Single-agent anti-PD-1 or combined with ipilimumab in patients with mucosal melanoma: an international, retrospective, cohort study.

BACKGROUND: Mucosal melanoma (MM) is a rare melanoma subtype with distinct biology and poor prognosis. Data on the efficacy of immune checkpoint inhibitors (ICIs) are limited. We determined the efficacy of ICIs in MM, analyzed by primary site and ethnicity/race. PATIENTS AND METHODS: A retrospective cohort study from 25 cancer centers in Australia, Europe, USA and Asia was carried out. Patients with histologically confirmed MM were treated with anti-programmed cell death protein 1 (PD-1) ± ipilimumab. Primary endpoints were response rate (RR), progression-free survival (PFS), overall survival (OS) by primary site (naso-oral, urogenital, anorectal, other), ethnicity/race (Caucasian, Asian, Other) and treatment. Univariate and multivariate Cox proportional hazards model analyses were conducted. RESULTS: In total, 545 patients were included: 331 (63%) Caucasian, 176 (33%) Asian and 20 (4%) Other. Primary sites included 113 (21%) anorectal, 178 (32%) urogenital, 206 (38%) naso-oral and 45 (8%) other. Three hundred and forty-eight (64%) patients received anti-PD-1 and 197 (36%) anti-PD-1/ipilimumab. RR, PFS and OS did not differ by primary site, ethnicity/race or treatment. RR for naso-oral was numerically higher for anti-PD-1/ipilimumab [40%, 95% confidence interval (CI) 29% to 54%] compared with anti-PD-1 (29%, 95% CI 21% to 37%). Thirty-five percent of patients who initially responded progressed. The median duration of response (mDoR) was 26 months (95% CI 18 months-not reached). Factors associated with short PFS were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≥3 (P < 0.01), lactate dehydrogenase (LDH) more than the upper limit of normal (ULN) (P = 0.01), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). Factors associated with short OS were ECOG PS ≥1 (P < 0.01), LDH >ULN (P = 0.03), lung metastases (P < 0.01) and ≥1 previous treatments (P < 0.01). CONCLUSIONS: MM has poor prognosis. Treatment efficacy of anti-PD-1 ± ipilimumab was similar and did not differ by ethnicity/race. Naso-oral primaries had numerically higher response to anti-PD-1/ipilimumab, without difference in survival. The addition of ipilimumab did not show greater benefit over anti-PD-1 for other primary sites. In responders, mDoR was short and acquired resistance was common. Other factors, including site and number of metastases, were associated with survival.

Management of early melanoma recurrence despite adjuvant anti-PD-1 antibody therapy☆.

BACKGROUND: Anti-programmed cell death protein 1 (PD-1) antibodies (PD1) prolong recurrence-free survival in high-risk resected melanoma; however, approximately 25%-30% of patients recur within 1 year. This study describes the pattern of recurrence, management and outcomes of patients who recur with adjuvant PD1 therapy. PATIENTS AND METHODS: Consecutive patients from 16 centres who recurred having received adjuvant PD1 therapy for resected stage III/IV melanoma were studied. Recurrence characteristics, management and outcomes were examined; patients with mucosal melanoma were analysed separately. RESULTS: Melanoma recurrence occurred in 147 (17%) of ∼850 patients treated with adjuvant PD1. In those with cutaneous melanoma (n = 136), median time to recurrence was 4.6 months (range 0.3-35.7); 104 (76%) recurred during (ON) adjuvant PD1 after a median 3.2 months and 32 (24%) following (OFF) treatment cessation after a median 12.5 months, including in 21 (15%) who ceased early for toxicity. Fifty-nine (43%) recurred with locoregional disease only and 77 (57%) with distant disease. Of those who recurred locally, 22/59 (37%) subsequently recurred distantly. Eighty-nine (65%) patients received systemic therapy after recurrence. Of those who recurred ON adjuvant PD1, none (0/6) responded to PD1 alone; 8/33 assessable patients (24%) responded to ipilimumab (alone or in combination with PD1) and 18/23 (78%) responded to BRAF/MEK inhibitors. Of those who recurred OFF adjuvant PD1, two out of five (40%) responded to PD1 monotherapy, two out of five (40%) responded to ipilimumab-based therapy and 9/10 (90%) responded to BRAF/MEK inhibitors. CONCLUSIONS: Most patients who recur early despite adjuvant PD1 develop distant metastases. In those who recur ON adjuvant PD1, there is minimal activity of further PD1 monotherapy, but ipilimumab (alone or in combination with PD1) and BRAF/MEK inhibitors have clinical utility. Retreatment with PD1 may have activity in select patients who recur OFF PD1.

