we show that chronic/persistent necroinflammation drives intrarenal extracellular matrix production during CKD. We found that renal expression of receptor-interacting protein kinase-1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL) increases with the production of intrarenal extracellular matrix and declined kidney function in both humans and mice. Furthermore, we found that TGFβ exposure induces the translocation of RIPK3 and MLKL to mitochondria resulting in mitochondrial dysfunction and ROS production. Mitochondrial ROS activates the serine-threonine kinase calcium/calmodulin-dependent protein kinases-II (CaMKII) that increases phosphorylation of Smad2/3 and subsequent production of alpha-smooth muscle actin (αSMA), collagen (Col) 1α1, etc. in response to TGFβ during the intrarenal extracellular matrix production. Consistent with this, deficiency or knockdown of RIPK3 or MLKL as well as pharmacological inhibition of RIPK1, RIPK3, and CaMKII prevents the intrarenal extracellular matrix production in oxalate-induced CKD and unilateral ureteral obstruction (UUO). Together, RIPK1, RIPK3, MLKL, CaMKII, and Smad2/3 are molecular targets to inhibit intrarenal extracellular matrix production and preserve kidney function during CKD.

Rationale: Declining lung function in patients with interstitial lung disease is accompanied by epithelial remodeling and progressive scarring of the gas-exchange region. There is a need to better understand the contribution of basal cell hyperplasia and associated mucosecretory dysfunction to the development of idiopathic pulmonary fibrosis (IPF). Objectives: We sought to decipher the transcriptome of freshly isolated epithelial cells from normal and IPF lungs to discern disease-dependent changes within basal stem cells. Methods: Single-cell RNA sequencing was used to map epithelial cell types of the normal and IPF human airways. Organoid and air–liquid interface cultures were used to investigate functional properties of basal cell subtypes. Measurements and Main Results: We found that basal cells included multipotent and secretory primed subsets in control adult lung tissue. Secretory primed basal cells include an overlapping molecular signature with basal cells obtained from the distal lung tissue of IPF lungs. We confirmed that NOTCH2 maintains undifferentiated basal cells and restricts basal-to-ciliated differentiation, and we present evidence that NOTCH3 functions to restrain secretory differentiation. Conclusions: Basal cells are dynamically regulated in disease and are specifically biased toward the expansion of the secretory primed basal cell subset in IPF. Modulation of basal cell plasticity may represent a relevant target for therapeutic intervention in IPF.

Fibrosis is a wound-healing process that results in tissue scarring and organ dysfunction. Several novel mechanisms of fibrogenesis have been discovered recently. In this review, we focus on the role of poly-ADP ribose polymerase (PARP) in major organ fibrosis, such as lungs, heart, liver, and kidneys. PARP is a dynamic enzyme that modulates different cellular proteins by the addition of PAR groups and mediates an array of cellular events in both normal physiological and pathophysiological states. The US Food and Drug Administration (FDA) and European Medicines Agency (EMA) recently approved several PARP inhibitors, such as olaparib, niraparib, talazoparib, and rucaparib, for the treatment of ovarian and germline BRCA-mutant breast cancers. Consequently, repurposing these drugs could provide an opportunity to counter organ fibrosis.

Introduction Bortezomib is a proteasome inhibitor used in the treatment of multiple myeloma, Waldenström’s macroglobulinemia, mantle cell lymphoma. The most reported adverse effects include fatigue, thrombocytopenia, gastrointestinal symptoms, and peripheral neuropathy, which mostly manifests as sensory neuropathic symptoms. We present a case of a patient who experienced motor neuropathy after initiating treatment with bortezomib. Case report An 87-year-old male was diagnosed with multiple myeloma and started on treatment with bortezomib, dexamethasone, and lenalidomide (VRd). After five cycles of therapy, he developed lower extremity weakness, which was severely debilitating, affecting his ability to walk, and this prompted his visit to the emergency department. Management and outcome The patient was admitted for further workup and underwent electromyography, which was consistent with demyelinating polyneuropathy with active denervation. His symptoms were attributed to bortezomib, and his VRd regimen was held. His symptoms failed to improve despite discontinuation of bortezomib. He then received steroids and intravenous immunoglobulin (IViG) with a gradual resolution of his symptoms. He was thereafter restarted on only lenalidomide and dexamethasone with no recurrence of his neuropathy. Discussion Clinicians need to be aware of the likely risk for motor neuropathy associated with bortezomib. Risk factors like older age and pre-existing neuropathy can predispose patients to this adverse effect, and clinicians should monitor for this toxicity and facilitate dose reduction or discontinuation of therapy if warranted. Sometimes, patients may also need further treatment with steroids or IVIG.

Content validity analyses of eight self-report instruments for assessing severity of personality disorder (PD), also known as Level of Personality Functioning (LPF), were conducted using the conceptual scheme of the Alternative Model for Personality Disorders (AMPD; APA, 2013). The item contents of these eight inventories were characterized for the LPF constructs of Identity (ID), Self-Direction (SD), Empathy (EM), and Intimacy (IN) along with the pathological personality trait domains of Negative Affectivity, Detachment, Antagonism, Disinhibition, and Psychoticism. Severity of pathology (SV) reflected in item content was also rated. Raters demonstrated robust agreement for AMPD and SV constructs across instruments. Similarity between instrument AMPD construct profiles was quantified by intraclass correlations (ICC). Results showed the instruments were generally similar in AMPD-construct coverage, but some important differences emerged. The subscales of the instruments also were characterized for the degree to which they reflect the four LPF (ID, SD, EM, IN) domain constructs. Collectively, these content validity comparisons clarify the equivalence of instruments for AMPD constructs and the relative proportions of construct coverage within instrument subscales. These results can inform future research with LPF self-report instruments and guide clinicians in selecting an LPF-related instrument for use in practice.

