Non-invasive estimation of the powder size distribution from a single speckle image

Non-invasive characterization of powders may take one of two approaches:imaging and counting individual particles;or relying on scattered light to estimate the particle size distribution(PSD)of the ensemble.The former approach runs into practical difficulties,as the system must conform to the working distance and other restrictions of the imaging optics.The latter approach requires an inverse map from the speckle autocorrelation to the particle sizes.The principle relies on the pupil function determining the basic sidelobe shape,whereas the particle size spread modulates the sidelobe intensity.We recently showed that it is feasible to invert the speckle autocorrelation and obtain the PSD using a neural network,trained efficiently through a physics-informed semi-generative approach.In this work,we eliminate one of the most time-consuming steps of our previous method by engineering the pupil function.By judiciously blocking portions of the pupil,we sacrifice some photons but in return we achieve much enhanced sidelobes and,hence,higher sensitivity to the change of the size distribution.The result is a 60×reduction in total acquisition and processing time,or 0.25 seconds per frame in our implementation.Almost real-time operation in our system is not only more appealing toward rapid industrial adoption,it also paves the way for quantitative characterization of complex spatial or temporal dynamics in drying,blending,and other chemical and pharmaceutical manufacturing processes.

A human translational model based on neuroplasticity for pharmacological agents potentially effective in Treatment-Resistant Depression: focus on dopaminergic system

Major depressive disorder(MDD)is a common psychiatric condition characterized by two main symptoms,low mood and anhedonia.About 15–30%of people suffering from MDD do not respond to standard-of-care antidepressants,e.g.,the serotonin re-uptake inhibitors(SSRI),and are considered affected by Treatment-Resistant Depression(TRD).The neurobiology of this condition is presently unknown.Recent attempts of developing novel treatments for TRD have been driven by four major breakthroughs:(1)Increasing dopaminergic neurotransmission improves TRD symptoms;(2)Anhedonia occurs when central dopaminergic neurotransmission is low;(3)Enhanced neuroplasticity is critical for the action of antidepressants;(4)Ketamine shows antidepressant properties in TRD patients and triggers neuroplasticity in preclinical animal models.These breakthroughs are at the basis of a putative human translational cellular model for antidepressant agents that we are proposing in this article.The rationale is briefly described here.

Understanding celiac disease monitoring patterns and outcomes after diagnosis:A multinational,retrospective chart review study

BACKGROUND Long-term outcomes and monitoring patterns in real-world practice are largely unknown among patients with celiac disease.AIM To understand patterns of follow-up and management of patients with celiac disease,and to characterize symptoms and villous atrophy after diagnosis.METHODS A retrospective chart review study was performed using medical chart data of patients diagnosed with celiac disease.Three gastroenterology referral centers,with substantial expertise in celiac disease,participated in the United Kingdom,United States,and Norway.Demographic and clinical data were collected from medical charts.Descriptive analyses were conducted on patients with biopsyconfirmed celiac disease,diagnosed between 2008 and 2012,with at least one follow-up visit before December 31,2017.Patient demographic and clinical characteristics,biopsy/serology tests and results,symptoms,and comorbidities were captured at diagnosis and for each clinic visit occurring within the study period(i.e.,before the study end date of December 31,2017).RESULTS A total of 300 patients were included in this study[72%female;mean age at diagnosis:38.9 years,standard deviation(SD)17.2].Patients were followed-up for a mean of 29.9 mo(SD 22.1)and there were,on average,three follow-up visits per patient during the study period.Over two-thirds(68.4%)of patients were recorded as having ongoing gastrointestinal symptoms and 11.0%had ongoing symptoms and enteropathy during follow-up.Approximately 80%of patients were referred to a dietician at least once during the follow-up period.Half(50.0%)of the patients underwent at least one follow-up duodenal biopsy and 36.6%had continued villous atrophy.Patterns of monitoring varied between sites.Biopsies were conducted more frequently in Norway and patients in the United States had a longer follow-up duration.CONCLUSION This real-world study demonstrates variable follow-up of patients with celiac disease despite most patients continuing to have abnormal histology and symptoms after diagnosis.

