Immune checkpoint inhibitors for POLE or POLD1 proofreading-deficient metastatic colorectal cancer.

BACKGROUND: POLE and POLD1 proofreading deficiency (POLE/D1pd) define a rare subtype of ultramutated metastatic colorectal cancer (mCRC; over 100 mut/Mb). Disease-specific data about the activity and efficacy of immune checkpoint inhibitors (ICIs) in POLE/D1pd mCRC are lacking and it is unknown whether outcomes may be different from mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H) mCRCs treated with ICIs. PATIENTS AND METHODS: In this global study, we collected 27 patients with mCRC harboring POLE/D1 mutations leading to proofreading deficiency and treated with anti-programmed cell death-ligand 1 alone +/- anti-cytotoxic T-lymphocyte antigen-4 agents. We collected clinicopathological and genomic characteristics, response, and survival outcomes after ICIs of POLE/D1pd mCRC and compared them with a cohort of 610 dMMR/MSI-H mCRC patients treated with ICIs. Further genomic analyses were carried out in an independent cohort of 7241 CRCs to define POLE and POLD1pd molecular profiles and mutational signatures. RESULTS: POLE/D1pd was associated with younger age, male sex, fewer RAS/BRAF driver mutations, and predominance of right-sided colon cancers. Patients with POLE/D1pd mCRC showed a significantly higher overall response rate (ORR) compared to dMMR/MSI-H mCRC (89% versus 54%; P = 0.01). After a median follow-up of 24.9 months (interquartile range: 11.3-43.0 months), patients with POLE/D1pd showed a significantly superior progression-free survival (PFS) compared to dMMR/MSI-H mCRC [hazard ratio (HR) = 0.24, 95% confidence interval (CI) 0.08-0.74, P = 0.01] and superior overall survival (OS) (HR = 0.38, 95% CI 0.12-1.18, P = 0.09). In multivariable analyses including the type of DNA repair defect, POLE/D1pd was associated with significantly improved PFS (HR = 0.17, 95% CI 0.04-0.69, P = 0.013) and OS (HR = 0.24, 95% CI 0.06-0.98, P = 0.047). Molecular profiling showed that POLE/D1pd tumors have higher tumor mutational burden (TMB). Responses were observed in both subtypes and were associated with the intensity of POLE/D1pd signature. CONCLUSIONS: Patients with POLE/D1pd mCRC showed more favorable outcomes compared to dMMR/MSI-H mCRC to treatment with ICIs in terms of tumor response and survival.

Scaphoid nonunion: a novel modification of Matti-Russe technique with enhanced recovery and full clinical and radiographic union.

BACKGROUND: A scaphoid fracture is a common injury affecting the wrist joint. A fracture of the carpus scaphoid can heal uneventfully or be complicated by non-union. Scaphoid non-union can result in persistent wrist pain, and with functional difficulties affecting all activities of daily living of the patients, this disability is expected to be significant since most of these patients are young active adults. HYPOTHESIS: Extensive removal of the bone from the scaphoid, with the application of a large amount of cancellous bone graft and fixation with two to three wires, could lead to a high union rate and a good functional outcome. METHODS: Eighteen patients with scaphoid fracture non-union were recruited during their visit to the upper limb clinic at our institute. Demographic data were collected, and data regarding comorbidities, smoking, manual work, and others were recorded. Data regarding the interval between injury and surgery, time to radiographic union, and functional wrist scores were reported as well. RESULTS: A cohort of 18 patients was included. The mean age of patients was 30 years; most of our patients were healthy (83.3%), and more than two-thirds were smokers (72.2%). The mean follow-up time was 18 months (1.5 years), 15 patients (83.3%) achieved radiographic unions by 2-3 months, and the remaining 3 patients (16.7%) achieved radiographic unions by (4-5) months, i.e., all patients achieved successful radiographic unions by 5 months at maximum. The mean Mayo score for our series was 83.6 (± 12.4), with 5 patients (27%) achieved ≥ 95% which indicates a significantly high functioning wrist in our cohort. CONCLUSION: Our modified technique with enhanced stability from using three k-wires can achieve full clinical and radiographic unions and result in enhanced recovery postoperatively with cast immobilization limited to 6 weeks total. LEVEL OF EVIDENCE: IV Case series study.