The outbreak of rapidly spreading COVID-19 pandemic in December 2019 has witnessed a major transformation in the health care system worldwide. This has led to the re-organization of the specialty services for the effective utilization of available resources and ensuring the safety of patients and healthcare workers. Suspension of oncology services will have major implications on cancer care due to delayed diagnosis and treatment leading to irreversible adverse consequences. Therefore various oncology organizations have called for a continuation of cancer care during this crisis with diligence. The COVID-19 pandemic has forced the clinicians to transform the components of care from screening to outpatient care and primary management. The purpose of this article is to establish guidelines and recommendations for ocular oncology in the management of ocular tumors set by a multidisciplinary team of experts including ocular, medical and radiation oncologists, and pathologists. As the pandemic is evolving fast, it will require constant updates and reformation of health strategies and guidelines for safe and quality health care.

Contains fulltext : 252341.pdf (Publisher’s version ) (Closed access) OBJECTIVE: Lifelong imaging surveillance is recommended following endovascular aneurysm repair (EVAR). This study aimed to examine the association between adherence to post-operative surveillance and survival and secondary interventions in patients with an initial post-operative computed tomography angiogram (CTA) without abnormalities. METHODS: All consecutive patients undergoing EVAR for intact abdominal aortic aneurysm (AAA) in 16 hospitals between 2007 and 2012 were identified retrospectively, with follow up until December 2018. Patients were included if the initial post-operative CTA showed no types I - III endoleak, kinking, infection, or limb occlusion. Discontinued follow up was defined as at least one 16 month period in which no imaging surveillance was performed. Primary outcomes were aneurysm related mortality and secondary interventions, and secondary outcome all cause mortality. Kaplan-Meier analysis was used to estimate survival, and Cox regression analyses to identify the association between independent variables and outcome. Sensitivity analyses were performed by varying the definition of continued yearly follow up. The study protocol was published (bmjopen-2019-033584). RESULTS: 1 596 patients (552 continued, 1 044 discontinued follow up) were included with a median (interquartile range) follow up of 89.1 months (52.6). Cumulative aneurysm related, overall, and intervention free survival was 99.4/94.8/96.1%, 98.5/72.9/85.9%, and 96.3/45.4/71.1% at 1, 5, and 10 years, respectively. American Society of Anesthesiologists (ASA) classification (ASA IV hazard ratio [HR] 3.810, 95% confidence interval [CI] 1.296 - 11.198), increase in AAA diameter (HR 3.299, 95% CI 1.408 - 7.729), and continued follow up (HR 3.611, 95% CI 1.780 - 7.323) were independently associated with aneurysm related mortality. The same variables and age (HR 1.063 per year, 95% CI 1.052 - 1.074) were significantly associated with all cause mortality. No difference in secondary interventions was observed between patients with continued vs. discontinued follow up (89/552; 16% vs. 136/1044; 13%; p = .091). Sensitivity analyses showed worse aneurysm related and overall survival in patients with continued follow up. CONCLUSION: Discontinued follow up is not associated with poor outcomes. Future prospective studies are indicated to determine in which patients imaging follow up can be safely reduced.

BACKGROUND Regular aerobic exercise can induce alterations in structural and hemodynamic physiology of the heart in both athletic and nonathletic populations. This is because due to cardiac adaptation to exercise improves cardiac workout capacity by increasing left ventricular function. The aim of the present study was to examine the effect of aerobic exercise on blood pressure and left ventricular structural and myocardial function in Ethiopian non-athletic males. METHODS Twenty male adults (aged 19-23 years) were recruited and they were engaged in aerobic exercise training for 3 months (3days/week, 50-75%MHR). Selected participants underwent standard transthoracic doppler echocardiographic examinations before and after intervention of the exercise training. Collected data were analyzed through Paired Sample T test using IBM SPSS version 21 statistical software with significance level set at p

Neutrophil extracellular traps (NETs) are associated with multiple disease pathologies including sepsis, asthma, rheumatoid arthritis, cancer, systemic lupus erythematosus, acute respiratory distress syndrome, and COVID-19. NETs, being a disintegrated death form, suffered inconsistency in their identification, nomenclature, and quantifications that hindered therapeutic approaches using NETs as a target. Multiple strategies including microscopy, ELISA, immunoblotting, flow cytometry, and image-stream-based methods have exhibited drawbacks such as being subjective, non-specific, error-prone, and not being high throughput, and thus demand the development of innovative and efficient approaches for their analyses. Here, we established an imaging and computational algorithm using high content screening (HCS)—cellomics platform that aid in easy, rapid, and specific detection as well as analyses of NETs. This method employed membrane-permeable and impermeable DNA dyes in situ to identify NET-forming cells. Automated algorithm-driven single-cell analysis of change in nuclear morphology, increase in nuclear area, and change in intensities provided precise detection of NET-forming cells and eliminated user bias with other cell death modalities. Further combination with Annexin V staining in situ detected specific death pathway, e.g., apoptosis, and thus, discriminated between NETs, apoptosis, and necrosis. Our approach does not utilize fixation and permeabilization steps that disturb NETs, and thus, allows the time-dependent monitoring of NETs. Together, this specific imaging-based high throughput method for NETs analyses may provide a good platform for the discovery of potential inhibitors of NET formation and/or agents to modulate neutrophil death, e.g., NETosis-apoptosis switch, as an alternative strategy to enhance the resolution of inflammation.

Globally, the suicide rate is two times higher for males than for females. Previous studies in Newfoundland and Labrador did not examine age-specific rates by sex. The objectives of this study were to determine suicide rates by sex and age group and to compare the demographic and clinical characteristics of males and females who died by suicide.This observational study analyzed a routinely collected dataset based on all medical examiner-determined suicide deaths among people aged 10 years and older in Newfoundland and Labrador, Canada, between 1997 and 2016. Age-standardized and age-specific suicide rates and rate ratios were calculated based on the number of deaths during the period, and descriptive statistics were used to compare demographic and clinical characteristics between males and females.The age-standardized suicide rate was 4.6 times higher among males than females and was higher for males in most age groups. Rates were highest in the young adult age groups for males (20 to 24 years) and females (35 to 39 years). Males who died by suicide were more likely to be from a rural community and to have died by firearm; females were more likely to die by self-poisoning and to have had a mental illness or substance use history.The results are broadly consistent with previous research, though this is the first study to report age-specific suicide rates among females across the life course in Newfoundland and Labrador. The results underscore the need to design public health and clinical interventions that account for sex differences in suicide risks.

