Safety and efficacy of quavonlimab, a novel anti-CTLA-4 antibody (MK-1308), in combination with pembrolizumab in first-line advanced non-small-cell lung cancer.

BACKGROUND: Quavonlimab (MK-1308), a novel anti-CTLA-4 antibody, in combination with pembrolizumab was investigated in a phase I study. PATIENTS AND METHODS: Dose-escalation (DE) phase: patients with advanced/metastatic solid tumors received an initial flat dose of quavonlimab as monotherapy [25 mg (cohort 1), 75 mg (cohort 2), or 200 mg (cohort 3)] followed by four treatments of the same quavonlimab dose plus pembrolizumab every 3 weeks (Q3W). Dose-confirmation phase (DC): patients with stage IIIB/IV non-small-cell lung cancer (NSCLC) received first-line quavonlimab [25 mg Q3W (arm A), 25 mg Q6W (arm B), 75 mg Q6W (arm C), or 75 mg Q3W (arm E)] plus pembrolizumab. Primary objectives were safety and tolerability and establishment of the recommended phase II dose (RP2D) of quavonlimab when used with pembrolizumab. Objective response rate (ORR) was a secondary endpoint. Efficacy based on PD-L1 expression, tumor mutational burden (TMB), and changes in circulating CD4+/CD8+ cells were exploratory endpoints. RESULTS: Thirty-nine patients were enrolled in DE [n = 14 (cohort 1); n = 17 (cohort 2); n = 8 (cohort 3)] and 134 in DC [n = 40 (arm A); n = 40 (arm B); n = 40 (arm C); n = 14 (arm E)]. Maximum-tolerated dose was not reached. Grade 3-5 treatment-related adverse events (AEs; graded according to NCI CTCAE v4.03) occurred in 0%, 23.5%, and 75.0% of patients in DE cohorts 1, 2, and 3, respectively, and 35.0%, 30.0%, 35.0%, and 57.1% of patients in DC arms A, B, C, and E, respectively. Efficacy was observed at all dose levels/schedules in patients with NSCLC. ORRs were 40.0% [95% confidence interval (CI), 24.9-56.7; arm A], 37.5% (95% CI, 22.7-54.2; arm B), 27.5% (95% CI, 14.6-43.9; arm C), and 35.7% (95% CI, 12.8-64.9; arm E). PD-L1 expression and total number of circulating CD4+ cells correlated with ORR. CONCLUSIONS: Quavonlimab 25 mg Q6W plus pembrolizumab demonstrated similar efficacy and a better safety profile among all quavonlimab doses/schedules evaluated; this regimen was the chosen RP2D.

3D-Volume Rendering of the Pelvis with Emphasis on Paraurethral Structures Based on MRI Scans and Comparisons between 3D Slicer and OsiriX®.

The feasibility of rendering three dimensional (3D) pelvic models of vaginal, urethral and paraurethral lesions from 2D MRI has been demonstrated previously. To quantitatively compare 3D models using two different image processing applications: 3D Slicer and OsiriX. Secondary analysis and processing of five MRI scan based image sets from female patients aged 29-43 years old with vaginal or paraurethral lesions. Cross sectional image sets were used to create 3D models of the pelvic structures with 3D Slicer and OsiriX image processing applications. The linear dimensions of the models created using the two different methods were compared using Bland-Altman plots. The comparisons demonstrated good agreement between measurements from the two applications. The two data sets obtained from different image processing methods demonstrated good agreement. Both 3D Slicer and OsiriX can be used interchangeably and produce almost similar results. The clinical role of this investigation modality remains to be further evaluated.

Genotype CC of rs12979860 is providing protection against infection rather than assisting in treatment response for HCV genotype 3a infection.

Recent discovery of single-nucleotide polymorphisms located in the upstream region of interleukin-28B (IL28B) has shown association with interferon (IFN) treatment response especially in hepatitis C virus (HCV) genotype 1-infected patients. Pakistan, being the country with second highest prevalence of HCV with predominantly 3a genotype infection, bears a significant disease burden. The present study was conducted to evaluate the effect of rs12979860 genotypes on treatment response in HCV-3a-infected patients. This study shows that the CC genotype is providing protection against infection to HCV. But once infected, the CC genotype patients show viral persistence following IFN therapy. The TT genotype is assisting the 3a patients in viral clearance after IFN treatment. To our knowledge, this is the first study showing rs12979860 genotype association with IFN response in Pakistani HCV-3a-infected patients.