Synthesis, 123I-Radiolabeling Optimization, and Initial Preclinical Evaluation of Novel Urea-Based PSMA Inhibitors with a Tributylstannyl Prosthetic Group in Their Structures.

Prostate-specific membrane antigen (PSMA) has been identified as a target for the development of theranostic agents. In our current work, we describe the design and synthesis of novel N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-(S)-L-lysine (DCL) urea-based PSMA inhibitors with a chlorine-substituted aromatic fragment at the lysine ε-nitrogen atom, a dipeptide including two phenylalanine residues in the L-configuration as the peptide fragment of the linker, and 3- or 4-(tributylstannyl)benzoic acid as a prosthetic group in their structures for radiolabeling. The standard compounds [127I]PSMA-m-IB and [127I]PSMA-p-IB for comparative and characterization studies were first synthesized using two alternative synthetic approaches. An important advantage of the alternative synthetic approach, in which the prosthetic group (NHS-activated esters of compounds) is first conjugated with the polypeptide sequence followed by replacement of the Sn(Bu)3 group with radioiodine, is that the radionuclide is introduced in the final step of synthesis, thereby minimizing operating time with iodine-123 during the radiolabeling process. The obtained DCL urea-based PSMA inhibitors were radiolabeled with iodine-123. The radiolabeling optimization results showed that the radiochemical yield of [123I]PSMA-p-IB was higher than that of [123I]PSMA-m-IB, which were 74.9 ± 1.0% and 49.4 ± 1.2%, respectively. The radiochemical purity of [123I]PSMA-p-IB after purification was greater than 99.50%. The initial preclinical evaluation of [123I]PSMA-p-IB demonstrated a considerable affinity and specific binding to PC-3 PIP (PSMA-expressing cells) in vitro. The in vivo biodistribution of this new radioligand [123I]PSMA-p-IB showed less accumulation than [177Lu]Lu-PSMA-617 in several normal organs (liver, kidney, and bone). These results warrant further preclinical development, including toxicology evaluation and experiments in tumor-bearing mice.

The geographic variation and spatiotemporal distribution of hepatitis C virus infection in Libya: 2007-2016.

BACKGROUND: Hepatitis C Virus infection has been considered an important hidden pandemic in developing countries, particularly in Africa. It varies greatly from one region to another and even within districts of the same region. Macroscopic geospatial analysis has become an important scientific tool for identifying the density and clustering of HCV infection and provides epidemiological information for planning interventions and control strategies. The application of these parameters provides a better knowledge of the hepatitis C virus infection prevalence at the national level and can help to implement pertinent strategies to address the HCV-related burdens. This study aims to determine the geographical variability of HCV infection in Libya and to identify the hot spots within regions and districts of the country, and to analyze the population-based demographic determinants involved and outline the intervention programs needed. METHODS: Disease mapping and spatial analysis were conducted using geographic information data available on all documented cases of HCV infections in Libya between 2007 and 2016. Spatial autocorrelation was tested using Moran's Index, which determines and measures the degree of clustering and dispersion of HCV infection in a country. RESULTS: A total 114,928 HCV infection cases during a ten-year period with accurate geographic information were studied. Ages ranged between 16 and 50 years and the male to female ratio was 2:1. HCV infection was unevenly distributed in Libya, and its incidence increased steadily over the study period. Several hot spots and cold spots were found mainly in the southern and eastern regions of the country. CONCLUSION: HCV infection in Libya was geographically variable, with several hot spots particularly in eastern and southern Libya associated with different demographic determinants. Future intervention planning should consider the geospatial variability and risk factors involved.

Ultrasound screening for interstitial lung disease in rheumatoid arthritis.