Purpose: Lifelong follow-up after endovascular abdominal aortic aneurysm repair (EVAR) is recommended due to a continued risk of complications, especially if the first postoperative imaging shows abnormal findings. We studied the long-term outcomes in patients with abnormalities on the first postoperative computed tomography angiography (CTA) following EVAR. Materials and Methods: This is a retrospective study of all consecutive patients who underwent elective EVAR for nonruptured abdominal aortic aneurysm (AAA) between January 2007 and January 2012 in 16 Dutch hospitals with follow-up until December 2018. Patients were included if the first postoperative CTA showed one of the following abnormal findings: endoleak type I–IV, endograft kinking, infection, or limb occlusion. AAA diameter, complications, and secondary interventions during follow-up were registered. Primary endpoint was overall survival, and other endpoints were secondary interventions and intervention-free survival. Kaplan-Meier analyses were used to estimate overall and intervention-free survival. Cox regression analyses were used to identify the association of independent determinants with survival and secondary interventions. Results: A total of 502 patients had abnormal findings on the first postoperative CTA after EVAR and had a median follow-up (interquartile range IQR) of 83.0 months (59.0). The estimated overall survival rate at 1, 5, and 10 years was 84.7%, 51.0%, and 30.8%, respectively. Age [hazard ratio (HR) 1.06, 95% confidence interval (CI) 1.05 to 1.10] and American Society of Anesthesiologists (ASA) classification (ASA IV HR 3.20, 95% CI 1.99 to 5.15) were significantly associated with all-cause mortality. Overall, 167 of the 502 patients (33.3%) underwent 238 secondary interventions in total. Fifty-eight patients (12%) underwent an intervention based on a finding on the first postoperative CTA. Overall survival was 38.4% for patients with secondary interventions and 44.5% for patients without (log rank; p=0.166). The intervention-free survival rate at 1, 5, and 10 years was 82.9%, 61.3%, and 45.6%, respectively. Conclusions: Patients with abnormalities on the first postoperative CTA after elective EVAR for infrarenal AAA cannot be discharged from regular imaging follow-up due to a high risk of secondary interventions. Patients who had a secondary intervention had similar overall survival as those without secondary interventions.

Background The suicide rate in Canada decreased by 24% during the past four decades. However, rates vary between provinces and territories, and not all jurisdictions experienced the same changes. This study examined suicide rates over time in the province of Newfoundland and Labrador. Methods We used cross-sectional surveillance data from the Canadian Vital Statistics Death Database to examine suicide rates in Newfoundland and Labrador from 1981 to 2018. We calculated annual age-standardized suicide mortality rates and used joinpoint regression to estimate the average annual percent change (AAPC) in suicide rates overall and by sex, age group, and means of suicide. Results From 1981 to 2018, 1759 deaths by suicide were recorded among people in Newfoundland and Labrador. The age-standardized suicide mortality rate increased more than threefold over the study period, from 4.6 to 15.4 deaths per 100,000. The suicide rate was higher among males than females, and accounted for 83.1% of suicide deaths (n = 1462); the male-to-female ratio of suicide deaths was 4.9 to 1. The average annual percent change in suicide rates was higher among females than males (6.3% versus 2.0%). Age-specific suicide rates increased significantly for all age groups, except seniors (aged 65 or older); the largest increase was among youth aged 10 to 24 years old (AAPC 3.5; 95% CI, 1.6 to 5.5). The predominant means of suicide was hanging/strangulation/suffocation, which accounted for 43.8% of all deaths by suicide. Conclusions The suicide rate in Newfoundland and Labrador increased steadily between 1981 and 2018, which was in contrast to the national rate decline. The disparity between the provincial and national suicide rates and the variations by sex and age underscore the need for a public health approach to prevention that accounts for geographic and demographic differences in the epidemiology of suicide.

Endoplasmic reticulum (ER) homeostasis orchestrates the folding, modification, and trafficking of secretory and membrane proteins to the Golgi compartment, thus governing cellular functions. Alterations in ER homeostasis result in the activation of signaling pathways, such as the unfolded protein response (UPR), to regain ER homeostasis. Nevertheless, failure of UPR leads to activation of autophagy-mediated cell death. Several recent studies emphasized the association of the ER stress (ERS) response with the initiation and progression of diabetes. In this review, we highlight the contribution of the ERS response, such as UPR and autophagy, in the initiation and progression of diabetes and associated microvascular complications, including diabetic nephropathy (DN), retinopathy, and neuropathy, in various experimental models, as well as in humans. We highlight the ERS as a putative therapeutic target for the treatment of diabetic microvascular complications and, thus, the urgent need for the development of improved synthetic and natural inhibitors of ERS.

The proteasome is essential for the selective degradation of most cellular proteins and is fine-tuned according to cellular needs. Proteasome activators serve as building blocks to adjust protein turnover in cell growth and differentiation. Understanding the cellular function of proteasome activation in more detail offers a new strategy for therapeutic targeting of proteasomal protein breakdown in disease. The role of the proteasome activator PA200 in cell function and its regulation in disease is unknown. In this study, we investigated the function of PA200 in myofibroblast differentiation and fibrotic tissue remodeling. PA200 was upregulated in hyperplastic basal cells and myofibroblasts of fibrotic lungs from patients with idiopathic pulmonary fibrosis. Increased expression of PA200 and enhanced formation of PA200-proteasome complexes was also evident in experimental fibrosis of the lung and kidney in vivo and in activated primary human myofibroblasts of the lung in vitro. Transient silencing and overexpression revealed that PA200 functions as a negative regulator of myofibroblast differentiation of human but not mouse cells. Our data thus suggest an unexpected and important role for PA200 in adjusting myofibroblast activation in response to pro-fibrotic stimuli, which fails in idiopathic pulmonary fibrosis.