Framework for assessing stewardship of the oral health system in Islamic Republic of Iran.

This study designed a framework for assessing the stewardship function of the oral health system in Islamic Republic of Iran. The modified RAND Corporation/University of California Los Angeles (RAND-UCLA) Appropriateness Method was used in a 2-step process that combined literature evidence and the collective judgement of experts. After a comprehensive literature review, policy instruments related to stewardship components were extracted as candidate standards and categorized according to the 6 sub-functions of stewardship (accountability; defining strategic direction; alignment of policy objectives and organizational structure; regulation; intersectoral leadership; and generation of intelligence). Five key informants then rated the appropriateness of the 85 standards on a 5-point Likert scale. The 38 highest ranked standards, including at least 2 standards in each of the 6 sub-functions, formed a set of proposed standards for evaluating the current stewardship of oral health system. Piloting of the instrument will be reported separately.

Bridging that gap: a qualitative study of perceptions of equality, diversity and inclusivity in colorectal surgery in the UK and Ireland.

BACKGROUND: There is a growing recognition on the importance of equality, diversity and inclusion (EDI) within surgery and the need to diversify the surgical community and its various organisations, in a bidto reflect the diverse populations they serve. To create, sustain and encourage a diverse surgical workforce requires an in-depth understanding of the current makeup of key surgical institutions, relevant issues pertaining to EDI and appropriate solutions and strategies to ensure tangible change. OBJECTIVES: Following on from the recent Kennedy Review into Diversity and Inclusion commissioned by the Royal College of Surgeons of England, the aim of this qualitative study was to understand the EDI issues which affected the membership of the Association of Coloproctology of Great Britain and Ireland, while seeking appropriate solutions to address them. DESIGN: Dedicated, online and qualitative focus groups. PARTICIPANTS: Colorectal surgeons, trainees and nurse specialists were recruited using a volunteer sampling strategy. METHODS: A series of online, dedicated, qualitative focus groups across the 20 chapter regions were held. Each focus group was run informed by a structured topic guide. All participants who were given the opportunity to remain anonymous were offered a debriefing at the end. This study has been reported in keeping with the Standards for Reporting Qualitative Research. RESULTS: Between April and May 2021, a total number of 20 focus groups were conducted, with a total of 260 participants across 19 chapter regions. Seven themes and one standalone code pertaining to EDI were identified: support, unconscious behaviours, psychological consequences, bystander behaviour, preconceptions, inclusivity and meritocracy and the one standalone code was institutional accountability. Five themes were identified pertaining to potential strategies and solutions: education, affirmative action, transparency, professional support and mentorship. CONCLUSION: The evidence presented here is of a range of EDI issues which affect the working lives of those within colorectal surgery in the UK and Ireland, and of potential strategies and solutions which can help build a more inclusive, equitable and diverse colorectal community.

Scaffold-based tissue engineering: Supercritical carbon dioxide as an alternative method for decellularization and sterilization of dense materials.