Multi-national observational study to assess quality of life and treatment preferences in patients with Crohn’s perianal fistulas

BACKGROUND Patients with Crohn’s disease(CD)are at risk of developing complications such as perianal fistulas.Patients with Crohn’s perianal fistulas(CPF)are affected by fecal incontinence(FI),bleeding,pain,swelling,and purulent perianal discharge,and METHODS This cross-sectional observational study was conducted in patients with CD aged 21-90 years via a web-enabled questionnaire in seven countries(April-August 2021).Patients were recruited into three cohorts:Cohort 1 included patients without perianal fistulas;cohort 2 included patients with perianal fistulas without fistula-related surgery;and cohort 3 included patients with perianal fistulas and fistula-related surgery.Validated patient-reported outcome measures were used to assess quality of life.Drivers of treatment preferences were measured using a discrete choice experiment(DCE).RESULTS In total,929 patients were recruited(cohort 1,n=620;cohort 2,n=174;cohort 3,n=135).Short Inflammatory Bowel Disease Questionnaire scores were worse for patients with CPF(cohorts 2 and 3)than for those with CD without CPF(cohort 1):Mean score 3.8 and 3.7 vs 4.1,respectively,(P<0.001).Similarly,mean Revised FI and FI Quality of Life scores were worse for patients with CPF than for those with CD without CPF.Quality of Life with Anal Fistula scores were similar in patients with CPF with or without CPF-related surgery(cohorts 2 and 3):Mean score 41 and 42,respectively.In the DCE,postoperative discomfort and fistula healing rate were the most important treatment attributes influencing treatment choice:Mean relative importance 35.7 and 24.7,respectively.CONCLUSION The burden of illness in CD is significantly higher for patients with CPF and patients rate lower postoperative discomfort and higher healing rates as the most desirable treatment attributes.

Vonoprazan 10 mg or 20 mg vs.lansoprazole 15 mg as maintenance therapy in Asian patients with healed erosive esophagitis:A randomized controlled trial

Background:Erosive esophagitis(EE)is a gastroesophageal reflux disease characterized by mucosal breaks in the esophagus.Proton pump inhibitors are widely used as maintenance therapy for EE,but many patients still relapse.In this trial,we evaluated the noninferiority of vonoprazan vs.lansoprazole as maintenance therapy in patients with healed EE.Methods:We performed a double-blind,double-dummy,multicenter,phase 3 clinical trial among non-Japanese Asian adults with endoscopically confirmed healed EE from April 2015 to February 2019.Patients from China,South Korea,and Malaysia were randomized to vonoprazan 10 mg or 20 mg once daily or lansoprazole 15 mg once daily for 24 weeks.The primary endpoint was endoscopically confirmed EE recurrence rate over 24 weeks with a noninferiority margin of 10%using a two-sided 95%confidence interval(CI).Treatment-emergent adverse events(TEAEs)were recorded.Results:Among 703 patients,EE recurrence was observed in 24/181(13.3%)and 21/171(12.3%)patients receiving vonoprazan 10 mg or 20 mg,respectively,and 47/184(25.5%)patients receiving lansoprazole(differences:-12.3%[95%CI,-20.3%to-4.3%]and-13.3%[95%CI,-21.3%to-5.3%],respectively),meeting the primary endpoint of noninferiority to lansoprazole in preventing EE recurrence at 24 weeks.Evidence of superiority(upper bound of 95%CI<0%)was also observed.At 12 weeks,endoscopically confirmed EE recurrence was observed in 5/18,2/20,and 7/20 of patients receiving vonoprazan 10 mg,vonoprazan 20 mg,and lansoprazole,respectively.TEAEs were experienced by 66.8%(157/235),69.0%(156/226),and 65.3%(158/242)of patients receiving vonoprazan 10 mg,vonoprazan 20 mg,and lansoprazole,respectively.The most common TEAE was upper respiratory tract infection in 12.8%(30/235)and 12.8%(29/226)patients in vonoprazan 10 mg and 20 mg groups,respectively and 8.7%(21/242)patients in lansoprazole group.Conclusion:Vonoprazan maintenance therapy was well-tolerated and noninferior to lansoprazole for preventing EE recurrence in Asian patients with healed EE.Trial Registration:https://clinicaltrials.gov;NCT02388737.

Prevalence of anal fistula in the United Kingdom

BACKGROUND Anal fistula is a pathological connection between the anal canal and perianal skin, which most commonly develops from an infected anal crypt. While the majority of anal fistulas are idiopathic, they are also associated with Crohn’s disease (CD) and other inflammatory conditions. The prevalence of anal fistula is estimated to be 1-2 per 10000 patients, but population-based studies on anal fistula epidemiology are limited and outdated. AIM To assess the prevalence of anal fistula and relevant comorbidities, with and without CD in the United Kingdom and Europe. METHODS A retrospective population-representative observational cohort study was performed in The Health Improvement Network (THIN), a United Kingdom primary care database. Mid-year point prevalence of anal fistula was calculated on the first of July for each year between 2014 and 2017. Estimates were calculated for anal fistula overall and by CD status and standardized to the United Kingdom and European population. Prevalence of relevant comorbidities including lymphogranuloma venereum, hidradenitis suppurativa, anal presentation of sexually transmitted diseases, diabetes mellitus, and radiation in the pelvic area was reported. RESULTS The United Kingdom-standardized overall point prevalence of anal fistula was 1.80 (95%CI: 1.65-1.94) per 10000 patients in 2017, while the Europe standardized estimate was 1.83 (95%CI: 1.68-1.98) per 10000 patients. Both these standardized point prevalence estimates ranged from 1.89 to 2.36 between 2014-2016. The United Kingdom-standardized point prevalence of anal fistula without CD was 1.35 (95%CI: 1.23-1.48) per 10000 patients, while the Europe-standardized estimate was 1.39 (95%CI: 1.26-1.52) per 10000 patients. In contrast, the standardized point prevalence estimate of anal fistula with CD was lower for both United Kingdom and Europe (0.44;95%CI United Kingdom: 0.37-0.52, 95%CI Europe: 0.37-0.51) per 10000 patients in 2017. In 2017, 19% of anal fistula patients without CD and 13% of anal fistula patients with CD had at least one relevant comorbidity. These results show that anal fistulas are infrequent in the general population. 24.5% of prevalent anal fistulas are associated with CD, but other potentially etiological comorbidities are rare. CONCLUSION This real-world evidence study estimated the United Kingdom-standardized prevalence of anal fistula was 1.80 per 10000 patients in 2017. Approximately 25% of cases may be associated with CD, while other comorbidities are rare.