Background Serum oxalate levels suddenly increase with certain dietary exposures or ethylene glycol poisoning and are a well known cause of AKI. Established contributors to oxalate crystal–induced renal necroinflammation include the NACHT, LRR and PYD domains-containing protein-3 (NLRP3) inflammasome and mixed lineage kinase domain-like (MLKL) protein–dependent tubule necroptosis. These studies examined the role of a novel form of necrosis triggered by altered mitochondrial function. Methods To better understand the molecular pathophysiology of oxalate-induced AIK, we conducted in vitro studies in mouse and human kidney cells and in vivo studies in mice, including wild-type mice and knockout mice deficient in peptidylprolyl isomerase F (Ppif) or deficient in both Ppif and Mlkl. Results Crystals of calcium oxalate, monosodium urate, or calcium pyrophosphate dihydrate, as well as silica microparticles, triggered cell necrosis involving PPIF–dependent mitochondrial permeability transition. This process involves crystal phagocytosis, lysosomal cathepsin leakage, and increased release of reactive oxygen species. Mice with acute oxalosis displayed calcium oxalate crystals inside distal tubular epithelial cells associated with mitochondrial changes characteristic of mitochondrial permeability transition. Mice lacking Ppif or Mlkl or given an inhibitor of mitochondrial permeability transition displayed attenuated oxalate-induced AKI. Dual genetic deletion of Ppif and Mlkl or pharmaceutical inhibition of necroptosis was partially redundant, implying interlinked roles of these two pathways of regulated necrosis in acute oxalosis. Similarly, inhibition of mitochondrial permeability transition suppressed crystal-induced cell death in primary human tubular epithelial cells. PPIF and phosphorylated MLKL localized to injured tubules in diagnostic human kidney biopsies of oxalosis-related AKI. Conclusions Mitochondrial permeability transition–related regulated necrosis and necroptosis both contribute to oxalate-induced AKI, identifying PPIF as a potential molecular target for renoprotective intervention.

Autism Spectrum disorder (ASD) is well known to be associated with significantly high rates of gastrointestinal problems, constipation being common among them, imposing a significant burden on child and the family. On account of multiple underlying factors, both diagnosis and subsequent management of constipation in children with ASD are much more challenging as compared to managing constipation in 'neurotypical' children. Associated higher rate of presentation to the hospital emergency and subsequent hospital admission rates add to the burden. Hence, there is a need for recognizing constipation as a problem in children with ASD. This review summarizes optimization of its management by adopting a multidisciplinary holistic approach to achieve good outcomes and enhance the quality of life for the child and the family.

Infant massage is a highly prevalent traditional practice in India and other parts of Asia. Clear guidance on safe and effective uses of infant massage is lacking especially in the contemporary times when the traditional knowledge is on the verge of extinction and preparations may differ from in the past. This paper presents a consensus guidance in the form of a standardized protocol for routine massage of infants in home settings. Furthermore, a feasible method to develop an integrative protocol involving traditional and modern medicine experts is described. A modified e-Delphi method was used to develop the protocol. A group of seventeen experts, including academicians and practitioners from disciplines as modern paediatrics, Ayurveda paediatrics, Physiotherapy and Naturopathy participated in three rounds of a Delphi study to evolve the consensus guidance. The present protocol for massage of infants born beyond 34 weeks of gestation and weighing above 1.8 kg is recommended for use by care givers. This provides guidance on the preparation for infant massage such as when to begin massaging the infant, checking fitness of the infant for massage, the appropriate time, environment, person and substance for infant massage and a detailed description of the procedure for infant massage. Paediatricians, obstetricians and other child care practitioners can use this protocol to guide care givers on how to peform infant massage.

Coronavirus disease 2019 (COVID-19) is the latest respiratory pandemic caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2). Although infection initiates in the proximal airways, severe and sometimes fatal symptoms of the disease are caused by infection of the alveolar type 2 (AT2) cells of the distal lung and associated inflammation. In this study, we develop primary human lung epithelial infection models to understand initial responses of proximal and distal lung epithelium to SARS-CoV-2 infection. Differentiated air-liquid interface (ALI) cultures of proximal airway epithelium and alveosphere cultures of distal lung AT2 cells are readily infected by SARS-CoV-2, leading to an epithelial cell-autonomous proinflammatory response with increased expression of interferon signaling genes. Studies to validate the efficacy of selected candidate COVID-19 drugs confirm that remdesivir strongly suppresses viral infection/replication. We provide a relevant platform for study of COVID-19 pathobiology and for rapid drug screening against SARS-CoV-2 and emergent respiratory pathogens., Graphical abstract, In vitro models of human lung epithelium, including diverse cell types of the proximo-distal axis, are critical for modeling infection. Mulay et al. show that alveospheres, with epithelial type 2- and type 1-like cells, are infected by SARS-CoV-2, initiating an interferon response, and serve as a platform for screening antiviral drugs.

Over 50,000 defendants are referred for competency to stand trial evaluations each year in the United States (Psychological evaluations for the courts: A handbook for mental health professionals and lawyers, New York, NY: The Guildford Press; 2018). Approximately 20% of those individuals are found by courts to be incompetent and are referred for "restoration" or remediation (Psychological evaluations for the courts: A handbook for mental health professionals and lawyers, 4th edn. New York, NY: The Guildford Press; 2018; Bull Am Acad Psychiatry Law. 1991;19:63-9). The majority of those incompetent defendants meet criteria for psychotic illnesses (J Am Acad Psychiatry Law. 2007;35:34-43). Forensic mental health professionals frequently have such patients/defendants decline recommended treatment with psychotropic medication. For a significant minority of defendants diagnosed with psychotic disorders, treatment with medication is thought to be necessary to restore their competency to stand trial. Without psychiatric intervention to restore competency, defendants may be held for lengthy and costly hospitalizations while criminal proceedings are suspended. In these situations, clinicians are guided by the Supreme Court decision, Sell v. United States (2003). The Sell opinion describes several clinical issues courts must consider when determining whether a defendant can be treated involuntarily solely for the purpose of restoring his/her competency. This paper offers some guidance to clinicians and evaluators who are faced with making recommendations or decisions about involuntary treatment. Using a question and answer format, the authors discuss data that support a decision to request, or not request, court authorization for involuntary treatment. Specifically, eight questions are posed for forensic evaluators to consider in determining the prognosis or viability of successful treatment and restoration. Finally, a clinical vignette is also presented to highlight important factors to consider in Sell-related evaluations.