Development of ready-to-use biomaterials and scaffolds is vital for further advancement of scaffold-based tissue engineering in clinical practice. Scaffolds need to mimic 3D ultrastructure, have adequate mechanical strength, are biocompatible, non-immunogenic and need to promote tissue regeneration in vivo. Although decellularization of native tissues seems promising to deliver scaffolds that meet these criteria, adequate decellularization of hard, poorly penetrable and poorly diffusible tissues remains challenging whilst being a very time-consuming process. In this study, a method to decellularize hard, dense tissues using supercritical carbon-dioxide preceded by a freeze/thaw cycle and followed by several washing steps is presented, demonstrating decellularisation efficiency and substantially reduced production/handling time. Additionally, supercritical carbon-dioxide treatment was used as sterilization method, further reducing the time required to produce the final scaffold. Histological evaluation showed that, after fine-tuning of the process, a partially acellular scaffold was obtained, with preservation of glycosaminoglycans and collagen fibers, albeit that the amount of residual dsDNA was still higher then chemically decellularized tissue. Biomechanical properties of the scaffold were similar to the native, non-decellularized tissue. After sterilization with supercritical carbon-dioxide the simulated functional outcome was more similar to native trachea, when compared to sterilization using gamma irradiation. Thus, decellularization and sterilization using supercritical carbon-dioxide with washing steps is an effective method for dense cartilaginous materials, and tuneable to meet different demands in other applications, but further optimization may be required. STATEMENT OF SIGNIFICANCE: Further advancement of the use of tissue engineered tracheal constructs is restricted by the lack of the ideal scaffold. Decellularized trachea is considered a promising scaffold, but the hard, poorly diffusible tissue remains challenging while forming a very time consumable process. Decellularization using supercritical carbon dioxide (scCO2) seems promising, resulting in efficient removal of cellular material while reducing production and handling time. Addition of scCO2 as a sterilization method resulted in further time reduction while improving functional outcome in comparison with traditional sterilization methods. This study presents an promising alternative method for decellularization and sterilization of dense materials, which can be tuned to meet different demands in other applications.

Patient Safety Friendly Hospital Initiative: from evidence to action in seven developing country hospitals.

QUALITY PROBLEM: Recent evidence in the level of patient safety from hospitals in six developing countries in the Eastern Mediterranean Region has demonstrated the high prevalence of adverse events, the excessive rate of death and permanent disability and their high preventability. The Patient Safety Friendly Hospital Initiative (PSFHI) has been launched to respond to these challenges. INITIAL ASSESSMENT: The principal approach of the PSFHI has been to develop an assessment manual that has 140 patient safety standards across five domains--leadership and management, patients and public involvement, safe evidence-based clinical practices, safe environment and lifelong learning. CHOICE OF SOLUTION AND IMPLEMENTATION: Ministries of health of seven countries--Egypt, Jordan, Morocco, Pakistan, Sudan, Tunisia and Yemen were asked to nominate one hospital for assessment and then follow-up with an improvement plan. EVALUATION: The standards are divided into critical (20), core (90) and developmental (30). The range of critical standards, the compulsory standards with which a hospital has to comply, achieved by participating hospitals was 8-78%. Overall, in the domain of leadership and management the highest compliance was 47%, for patients and public involvement 25%, for safe evidence-based clinical practice 53%, for safe environment 64% and for lifelong learning 27%. LESSONS LEARNED: This is the first systematic multi-country initiative in the Eastern Mediterranean Region, which provides compelling evidence that assessment of patient safety standards is feasible and applicable in resource-poor settings and there are significant opportunities for improving the level of patient safety in these hospitals.

Implementing the district health system in the framework of primary health care in Pakistan: can the evolving reforms enhance the pace towards the millennium development goals?

There is growing renewed trust in primary health care as the best approach for ensuring equity in the delivery of essential health services. However, Pakistan with one of the most widely spread district health system networks in the region, has not delivered at the expected capacity. A series of health system reform agendas are now stipulated which include the promulgation of an essential health service package, public private partnerships and a people-centred focus. Nevertheless, success of these reforms will hinge on the ability of the three tiers of the government and other stakeholders to work together to improve the overall performance of the district health system. This paper provides an overview of the district health system infrastructure and organization of primary health care services in Pakistan, the evolving governance pattern and the operational significance and merit of health system pillars for effective service implementation.

Live Salmonella recruits N-ethylmaleimide-sensitive fusion protein on phagosomal membrane and promotes fusion with early endosome.