Correction of faulty sensors in phased array radars using symmetrical sensor failure technique and cultural algorithm with differential evolution.

Three issues regarding sensor failure at any position in the antenna array are discussed. We assume that sensor position is known. The issues include raise in sidelobe levels, displacement of nulls from their original positions, and diminishing of null depth. The required null depth is achieved by making the weight of symmetrical complement sensor passive. A hybrid method based on memetic computing algorithm is proposed. The hybrid method combines the cultural algorithm with differential evolution (CADE) which is used for the reduction of sidelobe levels and placement of nulls at their original positions. Fitness function is used to minimize the error between the desired and estimated beam patterns along with null constraints. Simulation results for various scenarios have been given to exhibit the validity and performance of the proposed algorithm.

Analyzing invariants and employing successive reductions for the extended Kadomtsev Petviashvili equation in (3+1) dimensions.

In this research, we employ the potent technique of Lie group analysis to derive analytical solutions for the (3+1)-extended Kadomtsev-Petviashvili (3D-EKP) equation. The systematic application of this method enables the identification of Lie point symmetries associated with the equation, leading to the derivation of an optimal system of one-dimensional subalgebras relevant to the equation. This optimal system is utilized to obtain several invariant solutions. The Lie group method is subsequently applied to the reduced governing equations derived from the given equation. We complement our findings with Mathematica simulations illustrating some of the obtained solutions. Furthermore, a direct approach is used to investigate local conservation laws. Importantly, our study addresses a gap in the exploration of the 3D-EXP equation using group theoretic methods, making our findings novel in this context.

Assessing the accuracy and certainty in interpreting chest X-rays in the medical division.

The chest X-ray (CXR) is an important diagnostic tool in diagnosing and monitoring a spectrum of diseases. Despite our universal reliance on the CXR, our ability to confidently diagnose and accurately document our findings can be unreliable. We sought to assess the diagnostic accuracy and certainty of making a diagnosis based on 10 short clinical histories with one CXR each. We conclude from our study that specialist registrars (StRs) and consultants scored the highest marks with the highest average certainty levels. Junior trainees felt least certain about making their diagnosis and were less likely to be correct. We recommend that StRs and consultants review all the CXRs requested to ensure accuracy of diagnosis. There also needs to be discussion with the Joint Royal Colleges of Physicians Training Board (JRCPTB) about the need of including a separate CXR competency as part of a trainee's generic curriculum on the e-portfolio, something which is currently lacking.

Optimal system and dynamics of optical soliton solutions for the Schamel KdV equation.

In this research, we investigate the integrability properties of the Schamel-Korteweg-de Vries (S-KdV) equation, which is important for understanding the effect of electron trapping in the nonlinear interaction of ion-acoustic waves. Using the optimal system, we come over reduced ordinary differential equations (ODEs). To deal with reduced ODEs for this problem, Lie symmetry analysis is combined with the modified auxiliary equation (MAE) procedure and the generalized Jacobi elliptic function expansion (JEF) method. The analytical solutions reported here are novel and have a wide range of applications in mathematical physics.

Nosocomial Infection Among Burn Patients Admitted to a Tertiary Care Hospital of Bangladesh: A Cross-Sectional Study.