Percutaneous coronary intervention (PCI) in very small vessel coronary arteries is challenging due to adverse short-term as well as long-term outcomes. This single-arm, open-label, observational study assessed 1-year clinical outcomes of drug-eluting stents (DES) in Indian patients undergoing PCI for symptomatic very small-calibre coronary artery disease. It enrolled 66 Indian patients with 74 very small coronary artery lesions (reference vessel diameter: ≥2.0 and ≤ 2.25 mm); eligible for implantation with 2.25 mm DES. The primary endpoint of major adverse cardiovascular events (MACE) was 3.0% indicating favourable 1-year clinical outcomes of DES in very small coronary artery lesions in Indian patients.

Background: India has been amongst the most affected nations during the SARS CoV2 pandemic, with sparse data on country wide spread of asymptomatic infections and antibody persistence. This longitudinal cohort study was aimed to evaluate SARS CoV2 seropositivity rate as a marker of infection and evaluate temporal persistence of antibodies with neutralization capability and to infer possible risk factors for infection. Methods: Council of Scientific and Industrial Research, India (CSIR) with its more than 40 laboratories and centers in urban and semi urban settings spread across the country piloted the pan country surveillance. 10427 adult individuals working in CSIR laboratories and their family members based on voluntary participation were assessed for antibody presence and stability was analyzed over 6 months utilizing qualitative Elecysys SARS CoV2 specific antibody kit and GENScript cPass SARS CoV2 Neutralization Antibody Detection Kit. Along with demographic information, possible risk factors were evaluated through self to be filled online forms with data acquired on blood group type, occupation type, addiction and habits including smoking and alcohol, diet preferences, medical history and transport type utilized. Symptom history and information on possible contact and compliance with COVID 19 universal precautions was also obtained. Findings:1058 individuals (10.14%) had antibodies against SARS CoV2. A follow up on 346 seropositive individuals after three months revealed stable to higher antibody levels against SARS CoV2 but declining plasma activity for neutralizing SARS CoV2 receptor binding domain and ACE2 interaction. A repeat sampling of 35 individuals, at six months, revealed declining antibody levels while the neutralizing activity remained stable compared to three months. Majority of seropositive individuals (75%) did not recall even one of nine symptoms since March 2020. Fever was the most common symptom with one fourth reporting loss of taste or smell. Significantly associated risks for seropositivity (Odds Ratio, 95% CI, p value) were observed with usage of public transport (1.79, 1.43 to 2∙24, 2.81561x10-6), occupational responsibilities such as security, housekeeping personnel etc. (2.23, 1.92 to 2.59, 6.43969x10-26), non smokers (1.52, 1.16 to 1.99, 0.02) and non vegetarianism (1.67, 1.41 to 1.99, 3.03821x10-8). An iterative regression analysis was confirmatory and led to only modest changes to estimates. Predilections for seropositivity was noted with specific ABO blood groups; O was associated with a lower risk. Interpretation: In a first of its kind study from India, we report the seropositivity in a country wide cohort and identify variable susceptible associations for contacting infection. Serology and Neutralizing Antibody response provides much sought for general insights on the immune response to the virus among Indians and will be an important resource for designing vaccination strategies. Funding: Council of Scientific and Industrial Research, India (CSIR)

Diabetes is a chronic metabolic disorder with a high rate of morbidity and mortality. Insufficient insulin secretion and insulin action are two major causes for the development of diabetes, which is characterized by a persistent increase in blood glucose level. Diet and sedentary life style play pivotal role in development of vascular complications in type 2 diabetes. Dietary modification is associated with a reprogramming of nutrient intake, which are proven to be effective for the management of diabetes and associated complications. Dietary modifications modulate various molecular key players linked with the functions of nutrient signalling, regulation of autophagy, and energy metabolism. It activates silent mating type information regulation 2 homolog1 (SIRT1) and AMP-activated protein kinase (AMPK). AMPK mainly acts as an energy sensor and inhibits autophagy repressor Mammalian target of rapamycin (mTOR) under nutritional deprivation. Under calorie restriction (CR), SIRT1 gets activated directly or indirectly and plays a central role in autophagy via the regulation of protein acetylation. Dietary modification is also effective in controlling inflammation and apoptosis by decreasing the level of pro-inflammatory cytokines like nuclear factor kappa- beta (NF-kβ), tissue growth factor-beta (TGF-β), tissue necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). It also improves glucose homeostasis and insulin secretion through beta cell regeneration. This indicates calorie intake plays a crucial role in the pathogenesis of type 2 diabetes-associated complications. The present review, emphasizes the role of dietary modifications in diabetes and associated complications.