To understand intracellular trafficking modulations by live Salmonella, we investigated the characteristics of in vitro fusion between endosomes and phagosomes containing live (LSP) or dead Salmonella (DSP). We observed that fusion of both DSP and LSP were time, temperature and cytosol dependent. GTPgammaS and treatment of the phagosomes with Rab-GDI inhibited fusion, indicating involvement of Rab-GTPases. LSP were rich in rab5, alpha-SNAP, and NSF, while DSP mainly contained rab7. Fusion of endosomes with DSP was inhibited by ATP depletion, N-ethylmaleimide (NEM) treatment, and in NEM-sensitive factor (NSF)-depleted cytosol. In contrast, fusion of endosomes with LSP was not inhibited by ATP depletion or NEM treatment, and occurred in NSF-depleted cytosol. However, ATPgammaS inhibited both fusion events. Fusion of NEM-treated LSP with endosomes was abrogated in NSF- depleted cytosol and was restored by adding purified NSF, whereas no fusion occurred with NEM-treated DSP, indicating that NSF recruitment is dependent on continuous signals from live Salmonella. Binding of NSF with LSP required prior presence of rab5 on the phagosome. We have also shown that rab5 specifically binds with Sop E, a protein from Salmonella. Our results indicate that live Salmonella help binding of rab5 on the phagosomes, possibly activate the SNARE which leads to further recruitment of alpha-SNAP for subsequent binding with NSF to promote fusion of the LSP with early endosomes and inhibition of their transport to lysosomes.

Multicentre study to establish interpretive criteria for clofazimine drug susceptibility testing.

To conduct a multicentre study to establish the critical concentration (CC) for clofazimine (CFZ) for drug susceptibility testing (DST) of Mycobacterium tuberculosis on the MGIT™960™ system using the distribution of minimum inhibitory concentrations (MIC) and genotypic analyses of Rv0678 mutations. In phase I of the study, the MIC distribution of laboratory strains (H37Rv and in vitro-selected Rv0678 mutants) and clinical pan-susceptible isolates were determined (n = 70). In phase II, a tentative CC for CFZ (n = 55) was proposed. In phase III, the proposed CC was validated using clinical drug-resistant tuberculosis (DR-TB) isolates stratified by Rv0678 mutation (n = 85). The MIC distribution of CFZ for laboratory and clinical pan-susceptible strains ranged between 0.125 µg/ml and 0.5 µg/ml. As the MIC values of DR-TB isolates used for phase II ranged between 0.25 µg/ml and 1 µg/ml, a CC of 1 µg/ml was proposed. Validation of the CC in phase III showed that probably susceptible and probably resistant Rv0678 mutants overlapped at 1 µg/ml. We therefore recommend a CC of 1 µg/ml, with additional testing at 0.5 µg/ml to define an intermediate category. This was the first comprehensive study to establish a CC for routine phenotypic DST of CFZ using the MGIT960 system to guide therapeutic decisions. .

Evaluation of a novel endoluminal stapling procedure to restrict the lower esophageal sphincter and reduce reflux.

BACKGROUND AND STUDY AIMS: An effective, safe, and long-lasting endoluminal treatment for gastroesophageal reflux disease (GERD) would be an attractive prospect. We developed an endoluminal technique to restrict and tighten the lower esophageal sphincter (LES), by using a transoral endoscopic stapling device in a porcine model. PATIENTS AND METHODS: Pre-interventional evaluation comprised endoscopy, manometry, and 48-hour pH measurement of the distal esophagus using the catheterless BRAVO pH capsule. By placing the endoluminal stapling device at the LES and firing a 2.5-cm staple line, a vertical plication was created. In five pilot pigs (phase 1), plications were placed in various locations at the LES. In another five pigs (phase 2), plications were placed uniformly at the mid level of the LES on the lesser curvature side. Measurements were repeated 2 weeks after the procedure. Necropsy and histological analysis were performed. RESULTS: Endoluminal stapling was successfully completed in all animals. In phase 2, the median procedure time was 15 minutes (range 10-55 minutes). LES pressure increased from 10.5 mmHg (+/- 2.5 mmHg) to 14.3 mmHg (+/- 3.8 mmHg) (P = 0.038). Median percentage of time with pH below 4 decreased from 6.6% (range 2.9%-48.8%) to 2.2% (range 0%-10.4%) (P = 0.043). Histology showed the staple line involving the muscular layer in all pigs. A gap was present in the central part of the staple line in three pigs resulting in a mucosa-muscular bridge of tissue. This bridge did not influence the results. CONCLUSION: This novel endoluminal technique is feasible and safe in a porcine model over 2 weeks. It is appealing due to its simplicity and ease of application. Further studies aimed at eliminating the gap in the staple line and investigating more animals over longer survival periods are needed.

Drug susceptibility testing of Mycobacterium tuberculosis against second-line drugs using the Bactec MGIT 960 System.