Nosocomial infection is a major challenge for the appropriate management of burns. The present study aimed to investigate incidence, risk factors, and causative organisms of nosocomial infection in burn patients of Khulna, Bangladesh. This cross-sectional study was conducted among patients admitted to the Burn and Plastic Surgery Department of Khulna Medical College Hospital (KMCH) from January to December 2020. Relevant data were collected from the patients' hospital records. Samples of wound swabs and blood were collected and cultured in the microbiology laboratory of KMCH. Logistic regression models were used to determine risk factors for infective complications in burn patients. All statistical analyses were carried out using SPSS version 26.0. A total of 100 burn patients were included. Mean age was 29.2 years with a male-female ratio of 1.3:1. Flame burns were most prevalent among the patients (41%), followed by scald (23%) and electric burns (15%). Almost 40% patients had full thickness burn. The incidence of nosocomial infection was 42% (wound infection 33% and septicemia 9%). Total body surface area of burn >40% (OR 7.56, 95% CI 2.89-19.81), full thickness burn (OR 34.40, 95% CI 3.25-97.14) and prolonged hospital stay (aOR 1.31, 95% CI 1.15-1.51) were significant risk factors for nosocomial infection. Staphylococcus aureus was the most commonly isolated organism (45%), followed by Streptococcus (24%), Pseudomonas aeruginosa (19%) and Escherichia coli (12%). As the epidemiology of nosocomial infection is not the same in different health facilities, a facility-based comprehensive burn management protocol considering the local epidemiology and causative organisms of burn wound infection is crucial for the prevention and management of nosocomial infections in burn patients.

Les infections nosocomiales sont une préoccupation majeure du traitement bien conduit des brûlés. Cette étude a eu pour but d'évaluer l'incidence, les facteurs de risque de survenue et les bactéries isolées d'infections nosocomiales survenues dans le CTB de Kulna (Bangladesh). Elle a étudié les dossiers l'ensemble des 100 patients admis dans le CTB du CHU de Kulna en 2020. Les analyses bactériologiques ont été réalisées dans le laboratoire du CHU. Une régression logistique a été utilisée pour déterminer les facteurs de risque d'infection. Toutes les analyses statistiques ont été réalisées avec SSPS 26.0. L'âge moyen était de 29,2 ans, le sex-ratio de 1,3H/1F. Les flammes représentaient 41% des causes, les liquides 23% et l'électricité 15%. Quasiment 40% des patients avaient des brûlures profondes. L'incidence des accidents infectieux était de 42% (cutanée 33%, bactériémies 9%). Les facteurs de risque indépendants de survenue d'une infection étaient une atteinte sur >40 % SCT (OR 7,56; IC95 2,89-19,81), une brûlure profonde (OR 34,40 ; IC95 3,25-97,14) et un séjour prolongé (OR 1,31; IC95 1,15-1,51). Les quatre bactéries les plus fréquentes étaient S. aureus (45%), Streptococcus spp (24%), P. æruginosa (19%), et E. coli (12%). Les épidémiologies bactériennes variant selon les services d'où elles sont issues, c'est sur l'épidémiologie locale que doivent se centre les mesures de contrôle des infections nosocomiales.

Exogenous Ca/Mg quotient reduces the inhibitory effects of PEG induced osmotic stress on Avena sativa L.