OBJECTIVES: As interstitial lung disease (ILD) in rheumatoid arthritis (RA) patients is associated with increased mortality due to loss of diffusion capacity and pulmonary hypertension, regular screening for structural abnormalities of the lung is advised. In addition to standard radiological examination with computed x-ray tomography, ultrasound of the lung could allow non-invasive and radiation-free structural monitoring of the lung. The objective of this study was to test the frequency of abnormalities in lung sonography in patients with RA who did not have clinical signs or symptoms of lung disease. METHODS: In a prospective study of 64 consecutive patients with rheumatoid arthritis and 40 healthy volunteers, we screened the pleura and the pulmonary parenchyma for sonographic abnormalities. All RA patients underwent high resolution computer tomography of the lung. RESULTS: 28% of RA patients showed pleural nodules or B-line phenomena. In these patients, CT scans showed signs of incipient interstitial lung disease. Lung sonography showed sporadic abnormalities in 7% of the healthy controls. CONCLUSIONS: Transthoracic ultrasound of the lung is an inexpensive and safe tool to screen patients with RA for incipient pulmonary structural changes.

[Congenital esophageal duplication cysts: progressive dysphagia in adulthood]. / Kongenitale zystische Duplikatur des Ösophagus: Progrediente Dysphagie im Erwachsenenalter.

Esophageal duplications are congenital abnormalities of the foregut. We present the case of a 33-year-old woman suffering from progressive dysphagia who had surgery for esophageal duplication. The following three criteria define the cystic lesion: an intimate attachment to the esophageal wall, the presence of a smooth muscle coat and a mucosal lining consisting of squamous and/or ciliated respiratory epithelium. Diverticula, bronchogenic cysts and cystic neoplasms have to be considered in the differential diagnosis. Congenital cystic esophageal duplication is a rare cause of dysphagia in adulthood.

Activation of nuclear receptor CAR ameliorates diabetes and fatty liver disease.

Constitutive androstane receptor CAR (NR1I3) has been identified as a central mediator of coordinate responses to xenobiotic and endobiotic stress. Here we use leptin-deficient mice (ob/ob) and ob/ob, CAR(-/-) double mutant mice to identify a metabolic role of CAR in type 2 diabetes. Activation of CAR significantly reduces serum glucose levels and improves glucose tolerance and insulin sensitivity. Gene expression analyses and hyperinsulinemic euglycemic clamp results suggest that CAR activation ameliorates hyperglycemia by suppressing glucose production and stimulating glucose uptake and usage in the liver. In addition, CAR activation dramatically improves fatty liver by both inhibition of hepatic lipogenesis and induction of beta-oxidation. We conclude that CAR activation improves type 2 diabetes, and that these actions of CAR suggest therapeutic approaches to the disease.

Tracheomalacia after thyroidectomy for retrosternal goitres requiring sternotomy- a myth or reality?

INTRODUCTION: Tracheomalacia after thyroidectomy is not well understood. Reports on tracheomalacia are conflicting, with some suggesting a high rate and other large cohorts in which no tracheomalacia is reported. The aim of our study was to assess the incidence and factors associated with tracheomalacia after thyroidectomy in patients with retrosternal goitres requiring sternotomy at a high-volume tertiary care referral centre. METHODS: A longitudinal cohort study was conducted from January 2011 to December 2019. All adult patients who underwent thyroidectomy with sternotomy were included. Tracheomalacia was considered when tracheal rings were soft compared with other parts (proximal or distal) of the trachea and required either tracheostomy or resection with anastomosis. The decision to perform a tracheostomy or to administer continuous or bilevel positive airway pressure postoperatively was made depending on the degree of tracheomalacia. Logistic regression analysis was used to assess factors associated with tracheomalacia. RESULTS: We evaluated 40 patients who underwent thyroidectomy with sternotomy. The mean age of our cohort was 48.7 ± 11.3 years and the population was predominantly female (67.5%). One patient required tracheal resection with anastomosis, and two patients required tracheostomy. Multivariable logistic regression analysis did not reveal any patient- or thyroid-related factor significantly associated with the development of tracheomalacia in our cohort. CONCLUSIONS: The incidence of tracheomalacia after thyroidectomy with sternotomy appears to be very low. However, the occurrence of tracheomalacia after thyroidectomy in cases of large goitre is possible and hence worrisome.