OBJECTIVE: To establish the critical test concentrations for seven second-line anti-tuberculosis drugs in the Bactec Mycobacterial Growth Indicator Tube (MGIT) 960 TB system and to evaluate its efficacy compared to the Bactec 460 TB system. DESIGN: This study was carried out in three phases. In Phase I, pan-susceptible strains were tested to establish the minimum inhibitory concentration; in Phase II, mostly resistant strains were tested to determine a critical test concentration; and in Phase III, actual clinical isolates were tested to validate the optimal critical concentrations established in Phases I and II. RESULTS: The critical concentrations established for seven second-line drugs with the Bactec MGIT 960 system are amikacin 1.0 microg/ml, capreomycin 2.5 microg/ml, kanamycin 2.5 microg/ml, ofloxacin 2.0 microg/ml, moxifloxacin 1.0 microg/ml, ethionamide 5.0 microg/ml and para-amino salicylic acid 4.0 microg/ml. CONCLUSION: The Bactec MGIT 960 System is an accurate and reliable method for rapid drug susceptibility testing (DST) of Mycobacterium tuberculosis against second-line drugs. In the present study, few of the strains were resistant to fluoroquinolones and further DST for this group is required.

Day case laparoscopic rectopexy is feasible, safe, and cost effective for selected patients.

BACKGROUND: With the ever-present financial and bed pressures in the UK health care system, there is a drive toward increasing day surgery provision. Laparoscopic minimally invasive surgery lends itself well to the day case setting. This study aimed to show that day case laparoscopic rectopexy (DCLR) is safe, produces a good clinical outcome, and is cost effective for selected well-motivated patients. METHODS: Since 2001, 28 patients have undergone procedures for rectal prolapse at the authors' institution. Of 12 laparoscopic rectopexy patients, 5 were selected for DCLR on the basis of home circumstances, general fitness, and patient wishes. Patient satisfaction with DCLR was assessed by telephone questionnaire. A retrospective analysis of case notes was performed to compare complications, analgesia requirements, and length of hospital stay. In-hospital costs for all rectal prolapse procedures were calculated. RESULTS: The DCLR group consisted of generally younger and fitter patients. One patient in the DCLR group had persistent abdominal pain and diarrhea requiring an emergency visit. Four of the five patients in the DCLR group were available for telephone interview. Three had stopped analgesia by the third day, reporting their experience as excellent or good. They had no hesitation recommending the procedure for day case usage. Whereas Delorme's procedure and inpatient laparoscopic rectopexy cost much the same, there is a clear cost benefit with DCLR for selected patients of approximately pound1,000 ($1,962) per patient. CONCLUSION: Day case laparoscopic rectopexy has never been reported previously. It is safe, feasible, and acceptable for selected well-motivated patients. Compared with Delorme's procedure and inpatient laparoscopic rectopexy, savings of pound1,000 per patient can be achieved because of an average 3-day decrease in bed occupancy.

Towards sustainable delivery of health services in Afghanistan: options for the future.

Disruption caused by decades of war and civil strife in Afghanistan has led many international and national nongovernmental organizations (NGOs) to assume responsibility for the delivery of health services through contracts with donor agencies. Recently the Afghan Government has pursued the policy of contracting for a basic package of health services (BPHS) supported by funds from three major donors-the World Bank, the United States Agency for International Development (USAID) and the European Commission. With the gradual strengthening of the public health ministry, options for the future include pursuing the contracting option or increasing public provision of health services. Should contracting with NGOs be pursued, a clear strategy is required that includes developing accreditation instruments, better contracting mechanisms and a system for monitoring and evaluating the entire process. Should the government opt for an increasing role, problems to be solved include securing the transition to public provision, optining guarantees that appropriate financing will be provided and reconfiguration of the public health delivery system. Large-scale contracting with the private for-profit sector cannot be recommended at this stage, although this option could be explored via subcontracting by larger NGOs or small-scale trial contracts initiated by the public health ministry. Irrespective of the option chosen, an important challenge remaining is the recalcitrant problem of high out-of-pocket payments. Sustainable delivery of health services in Afghanistan can only be achieved with a clear national strategy in which all stakeholders have roles to play in the financing, regulation and delivery of services.