Drought is one of the most damaging abiotic stress that hinder plant growth and development. The present study aimed to determine the effects of various Ca/Mg quotients under polyethylene glycol (PEG)-induced osmotic stress on growth, uptake and translocation of Ca and Mg in Avena sativa (L). Plants were grown in nutrient solution supplemented with three different Ca/Mg molar quotients (0.18, 2, and 4). After 30 days plants were exposed to two different PEG (Polyethylene glycol) concentrations (0.6 MPa & 0.2 MPa) for 8 days, and solutions were renewed after 4 days. A solution containing Ca and Mg nutrients has mitigated the negative impact caused via osmotic stress on relative growth rate (RGR), absolute growth rate (AGR), crop growth rate (CGR), leaf area ratio (LAR), Leaf index ratio (LAI), root-shoot ratio (RSR), water use efficiency (WUE) and net assimilation rate (NAR). In addition, it adversely affected germination parameters, including final emergence percentage (FEP), mean germination time (MGT), Timson germination Index (TGI), germination rate index (GRI) and percent field capacity (%FC), of oat (Avena sativa L.). Mg and Ca in shoot and root and Ca translocation factor decreased with increasing Ca in solution, while Mg translocation factor increased with increasing Ca in nutrient solution. In this work, the combined effects of various Ca/Mg quotients and osmotic stress produced by polyethylene glycol (PEG) in different concentrations (0.6 MPa, 0.2 MPa) on the growth and element uptake of Avena sativa L. are examined. As a result, the Ca/Mg Quotient may naturally combat the moderate drought stress experienced by field crops.

Achieving Millennium Development Goals 4 and 5 in Pakistan.

Pakistan is a signatory of many international development strategies including the Millennium Development Goals, and the government is committed to achieving a reduction in infant mortality rate from 72 to <55 per 1000 live births, the newborn mortality rate from 55 to <40 per 1000 live births and the maternal mortality rate from 276 per 100,000 to 140 per 100,000 live births by 2015. Maternal, newborn and child health play a key role in reducing poverty and promoting social and economic development. Improvement in maternal and child health is a priority agenda of the Government of Pakistan.

A systematic overview of the medicinal importance of sanguivorous leeches.

Leeches are a class of segmented invertebrates, known for their blood-feeding habits and used in phlebotomy to treat various ailments since antiquity. In Europe, medicinal leeches have recently been rediscovered and are used by maxillofacial and other microsurgeons to aid salvage of compromised venous engorged tissue and amputations, such as digits, ears, and nasal tips. Because of their important salivary components, blood-sucking (sanguivorous) leeches, such as Hirudo medicinalis and related species, have engendered great interest from pharmaceutical companies searching for anticoagulants to prevent blood clotting during microsurgeries. Scientific research reveals that the beneficial effects of leeching, in addition to decongestion, include injection of a cocktail of several medicinally useful bioactive molecules present in their saliva. Owing to its therapeutic potential, the research is continuing as many new salivary compounds are being isolated and synthesized.

Use of a segmental thermoexpandable metal alloy stent in the management of malignant ureteric obstruction: a single centre experience in the UK.

INTRODUCTION: The Memokath 051™ is a semipermanent inert metal alloy ureteric stent which can bridge strictures and, compared to double J stents, causes less bladder irritation and pain, is more resistant to external compression forces and may be more effective in patients with malignant ureteric obstruction. We present our experience with this novel stent in such cases. METHODS: All suitable patients referred to us with malignancy-associated ureteric strictures over a 4-year period had ureteric Memokath 051™ stents inserted. Data on aetiology and position of the strictures as well as length of the Memokath stents used and their efficacy and complications were recorded prospectively. RESULTS: 42 ureteric Memokath 051™ stents were inserted in 37 patients (mean age 64 years). 40.5% of strictures were related to gynaecological cancer, 21% to bowel cancer, 14% were post radiation, 14% occurred in prostate cancer patients and 9.5% were found in other cancers. The mean follow-up was 22 months (range 5-60 months). The main complications were stent migrations in 5, urinary tract infections in 3 and blockage of stent due to progressive transitional cell carcinoma of the ureter in 2 cases. CONCLUSION: Memokath 051™ ureteric stents are safe, effective and durable in the long-term treatment of malignant strictures.

Neuro-developmental Outcome of High Risk Neonates in a Tertiary Level Hospital.