Prevalence and characteristics of autistic children attending autism centres in 2 major cities in Saudi Arabia: A cross-sectional study.

OBJECTIVES: To assess the prevalence and characteristics of Autism Spectrum Disorder (ASD)-affected children attending autistic centers in 2 major cities in Saudi Arabia. METHODS: A cross-sectional study, including ASD centers and schools (37 centers) in Makkah and Jeddah, Saudi Arabia was conducted between January and March 2020. Data were collected from records and parents of children with ASD using a questionnaire on sociodemographic, family history, consanguinity, severity, and maternal risk factors. RESULTS: All centers in Makkah and Jeddah participated, with a total of 1,023 ASD children. The prevalence of ASD was 2.618 per 1,000 children for Jeddah, 3.68 per 1,000 children for Makkah and 2.81 per 1,000 children for both Jeddah and Makkah. There was no statistically significant relationship between the severity of ASD and sociodemographic, family and maternal risk factors. However, there was statistically significant relationship between severe ASD and ASD family history (p=0.029, OR: 3.46 and 95% CI 1.14 to 10.5). CONCLUSIONS: The prevalence of ASD in Makkah and Jeddah was lower than the global prevalence of ASD. Individuals with a family history of ASD were more likely to have more severe ASD.

Safety of the LCP Pediatric Hip Plate in Proximal Femoral Osteotomy in Children with Cerebral Palsy.

PURPOSE: Proximal femoral osteotomy in cerebral palsy patients is a demanding procedure. The fixation of the osteotomy can fail due to the weak osteoporotic bone. The LCP pediatric hip plate with its good grip makes these procedures safe. The aims of the present study are to evaluate the radiological outcome of proximal femoral osteotomy that was fixed with the pediatric LCP in cerebral palsy patients and to raise safety issues regarding its low rate of complications. PATIENTS AND METHODS: Sixteen patients with cerebral palsy who were operated in our department were included in this retrospective study. Data collected from medical charts and X-ray measurements retrospectively reviewed. RESULTS: In total, 16 patients (21 hips), ie, 9 males and 7 females, were included in this analysis. The mean age at the time of the index surgery was 11.9 years (5.9-18.0). The mean follow-up period was 4.78 years (1.5-8.0). Five patients had bilateral hip involvement and 11 had unilateral involvement. All patients had spastic cerebral palsy. The mean values of varus correction and de-rotation were 25° (0°-45°) and 35° (20°-50°), respectively. Neck shaft angle and the Reimer's migration index were significantly improved postoperatively (p<0.01 for both). Seventeen hips showed complete consolidation within 14 weeks of fixation and four hips needed 16 weeks. These four hips were in three patients who were 16 years of age or older. The correlation between age at surgery and the time needed for consolidation was statistically significant (p=0.005). Avascular necrosis, revision surgeries, failure of fixation, acetabular penetration, screw loosening or fracture of the femur were not seen in this study. CONCLUSION: The LCP pediatric hip plate can be used safely in CP patients. The plate provides a strong stable fixation on osteoporotic bone with a low rate of complications.

Identification and Quantitation of Malonic Acid Biomarkers of In-Born Error Metabolism by Targeted Metabolomics.