Ketamine enhances structural plasticity in human dopaminergic neurons:possible relevance for treatment-resistant depression

Depression refers to a series of mental health issues characterized by loss of interest and enjoyment in everyday life,low mood and selected emotional,cognitive,physical and behavioral symptoms.Depression is a common disorder,affecting 5–15%of the general population.When diagnosed as major depressive disorder（MDD）,patients are currentlytreated with pharmacological agents such as serotonin or noradren- aline uptake inhibitors （SSRI or SNRI） or tricyclics.

Non-responsive celiac disease in children on a gluten free diet

BACKGROUND Non-responsive celiac disease(NRCD) is defined as the persistence of symptoms in individuals with celiac disease(CeD) despite being on a gluten-free diet(GFD). There is scant literature about NRCD in the pediatric population.AIM To determine the incidence, clinical characteristics and underlying causes of NRCD in children.METHODS Retrospective cohort study performed at Boston Children’s Hospital(BCH). Children < 18 years diagnosed with CeD by positive serology and duodenal biopsies compatible with Marsh Ⅲ histology between 2008 and 2012 were identified in the BCH’s Celiac Disease Program database. Medical records were longitudinally reviewed from the time of diagnosis through September 2015. NRCD was defined as persistent symptoms at 6 mo after the initiation of a GFD and causes of NRCD as well as symptom evolution were detailed. The children without symptoms at 6 mo(responders) were compared with the NRCD group. Additionally, presenting signs and symptoms at the time of diagnosis of CeD among the responders and NRCD patients were collected and compared to identify any potential predictors for NRCD at 6 mo of GFD therapy.RESULTS Six hundred and sixteen children were included. Ninety-one(15%) met criteria for NRCD. Most were female(77%). Abdominal pain [odds ratio(OR) 1.8 95% confidence interval(CI) 1.1-2.9], constipation(OR 3.1 95%CI 1.9-4.9) and absence of abdominal distension(OR for abdominal distension 0.4 95%CI 0.1-0.98) at diagnosis were associated with NRCD. NRCD was attributed to a wide variety of diagnoses with gluten exposure(30%) and constipation(20%) being the most common causes. Other causes for NRCD included lactose intolerance(9%), gastroesophageal reflux(8%), functional abdominal pain(7%), irritable bowel syndrome(3%), depression/anxiety(3%), eosinophilic esophagitis(2%), food allergy(1%), eating disorder(1%), gastric ulcer with Helicobacter pylori(1%), lymphocytic colitis(1%), aerophagia(1%) and undetermined(13%). 64% of children with NRCD improved on follow-up.CONCLUSION NRCD after ≥ 6 mo GFD is frequent among children, especially females, and is associated with initial presenting symptoms of constipation and/or abdominal pain. Gluten exposure is the most frequent cause.

Gentamicin Renal Excretion in Rats: Probing Strategies to Mitigate Drug-Induced Nephrotoxicity