3-deaza- and 7-deaza-5'-noraristeromycin and their antiviral properties.

An enantiospecific synthesis of 3-deaza-5'-noraristeromycin as its dihydrochloride ((-)-6) has been accomplished in six steps beginning with the reaction of (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate with 4-chloro-1H-imidazo[4,5-c]pyridine. The preparation of 7-deaza-5'-noraristeromycin ((-)-7) was described previously. Compounds (-)-6 and (-)-7 were evaluated for antiviral activity against a large number of viruses. Compound (-)-6 produced an antiviral activity pattern similar to 5'-noraristeromycin but was less potent. Compound (-)-6 inhibited CEM cell proliferation at a 50% inhibitory concentration of 27 micrograms/mL but proved not inhibitory to HEL cell proliferation and not toxic to E6SM, HeLa, Vero, and MDCK cells at concentrations up to 200 micrograms/mL. While (-)-6 showed inhibition of S-adenosyl-L-homocysteine (AdoHcy) hydrolase, it was less inhibitory than 5'-noraristeromycin. Compound (-)-7 displayed no antiviral properties or inhibitory effects toward AdoHcy hydrolase.

Tetrahydrobenzothiophenone derivatives as a novel class of adenosine receptor antagonists.

A novel class of non-nitrogen-containing heterocycles, the tetrahydrobenzothiophenones, was found to bind to adenosine receptors as antagonists in the micromolar range. Affinity was determined in radioligand-binding assays at rat brain A1 and A2a receptors. A structure-activity analysis indicated that a 3-thioether group is favored and affinity at A2a, but not at A1, receptors is highly dependent on this thioether substituent. A carboxylic acid-derived substituent is required at the 1-position of the thiophene ring, with esters being more potent in binding at A1 receptors than the corresponding carboxyl hydrazide or carboxylic acid derivatives. The methyl (15) and ethyl (16) esters are about equipotent at A1 but not at A2a receptors. A 4-keto group on the saturated ring is favored for receptor affinity. Dimethyl substitution at the 6-position of the saturated ring is allowed. One of the most potent derivatives was the nonselective compound ethyl 3-(benzylthio)-4-oxo-4,5,6,7-tetrahydrobenzo[c] thiophene-1-carboxylate (BTH4, 7; Figure 1), which antagonized adenosine agonist-induced inhibition of adenylyl cyclase in rat adipocyte membranes with a KB value of 1.62 +/- 0.73 microM and adenosine agonist-induced stimulation of adenylyl cyclase in pheochromocytoma cell membranes with a KB value of 9.19 +/- 0.98 microM. Displacement of radioligand binding by BTH4 (7) at cloned human A3 receptors was negligible but one slightly A3 selective compound (11, 3.9-fold over A1 and >7.5-fold over A2a) was found. A 1-methylpropyl thioether (17) was 29-fold selective for A1 and A2a receptors. BTH4 (7) alone, at 10 mg/kg, stimulated locomotor activity in mice but paradoxically acted, under certain circumstances, synergistically with an A1 selective agonist to depress locomotor activity. A pharmacophore model relating structural features of xanthine and non-xanthine adenosine antagonists to BTH4 (7) suggests a high degree of similarity in electrostatic surfaces, assuming that the thiophene ring superimposes the region of the uracil ring of xanthines.

Antiviral enantiomeric preference for 5'-noraristeromycin.

In order to determine if the potent antiviral properties of (+/-)-5'-noraristeromycin reside in one of its enantiomers, an analysis of each enantiomer has been carried out. A five-step route to the (+)-stereoisomer is described from (+)-(1R,4S)-4-hydroxy-2-cyclopenten-1-yl acetate, whereas the synthesis of the (-)-enantiomer had been reported previously from the same starting material. The (-)-2 and (+)-2 enantiomers were evaluated for antiviral activity against a large number of viruses and found to display an antiviral activity spectrum characteristic of (S)-adenosyl-L-homocysteine hydrolase inhibitors. The (-)-enantiomer retained the significant anticytomegalovirus properties previously reported for the racemic 2 and was, on the average, 10-fold more potent than (+)-2 in inhibiting virus replication, tumor cell growth, and (S)-adenosyl-L-homocysteine hydrolase activity.