Background: Suicide rates are higher in rural compared to urban areas. Although this pattern appears to be driven by higher rates among men, there is limited evidence about the characteristics of rural people who die by suicide in Canada. The objective of this study was to examine the demographics, manner of death, and social and clinical antecedents of people who died by suicide in rural areas compared to urban areas. Methods: We conducted an observational study of all suicide deaths that occurred among Newfoundland and Labrador residents between 1997 and 2016 using a linked data set derived from a comprehensive review of provincial medical examiner records. We used t tests and χ2 to assess associations between rural/urban status and variables related to demographics, circumstances, and manner of death, as well as social and medical history. Logistic regression was utilized to assess the independent contribution of any variable found to be significant in univariate analysis. Results: Rural people who died by suicide accounted for 54.8% of all deaths over a 20-year period. Overall, 81.6% of people who died were male. Compared to urban, rural people who died by suicide were younger, more likely to use firearms or hanging, and had a higher mean blood alcohol content at the time of death (27.69 vs. 22.95 mmol/L). Rural people were also less likely to have had a known history of a prior suicide attempt, psychiatric disorder, alcohol or substance abuse, or chronic pain. Discussion: The demographic and clinical differences between rural and urban people who died by suicide underscore the need for suicide prevention approaches that account for place-based differences. A key challenge for suicide prevention in rural communities is to ensure that interventions are developed and implemented in a manner that fits local contexts.

Background Early morbidity and mortality are low after endovascular abdominal aneurysm repair (EVAR), but secondary interventions and late complications are common. The aim of the present multicenter cohort study is to detail the frequency and indication for interventions after EVAR and the impact on long-term survival. Methods A retrospective multicenter cohort study of secondary interventions after elective EVAR for an infrarenal abdominal aortic aneurysm was conducted. Consecutive patients (n = 349) undergoing EVAR between January 2007 and January 2012 were analyzed, with long-term follow-up until December 2018. Those requiring intervention were classified in accordance with the indications and specific nature of the intervention and treatment. The primary study end point was overall survival classified for patients with and without intervention. Kaplan-Meier analysis was used to estimate overall survival for those who did and who did not undergo secondary interventions. Univariable and multivariable Cox regression were performed to identify independent variables associated with mortality. Results Some 56 patients (16%) underwent 72 secondary interventions after EVAR during a median (interquartile range) follow-up period of 53.2 months (60.1). Some 45 patients (80.4%) underwent one intervention. Indications for intervention included mainly endograft kinking/outflow obstruction and type II endoleak. An endovascular technique was used in 40.3% of interventions. Median time to secondary intervention was 24.1 months. In 93 patients with abnormalities on imaging, no intervention was performed mainly because the abnormality had disappeared on follow-up imaging (43%). Kaplan-Meier curves showed no difference in survival for patients with and without secondary interventions (P = 0.153). Age (hazard ratio [HR]: 1.089, 95% confidence interval [CI]: 1.063–1.116), ASA classification (ASA III, IV HR: 1.517, 95% CI: 1.056–2.178) were significantly related to mortality. Conclusions Secondary intervention rates are still considerable after EVAR. Endograft kinking/outflow obstruction and endoleak type II are the most common indications for a secondary intervention. Secondary interventions did not adversely affect long-term overall survival after EVAR.

Vertebral labelling and segmentation are two fundamental tasks in an automated spine processing pipeline. Reliable and accurate processing of spine images is expected to benefit clinical decision-support systems for diagnosis, surgery planning, and population-based analysis on spine and bone health. However, designing automated algorithms for spine processing is challenging predominantly due to considerable variations in anatomy and acquisition protocols and due to a severe shortage of publicly available data. Addressing these limitations, the Large Scale Vertebrae Segmentation Challenge (VerSe) was organised in conjunction with the International Conference on Medical Image Computing and Computer Assisted Intervention (MICCAI) in 2019 and 2020, with a call for algorithms towards labelling and segmentation of vertebrae. Two datasets containing a total of 374 multi-detector CT scans from 355 patients were prepared and 4505 vertebrae have individually been annotated at voxel-level by a human-machine hybrid algorithm (https://osf.io/nqjyw/, https://osf.io/t98fz/). A total of 25 algorithms were benchmarked on these datasets. In this work, we present the the results of this evaluation and further investigate the performance-variation at vertebra-level, scan-level, and at different fields-of-view. We also evaluate the generalisability of the approaches to an implicit domain shift in data by evaluating the top performing algorithms of one challenge iteration on data from the other iteration. The principal takeaway from VerSe: the performance of an algorithm in labelling and segmenting a spine scan hinges on its ability to correctly identify vertebrae in cases of rare anatomical variations. The content and code concerning VerSe can be accessed at: https://github.com/anjany/verse., Comment: Challenge report for the VerSe 2019 and 2020. Published in Medical Image Analysis (DOI: https://doi.org/10.1016/j.media.2021.102166)

The lack of health infrastructure in developing countries to provide women with modern obstetric care and universal access to maternal and child health services has largely contributed to the existing high maternal and infant deaths. Access to basic obstetric care for pregnant women and their unborn babies is key to reducing maternal and infants' deaths, especially at the community-level. This calls for the strengthening of the primary health care systems in all developing countries, including Ghana. Financial access and utilization of maternal and child health care services need action at the community-level across rural Ghana to avoid preventable deaths. Financial access and usage of maternal and child health services in rural Ghana is poor. Lack of financial access is a strong barrier to the use of maternal and child health services, particularly in rural Ghana. The sustainability of the national health insurance scheme is vital in ensuring full access to care in remote communities.