An observational longitudinal study was conducted in the Department of Neonatology and Child Developmental Center, Mymensingh Medical College Hospital (MMCH), Bangladesh during the period of September 2016 to February 2018 to find out the neuro-developmental outcome of high risk neonates at the age of 6 months. Five hundred seventy six (576) high risk neonate who were admitted in the neonatology department in Mymensingh Medical College Hospital were selected as study population by Purposive sampling technique. After admission written informed consent from parents or guardians obtained and Data was collected in a pre-designed case record form. At 6th months of age total 400 baby were came to Child Development Centre and their motor, cognition and behavior development were assessed by Bayley Scale of Infant Development and severity of cognitive, motor and behavior impairment were graded. All data were compiled, tabulated and then analyzed by computer software SPSS version 20.00. Mean age was 7.2±3.3 days. Among studied newborns 18.1% were preterm and 81.9% were term. Most of the newborn were male (63.0%). Developmental delay was found in 81.5% and neuro-developmental outcome was found normal in only 18.5% newborns. Significant delayed motor performance was found in 52% newborns where 17% had mild delay. Significantly delayed mental performance was found in 57.0% and 28.52% had mildly delayed mental performance. Non-optimal behavior was found in 57.0% newborns and14% had questionable behavior. Very low birth weight, preterm very low birth weight, home delivery, perinatal asphyxia and neonatal seizure were found to have significant relation with developmental delay. Most of the high risk neonates develop developmental delay.

Lifestyle and Depression in Urban Elderly of Selected District of Bangladesh.

Global population is ageing and Bangladesh has one of the fastest growing ageing populations in this region. Growth in the elderly population relative to other age groups challenges existing health services, family relationships and social security. Combined with this, depression has become a major mental health problem for elderly people especially for urban elderly for nuclear family norm in urban areas. The study was descriptive type of cross-sectional in nature and was conducted in Rangpur Medical College Hospital, Rangpur & Prime Medical College Hospital, Rangpur, Bangladesh. The objective of this study was to assess the lifestyle and level of depression in urban elderly. Depression was measured by questionnaire of geriatric depression scale among 254 respondents. 87.8% of the respondents were age between 60-70 years. Majorities (63%) of the respondents were male, 54% of the respondents lived in nuclear type family and the rest (46%) in joint type of family. Among respondents near half (47.2%) of the respondents found Mild depressive, around one third (32.7%) were severe depressive, and the rest (20.1%) were normal. There was significant association between occupational status of the respondents and depression (x² = 45.600, df=14, p=0.000). Farmers unemployed found severely depressive (52.1%) followed by day-labourer (50%) and businessmen (37.5%). There was significant association between financial self dependency and depression of the respondents (x²= 34.072, df=4, p=0.000). Severe depression (43.8%) was found among those who were not financially self dependent. There was also significant association between monthly income and depression of the respondents (x²= 67.327, df=8, p=0.000). The study also found that lower income group (

Curvularia geniculata fungal peritonitis: a case report with review of literature.

Peritonitis is the "Achilles heel" of patients on peritoneal dialysis. Fungal peritonitis though not that common is associated with increased morbidity and mortality. We report the first case in the literature of a patient who developed peritonitis caused by Curvularia geniculata. We discuss the reported cases of Curvularia lunata peritonitis in literature and emphasize the early removal of catheter and treatment with intravenous amphotericin B.

Reactions within association complexes: the reaction of imidazole with substituted phenyl acetates in the presence of detergents in aqueous solution

The bimolecular rate constants for reaction of imidazole with phenyl acetates complexed with sodium dodecyl sulfate (SDS) or cetyltrimethylammonium bromide (CTAB) micelles obey Bronsted equations with beta 1g similar to that of the reaction in aqueous solution. The dissociation constants of ester (Ks) and the hypothetical dissociation constant (KTS) of the transition state of the micelle complexes obey Hansch equations with similar sensitivities (p) to pi (-0.66 and -0.589 for KS and -0.735 and -0.495 for KTS, respectively). The slopes also indicate that the microsolvation environments associated with the transition state and the complexed ester have aqueous character. The relative values of KTS and KS indicate that the transition state of the reaction of imidazole with ester is more weakly complexed to both micelles than is the reactant ester. Log KTS values are linear functions of log KS for reactions with both CTAB and SDS; the slopes are, respectively, -0.893 and -1.19 consistent with a slightly more "water-like" medium for the transition state than for the site of binding of ester with CTAB-micelle and slightly less for the SDS-micelle. The results for ester and transition state are consistent with the location of the phenyl residue in a hydrophobic region that possesses water molecules. It is concluded that the acetyl group in the complexed transition state is located in an aqueous part of the Stern region, whereas the phenyl residue is in a part of the Stern region that possesses alkane components. The derived kinetic and complexation parameters in these experiments refer to micelles with Stern regions that have been maintained at constant ionic compositions.