Malonic acid (MA), methylmalonic acid (MMA), and ethylmalonic acid (EMA) metabolites are implicated in various non-cancer disorders that are associated with inborn-error metabolism. In this study, we have slightly modified the published 3-nitrophenylhydrazine (3NPH) derivatization method and applied it to derivatize MA, MMA, and EMA to their hydrazone derivatives, which were amenable for liquid chromatography- mass spectrometry (LC-MS) quantitation. 3NPH was used to derivatize MA, MMA, and EMA, and multiple reaction monitoring (MRM) transitions of the corresponding derivatives were determined by product-ion experiments. Data normalization and absolute quantitation were achieved by using 3NPH derivatized isotopic labeled compounds 13C2-MA, MMA-D3, and EMA-D3. The detection limits were found to be at nanomolar concentrations and a good linearity was achieved from nanomolar to millimolar concentrations. As a proof of concept study, we have investigated the levels of malonic acids in mouse plasma with malonyl-CoA decarboxylase deficiency (MCD-D), and we have successfully applied 3NPH method to identify and quantitate all three malonic acids in wild type (WT) and MCD-D plasma with high accuracy. The results of this method were compared with that of underivatized malonic acid standards experiments that were performed using hydrophilic interaction liquid chromatography (HILIC)-MRM. Compared with HILIC method, 3NPH derivatization strategy was found to be very efficient to identify these molecules as it greatly improved the sensitivity, quantitation accuracy, as well as peak shape and resolution. Furthermore, there was no matrix effect in LC-MS analysis and the derivatized metabolites were found to be very stable for longer time. Graphical Abstract ᅟ.

Chromophobe renal cell carcinoma occurring in the renal allograft of a transplant recipient presenting with weight loss.

The incidence of renal cell carcinomas (RCCs) in renal transplant recipients is reported as 1.1-1.5% in the native kidneys and 0.22-0.25% in the renal allograft. There are no data to support routine surveillance for tumors in transplant recipients. Most reported cases of RCCs occurring in renal allografts were incidental findings in asymptomatic patients. Herein, we report the second case of lone chromophobe RCC (ChRCC) of the renal allograft presenting with weight loss. Loss of weight is a presenting symptom in one-third of ChRCCs occurring in the native kidneys in the general population. Based on the age of the patient, R.E.N.A.L nephrometry score of the tumor and the lack of data on the prognosis of this histological subtype in a climate of long-term immunosuppression, we elected for radical nephrectomy. We suggest that RCCs should be considered in the differential diagnosis of a transplant recipient presenting with weight loss even in the absence of localizing symptoms or signs.

Cytokeratin expression patterns as an indicator of tumour progression in oesophageal squamous cell carcinoma.

Recent studies point out that cytokeratins (CKs) are involved in dynamic cell remodeling during cancer progression and particularly, CK expression patterns have been associated with invasion and metastasis. In oesophageal squamous cell cancer (ESCC), lymph node (LNN) metastasis is an important step in disease progression, invariably associated with an ominous prognosis. To assess whether specific CK expression patterns could represent reliable markers of tumor progression, a series of 111 ESCCs (59 lymph node-positive, 52-negative) derived from the high- incidence area of Linxian (Northern China), were subjected to immunohistochemical (IHC) analysis with an extensive panel of CK antibodies. Statistically significant differences were observed for CK18 (p=0.01), CK19 (p=0.04) and PKK1 (p=0.02) expression between the LNN-negative and LNN-positive ESCCs. Furthermore, significant correlation between specific CK distribution pattern and progressive disease (i.e., LNN metastasis) was evidenced. The results suggest that CK8, CK18 and CK19 expression and distribution pattern could be of predictive value as a marker of disease progression as defined by the appearance of lymph node metastases in oesophageal squamous cell cancer.

Morphological changes in the articular cartilage after meniscectomy. An experimental study in the monkey.

The medial meniscus was resected from the right knees of twelve young grivet monkeys that were killed at intervals of twenty-one to 252 days after operation. The knees operated upon and the control knees were investigated radiologically and histologically. Degenerative changes occurred in the medial femoral and tibial condyles. At first there was loss of cells from the superficial layer of the articular cartilage, with a marked decrease in the acid mucopolysaccharide content of the matrix. The chondrocytes in the deeper layer of the non-calcified zone proliferated to form clones before finally degenerating. The acellular cartilage showed splitting, and with progress of the degenerative process there was thinning and erosion of the cartilage. Eventually there was complete loss of articular cartilage with thickening and exposure of the subchondral bone. These degenerative changes were confined to a small area of the articular cartilage and had occurred despite regeneration of the meniscus. The rest of the cartilage looked normal. It is concluded that articular cartilage deprived of the protection of a meniscus may undergo arthritic changes.