Purpose SARS-CoV-2 engages human ACE2 through its spike (S) protein receptor binding domain (RBD) to enter the host cell. Recent computational studies have reported that withanone and withaferin A, phytochemicals found in Withania somnifera, target viral main protease (MPro) and host transmembrane TMPRSS2, and glucose related protein 78 (GRP78), respectively, implicating their potential as viral entry inhibitors. Absence of specific treatment against SARS-CoV-2 infection has encouraged exploration of phytochemicals as potential antivirals. Aim This study aimed at in silico exploration, along with in vitro and in vivo validation of antiviral efficacy of the phytochemical withanone. Methods Through molecular docking, molecular dynamic (MD) simulation and electrostatic energy calculation the plausible biochemical interactions between withanone and the ACE2-RBD complex were investigated. These in silico observations were biochemically validated by ELISA-based assays. Withanone-enriched extract from W. somnifera was tested for its ability to ameliorate clinically relevant pathological features, modelled in humanized zebrafish through SARS-CoV-2 recombinant spike (S) protein induction. Results Withanone bound efficiently at the interacting interface of the ACE2-RBD complex and destabilized it energetically. The electrostatic component of binding free energies of the complex was significantly decreased. The two intrachain salt bridge interactions (K31-E35) and the interchain long-range ion-pair (K31-E484), at the ACE2-RBD interface were completely abolished by withanone, in the 50 ns simulation. In vitro binding assay experimentally validated that withanone efficiently inhibited (IC50=0.33 ng/mL) the interaction between ACE2 and RBD, in a dose-dependent manner. A withanone-enriched extract, without any co-extracted withaferin A, was prepared from W. somnifera leaves. This enriched extract was found to be efficient in ameliorating human-like pathological responses induced in humanized zebrafish by SARS-CoV-2 recombinant spike (S) protein. Conclusion In conclusion, this study provided experimental validation for computational insight into the potential of withanone as a potent inhibitor of SARS-CoV-2 coronavirus entry into the host cells., Video abstract Point your SmartPhone at the code above. If you have a QR code reader the video abstract will appear. Or use: https://youtu.be/6dSVJvU4sGE

Aims Mineralization of crystalline particles and the formation of renal calculi contribute to the pathogenesis of crystal nephropathies. Several recent studies on the biology of crystal handling implicated intrarenal crystal deposition-induced necroinflammation in their pathogenesis. We hypothesized that 6,7-dihydroxycoumarin (DHC) inhibit intrarenal crystal cytotoxicity and necroinflammation, and ameliorate crystal-induced chronic kidney disease (CKD). Main methods An unbiased high content screening coupled with fluorescence microscopy was used to identify compounds that inhibit CaOx crystal cytotoxicity. The ligand-protein interactions were identified using computational models e.g. molecular docking and molecular dynamics simulations. Furthermore, mice and rat models of oxalate-induced CKD were used for in-vivo studies. Renal injury, crystal deposition, and fibrosis were assessed by histology analysis. Western blots were used to quantify the protein expression. Data were expressed as boxplots and analyzed using one way ANOVA. Key findings An unbiased high-content screening in-vitro identified 6,7-DHC as a promising candidate. Further, 6,7-DHC protected human and mouse cells from calcium oxalate (CaOx) crystal-induced necroptosis in-vitro as well as mice and rats from oxalate-induced CKD in either preventive or therapeutic manner. Computational modeling demonstrated that 6,7-DHC interact with MLKL, the key protein in the necroptosis machinery, and inhibit its phosphorylation by ATP, which was evident in both in-vitro and in-vivo analyses. Significance Together, our results indicate that 6,7-DHC possesses a novel pharmacological property as a MLKL inhibitor and could serve as a lead molecule for further development of coumarin-based novel MLKL inhibitors. Furthermore, our data identify 6,7-DHC as a novel therapeutic strategy to combat crystal nephropathies.

Due to a tragic increase in the incidences of diabetes globally, diabetic kidney disease (DKD) has emerged as one of the leading causes of end-stage renal diseases (ESRD). Hyperglycaemia-mediated overactivation of the renin-angiotensin-aldosterone system (RAAS) is key to the development and progression of DKD. Consequently, RAAS inhibition by angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARBs) is the first-line therapy for the clinical management of DKD. However, numerous clinical and preclinical evidences suggested that RAAS inhibition can only halt the progression of the DKD to a certain extent, and they are inadequate to cure DKD completely. Recent studies have improved understanding of the complexity of the RAAS. It consists of two counter-regulatory arms, the deleterious pressor arm (ACE/angiotensin II/AT1 receptor axis) and the beneficial depressor arm (ACE2/angiotensin-(1-7)/Mas receptor axis). These advances have paved the way for the development of new therapies targeting the RAAS for better treatment of DKD. In this review, we aimed to summarise the involvement of the depressor arm of the RAAS in DKD. Moreover, in modern drug discovery and development, an advance approach is the bispecific therapeutics, targeting two independent signalling pathways. Here, we discuss available reports of these bispecific drugs involving the RAAS as well as propose potential treatments based on neurohormonal balance as credible therapeutic strategies for DKD.

Neutrophils are first responders of antimicrobial host defense and sterile inflammation, and therefore, play important roles during health and disease [...]

Background As the coronavirus 2019 pandemic continues, healthcare services need to adapt to continue providing optimal and safe services for patients. We detail our adaptive framework as a large Developmental and Behavioral Pediatrics service in a tertiary academic institution in Singapore. Methods The multidisciplinary team at our unit implemented various adaptations and workflow processes during this evolving pandemic in providing continued clinical care tailored to the challenges specific to our patient population. Services were continued via teleconsultation mode during the ‘Circuit Breaker’ (enhanced movement restriction) period. Specific workflow processes, IT infrastructure, and staff training were put in place to support smooth running of this service. Segregation of services into two teams based at two separate sites and implementation of stringent infection control measures surrounding the clinic visit by providers, patients and their families were incorporated to ensure safety. Measures were also taken to ensure providers' mental wellbeing. Results The clinical service was continued for the majority of our patients with a lowest reduction in patient consultations to half of baseline during the ‘Circuit Breaker’ period. We received positive feedback from families for teleconsultation services provided. Conclusion We have been able to continue services in our DBP clinics due to our dynamic reassessment of workflow processes and their prompt implementation in conjunction with the hospital and national public health response to the pandemic. Given that this pandemic is likely to be long drawn, our unit remains ready to constantly adjust these workflows and make adaptations as we go along, together with the support for mental health of patients, parents and staff. Continual improvements in workflows will be helpful even beyond the pandemic to ensure good continuity of care for our patients and families.