The renal excretion of gentamicin, an aminoglycoside antibiotic, was studied in the isolated perfused rat kidney (IPRK) model. Dose-linearity experiments were carried out at four doses (400, 800, 1600, 3200 μg), targeting initial perfusate levels of 5, 10, 20 and 40 μg/ml. Additionally, gentamicin was co-perfused with sodium bicarbonate (0.25 mM) and/or cimetidine (2 mM) to evaluate the effect of urinary alkalization and secretory inhibition on gentamicin excretion and kidney accumulation. Gentamicin displayed net reabsorption in the IPRK, consistent with extensive luminal uptake. Kinetic analysis indicated that luminal transport of gentamicin (kidney ? urine) is the rate-determining step for gentamicin urinary excretion. Clearance and cumulative excretion decreased with increased gentamicin dose. Gentamicin kidney accumulation, estimated by mass balance, ranged from ~20% - 30%. Urinary alkalization significantly increased gentamicin excretion, with no effect on kidney accumulation. Conversely, cimetidine co-administration did not affect gentamicin clearance in the IPRK, but kidney accumulation was significantly reduced. When both sodium bicarbonate and cimetidine were administered together, gentamicin kidney accumulation decreased ~80% with corresponding increases in clearance and excretion ratio (XR) compared to gentamicin alone. A main strategy to reduce the incidence of nephrotoxicity with gentamicin therapy (up to ~25%) involves reducing kidney accumulation of the compound. The results of this research suggest that the combination of urinary alkalization and inhibition of basolateral secretion (blood → kidney) may be a viable approach to mitigate aminoglycoside toxicity, and warrants further investigation.

Synthetic biology approaches for improving the specificity and efficacy of cancer immunotherapy

Immunotherapy has shown robust efficacy in treating a broad spectrum of hematological and solid cancers.Despite the transformative impact of immunotherapy on cancer treatment,several outstanding challenges remain.These challenges include on-target off-tumor toxicity,systemic toxicity,and the complexity of achieving potent and sustainable therapeutic efficacy.Synthetic biology has emerged as a promising approach to overcome these obstacles,offering innovative tools for engineering living cells with customized functions.This review provides an overview of the current landscape and future prospects of cancer immunotherapy,particularly emphasizing the role of synthetic biology in augmenting its specificity,controllability,and efficacy.We delineate and discuss two principal synthetic biology strategies:those targeting tumor surface antigens with engineered immune cells and those detecting intratumoral disease signatures with engineered gene circuits.This review concludes with a forwardlooking perspective on the enduring challenges in cancer immunotherapy and the potential breakthroughs that synthetic biology may contribute to the field.

Recent advances in the translation of drug metabolism and pharmacokinetics science for drug discovery and development

Drug metabolism and pharmacokinetics(DMPK) is an important branch of pharmaceutical sciences.The nature of ADME(absorption,distribution,metabolism,excretion) and PK(pharmacokinetics) inquiries during drug discovery and development has evolved in recent years from being largely descriptive to seeking a more quantitative and mechanistic understanding of the fate of drug candidates in biological systems.Tremendous progress has been made in the past decade,not only in the characterization of physiochemical properties of drugs that influence their ADME,target organ exposure,and toxicity,but also in the identification of design principles that can minimize drug-drug interaction(DDI) potentials and reduce the attritions.The importance of membrane transporters in drug disposition,efficacy,and safety,as well as the interplay with metabolic processes,has been increasingly recognized.Dramatic increases in investments on new modalities beyond traditional small and large molecule drugs,such as peptides,oligonucleotides,and antibody-drug conjugates,necessitated further innovations in bioanalytical and experimental tools for the characterization of their ADME properties.In this review,we highlight some of the most notable advances in the last decade,and provide future perspectives on potential major breakthroughs and innovations in the translation of DMPK science in various stages of drug discovery and development.

Vedolizumab use in patients with inflammatory bowel diseases undergoing surgery:clinical trials and post-marketing experience

Background:Patients with inflammatory bowel diseases frequently require surgery,but immunotherapies used in disease management may increase the risk of post-operative complications.We investigated frequencies of post-operative complications in patients who received vedolizumab—a gut-selective antibody approved for the treatment of moderately to severely active ulcerative colitis and Crohn’s disease—in clinical-trial and post-marketing settings.Methods:This post hoc analysis of safety data from GEMINI 1,GEMINI 2,and long-term safety studies included patients who had had colectomy or bowel surgery/resection.Data from the post-marketing Vedolizumab Global Safety Database were also analysed(data cutoff point:19 May 2016).Adverse events relating to post-operative complications were identified using Medical Dictionary for Regulatory Activities preferred terms.Results:Of 58 total surgeries in patients included in GEMINI 1 and GEMINI 2,post-operative complications were reported for 3/51 vedolizumab-treated patients(5.9%)and 1/7 placebo-treated patients(14.3%).In the long-term safety study,157/2,243 patients(7%)had colectomy or bowel surgery/resection;of these 157 patients who underwent surgery,11(7%)experienced a post-operative complication.Median time between last pre-operative vedolizumab dose and surgery was 23 days in GEMINI 1,20 days in GEMINI 2,and 39–40 days in the long-termsafety study.In the post-marketing setting,based on data covering approximately 46,978 patient-years of vedolizumab exposure,post-operative complications were reported in 19 patients.Conclusions:In clinical trials,complications of colectomy and bowel surgery/resection appeared infrequent,with minimal difference between vedolizumab and placebo.The frequency of post-operative complications in the post-marketing setting appears low.