Knowledge and Practice of Diabetic Foot Care in an In- Patient Setting at a Tertiary Medical Center.

Good knowledge and practice regarding diabetic foot care will reduce the risk of diabetic foot complications and ultimately amputation. This study is conducted to assess patients' knowledge and compliance of diabetic foot care. A cross sectional study performed on patients who were admitted to HSNZ from the 1st September 2013 to 30th April 2014 for diabetic foot infections. They were interviewed with a questionnaire of 15 'yes' or 'no' questions on foot care knowledge and practice. Score of 1 was given for each 'yes' answer. The level of knowledge and practice, whether good or poor, was determined based on the median score of each category. The result was tested using a chi-square test in SPSS version 17. A total of 157 patients were included in this study with a mean age of 56.33 years (31-77). There were 72 male (45.9%) and 85 female (54.1%) patients with the majority of them being Malays (154 patients, 98.1%). Majority of the patients (58%) had poor foot care knowledge while 97 patients (61.8%) had poor diabetic foot care practice as compared to the median score. Based on the chi square test of relatedness, there was no significant association between knowledge and practice with any of the variables. In conclusion, the majority of patients admitted for diabetic foot infections had poor knowledge and practice of diabetic foot care. Education regarding foot care strategies should be emphasized and empowered within the diabetic population.

Pulmonary echography in systemic sclerosis.

In systemic sclerosis patients, interstitial lung disease and pulmonary hypertension are highly associated with mortality. The time point of detecting manifestations like pulmonary hypertension and interstitial lung disease (ILD) is of vital importance. High-resolution computed tomography (HRCT) to date is the gold standard to diagnose ILD. In addition, an ultrasound of the lung is suggested as a noninvasive and radiation-free method of structural monitoring of the lung. We tested the reliability of lung sonography for the assessment of patients with systemic sclerosis. In a pilot study involving 25 patients with systemic sclerosis and 40 healthy volunteers, we screened the pleura and the pulmonary parenchyma for sonographic abnormalities. The occurrence of B lines, comet tail phenomena, and pleural irregularities was scored. All systemic sclerosis (SSc) patients were subjected to computed x-ray tomography of the chest. Forty-four percent of SSc patients showed B line phenomena and pleural thickening. The diagnosis of ILD in these patients was confirmed by HRCT scan. B line phenomena and pleural irregularities were significantly more common in SSc patients. Patients with ILD had higher pleural scores and comet scores when compared to systemic sclerosis patients without radiographic ILD. If our results are confirmed in larger studies, transthoracic ultrasound of the lung might turn out to be a suitable method for screening patients with systemic sclerosis for incipient pulmonary structural changes.

Proliferative activity of cells from remaining dental pulp in response to treatment with dental materials.

BACKGROUND: The biological examination of pulp injury, repair events and response of dental pulp stem cells to dental restorative materials is important to accomplish restorative treatment, especially to commonly used dental materials in paediatric dentistry, such as glass ionomer cement (GIC) and calcium hydroxide (Ca(OH)(2)) lining cement. METHODS: Healthy patients aged between 9 to 11 years with carious primary molars without pulp exposure were selected and divided into two groups: Group 1 (teeth restored with GIC) and Group 2 (teeth lined using Ca(OH)(2) and restored with GIC). The proliferative activity of stem cells of teeth between these two groups was compared using colourimetric cell proliferation reagent, alamarBlue. Immunocytochemistry and flow cytometry confirmation were performed using mesenchymal stem cell markers, CD105 and CD166. RESULTS: The proliferative activity using alamarBlue assay showed that cells derived from the remaining dental pulp of exfoliated deciduous teeth were positive for CD105 and CD166 and exhibited no difference between the two groups. CONCLUSIONS: It can be concluded that the use of Ca(OH)(2) or GIC as a lining material in indirect pulp capping procedures has the same effect on cells derived from the remaining dental pulp of exfoliated deciduous teeth which have responded favourably to the restorative treatments.