We describe the pertinent research steps and analysis, many of which are chemical, to achieve a novel molecular probe for glutathione (GSH) which has been published and patented based on two recent articles: "Exceptional time response, stability and selectivity in doubly-activated phenyl selenium-based glutathione-selective platform" and "Enhanced Doubly Activated Dual Emission Fluorescent Probes for Selective Imaging of Glutathione or Cysteine in Living Systems" (Kim et al., 2015; Mulay et al., 2018). The papers involve coumarin probes. Reaction/detection unfolds with aminothiol attack at an electrophilic ring carbon position. An adjacent -CHO group is heavily involved in resonance aspects of the C-Se position, as well as the binding of the pendant N-group; the coumarin lactone carbonyl also allows for resonance to be achieved (vide infra). The leaving group, -SePh, while precedented in some systems, depends on electronic tuning (Fig. 1). For 1, the response times with GSH was ~100ms; a 100-fold fluorescence increase is observed (Compound 1). The probe also reacts with cysteine (Cys) and homocysteine (Hcy), albeit differently. For glutathione probing, the greater wavelength maxima (1: 550nm, DACP-1: 555nm, DACP-2: 590nm) enabled eventual cell studies (confocal microscopy) and animal studies. The limits of detection (LOD, 1: 270nM DACP-1: 10.1nM DACP-2: 17.0nM), as measured using the 3σ/k method. We provide a didactic presentation from probe conception to probe in vivo testing, etc., with additional considerations presented; a variety of factors/issues (2.1-2.28) help maintain a realistic sequence, a flow from wider to narrower, of the factors that go into developing medical, biological and neurodegenerative disease-related probes, meant to help other researchers follow our intention, gain perspective, and overcome current limitations.

The COVID-19 pandemic is progressing worldwide with an alarming death toll. There is an urgent need for novel therapeutic strategies to combat potentially fatal complications. Distinctive clinical features of severe COVID-19 include acute respiratory distress syndrome, neutrophilia, and cytokine storm, along with severe inflammatory response syndrome or sepsis. Here, we propose the putative role of enhanced neutrophil infiltration and the release of neutrophil extracellular traps, complement activation and vascular thrombosis during necroinflammation in COVID-19. Furthermore, we discuss how neutrophilic inflammation contributes to the higher mortality of COVID-19 in patients with underlying co-morbidities such as diabetes and cardiovascular diseases. This perspective highlights neutrophils as a putative target for the immunopathologic complications of severely ill COVID-19 patients. Development of the novel therapeutic strategies targeting neutrophils may help reduce the overall disease fatality rate of COVID-19.

An individual's interpersonal features are pertinent to treatment within clinical populations. The Personality Assessment Inventory (PAI) contains two scales that assess the interpersonal features of warmth (WRM) and dominance (DOM), as well as two additional measures to assess to treatment prediction, process, and rejection (RXR; TPI). The current study examined associations between these PAI scales in a sample of 92 men who underwent comprehensive evaluations of sexual behavior after being charged with or convicted of a sexual offense. Analyses indicated that RXR was positively associated with WRM and DOM, TPI was negatively associated with WRM, and the two interpersonal scales of WRM and DOM were positively correlated with each other. A significant inverse relationship was found between the two treatment scales RXR and TPI indicating that motivation for treatment may have a limited relationship with the treatment process. WRM significantly predicted scores on the TPI, and both WRM and DOM predicted individual scores on RXR. Higher scores on positive impression management (PIM) were predictive of lower TPI and higher RXR, as individuals with higher stakes cases may score higher on PIM and underreport obstacles within treatment or be unwilling to accept the need for treatment. Overall, findings suggest that interpersonal characteristics identified by the PAI scales may be advantageous in approaching treatment within this population.

This review highlights recent literature regarding online sexual offending, including the prevalence, characteristics, a brief review of recent typology literature, victimization risk factors, risk factors of being a “crossover” offender, rates and risk factors for recidivism, and a discussion of prevention efforts. Online sexual offenders are overwhelmingly White men with relationship problems who were rarely previously arrested for felonies. They score lower on measures of antisocial behavior, compared to offenders who commit contact sexual offenses against children. Individuals who commit pornography offenses are at lower risk to commit contact offenses and their risk factors include having sexual interest in children and antisocial attitudes. Online offenders are different from contact sexual offenders and from offenders who commit both types of offenses. Recidivism in online noncontact offenders is difficult to assess due to the lack of empirically supported tools and the inappropriateness of using popular actuarial tools that lack norms on these offenders, but a new measure (CPORT) is being studied for use with this population.

Purpose To characterize the clinical features of subtype-specific lacrimal gland lymphoma and their effect on patient survival. Design Multicenter retrospective interventional case series. Methods Patient data were collected from 6 international eye cancer centers from January 1, 1980, through December 31, 2017. All patients with histologically verified primary or secondary lymphoma of the lacrimal gland were included. Primary endpoints were overall survival (OS) and disease-specific survival (DSS). Results A total of 260 patients with lacrimal gland lymphoma were identified. The median age was 58 years and 52% of patients were men. Non-Hodgkin B-cell lymphomas constituted 99% (n = 258) and T-cell lymphomas constituted 1% (n = 2). The most frequent lymphoma subtypes were extranodal marginal zone B-cell lymphoma (EMZL) (n = 177, 68%), follicular lymphoma (FL) (n = 26, 10%), diffuse large B-cell lymphoma (DLBCL) (n = 25, 10%), and mantle cell lymphoma (MCL) (n = 17, 7%). Low-grade lymphomas (EMZL and FL) were most commonly treated with external beam radiotherapy (EBRT), whereas high-grade lymphomas (DLBCL and MCL) were treated with chemotherapy in combination with rituximab and/or EBRT. The prognosis was relatively good with a 5-year OS and DSS of 73.8% and 87.5%, respectively. Lymphoma subtype was a statistically significant predictor for DSS, with EMZL (5-year DSS: 93.4%) having the best prognosis and DLBCL (5-year DSS: 52.6%) having the poorest. Conclusions This is the largest reported collection of data of subtype-specific lacrimal gland lymphoma. The subtype distribution of lacrimal gland lymphoma resembles that of the ocular adnexa. Prognosis is good and the histologic subtype is a significant predictor for disease-specific survival.