The stability of benzoyl peroxide formulations determined from isothermal microcalorimetric studies.

Recent developments in the analysis of microcalorimetric data output allow the possibility of determining both thermodynamic and kinetic parameters for complex reaction systems. Such experiments routinely take around 50 h, hence qualifying for the description rapid. The methods have earlier been applied to a study of the stability of benzoyl peroxide itself in aqueous suspension. This paper reports the results of isothermal microcalorimetric study of the stability of benzoyl peroxide in the presence of a wide range of excipients and in formulated materials. The results are shown to assist in formulation design, are achieved rapidly and are derived from direct experimental study of the complex systems themselves. That is, no ancillary information is required nor are the studies invasive or destructive.

The stability of benzoyl peroxide by isothermal microcalorimetry.

Isothermal microcalorimetry may be used to determine kinetic and thermodynamic parameters for chemical reactions. This paper reports rate constants, determined as a function of temperature, and the activation enthalpy for the degradation of solid benzoyl peroxide as determined by isothermal microcalorimetry. Studies were conducted on aqueous suspension phase, solid benzoyl peroxide. In addition, supporting evidence is cited from work carried out in this laboratory on the solution phase degradation of benzoyl peroxide using UV-visible spectrophotometry. The activation energy obtained by microcalorimetry was E(a)=137.8+/-6.6 kJ mol(-1) and the activation energy obtained from UV-visible spectrophotometry was E(a)=112.7+/-4.2 kJ mol(-1).

FIGO Save the Mothers Initiative: the Pakistan-UK collaboration.

The pilot study in Punjab, Pakistan was one of the five paired demonstration projects sponsored by FIGO in the "Save the Mothers" maternal mortality project. The goal of the project was to bring basic and comprehensive emergency obstetric care (EmOC) to a semiurban and rural area some 30 km from Lahore, where effectively there was none. The aim was to achieve this by using the existing facilities within the rural health system without the deployment of extra specialist staff other than as initial facilitators. This report shows trebling of some performance indicators and an improvement in met need. There is coincidentally a similar increase in the uptake of general medical services. Reducing maternal mortality requires building local capacity for EmOC; the essential components being the premises, trained personnel, equipment, and availability of drugs and blood. Availability and provision of EmOC coupled with changes in the attitude of the population resulted in marked improvement of process indicators.

Association of various point mutations as risk factors for synthetic graft thrombosis in African American hemodialysis patients.

Single-nucleotide polymorphisms in the genes that code for coagulation factor V (factor V (Leiden)) and II (prothrombin G20210A), as well as the methyltetrahydrofolate reductase (MTHFR) have been implicated in the majority of cases of hereditary thrombophilia. In our hemodialysis patient population, comprised mainly of African Americans, we have seen a high incidence of early vascular access thrombosis without any identifiable predisposing factors. In some instances, there is recurrent access thrombosis that may be related to an inherited condition. In this study we evaluated the presence of these gene mutations and their association with increased risk of recurrent vascular access thrombosis in our hemodialysis patient population. Our results show that factor V Leiden and factor II prothrombin point mutations did not appear to increase the risk of vascular access thrombosis in African Americans with end-stage renal disease on hemodialysis. Patients heterozygous for the MTHFR gene, also did not show a significant increased risk for synthetic graft thrombosis.