High success and low recurrence with shorter treatment regimen for multidrug-resistant TB in Nepal.

SETTING: Nine drug-resistant TB centres, some of them supported by Damien Foundation in Nepal where >80% of multidrug-resistant/rifampicin-resistant TB (MDR/RR-TB) patients are treated. OBJECTIVE: To assess the uptake, effectiveness and safety of the 9-12-month shorter treatment regimen (STR) in MDR/RR-TB patients registered from January 2018 to December 2019. DESIGN: This was a cohort study involving secondary programme data. RESULTS: Of 631 patients, 301 (48.0%) started and continued STR. Key reasons for ineligibility to start/continue STR were baseline resistance or exposure to second-line drugs (62.0%), contact with extensively drug-resistant TB (XDR-TB) or pre-XDR-TB (7.0%) patients and unavailability of STR drugs (6.0%). Treatment success was 79.6%; unsuccessful outcomes were death (12.0%), lost to follow-up (5.3%), failure (2.7%) and not evaluated (0.7%). Unsuccessful outcomes were significantly associated with HIV positivity and patient age ⩾55 years, with adjusted relative risk of respectively 2.39 (95% CI 1.52-3.77) and 3.86 (95% CI 2.30-6.46). Post-treatment recurrence at 6 and 12 months was respectively 0.5% and 2.4%. Serious adverse events (SAEs) were seen in 15.3% patients - hepatotoxicity and ototoxicity were most common. CONCLUSION: STR had a modest uptake, high treatment success and low post-treatment recurrence. For proper detection and management of SAEs, improving pharmacovigilance might be considered. Availability of rapid diagnostic test for second-line drugs is crucial for correct patient management.

CADRE: Neuf centres de traitement de la TB pharmacorésistante, dont certains sont financés par Action Damien au Népal où >80% des patients atteints de TB multirésistante/résistante à la rifampicine (MDR/RR-TB) sont traités. OBJECTIF: Évaluer l'utilisation, l'efficacité et l'innocuité d'un schéma thérapeutique plus court (STR) de 9-12 mois chez les patients atteints de MDR/RR-TB enregistrés de janvier 2018 à décembre 2019. MÉTHODE: Étude de cohorte comprenant des données programmatiques secondaires. RÉSULTATS: Sur 631 patients, 301 (48,0%) ont démarré et poursuivi un STR. Les raisons principales d'inéligibilité à l'instauration/la poursuite d'un STR étaient une résistance initiale ou une exposition aux médicaments de deuxième intention (62,0%), un contact avec des patients atteints de TB ultrarésistante (XDR-TB) ou de pré-XDR-TB (7,0%) et la non-disponibilité des médicaments pour le STR (6,0%). Le taux de réussite thérapeutique était de 79,6%. Les résultats liés à la non-réussite thérapeutique étaient décès (12,0%), perte de vue (5,3%), échec thérapeutique (2,7%) et absence d'évaluation (0,7%). Les résultats liés à la non-réussite thérapeutique étaient significativement associés à l'infection par le VIH et aux patients âgés ⩾55 ans avec un risque relatif ajusté de 2,39 (IC 95% 1,52­3,77) et de 3,86 (IC 95% 2,30­6,46), respectivement. Le taux de récidive post-traitement à 6 et 12 mois était de 0,5% et 2,4%, respectivement. Des évènements indésirables graves (SAE) ont été observés chez 15,3% des patients, le plus souvent hépatotoxicité et ototoxicité. CONCLUSION: Le STR a été associé à une utilisation modérée, à une réussite thérapeutique élevée et à un faible taux de récidive post-traitement. Pour une détection et une prise en charge adéquates des SAE, l'amélioration de la pharmacovigilance peut être envisagée. La disponibilité de tests diagnostiques rapides pour les médicaments de deuxième intention est essentielle à une prise en charge adéquate des patients.

Bifurcation of the inferior dental nerve canal: an anatomical study.

The aims of this study were to find the incidence of bifurcation of the inferior dental nerve (IDN) canal, to describe the characteristics of this variant, and to examine the sensitivity and specificity of dental panoramic tomography to identify it. We classified bifurcations by size and position relative to the main canal and the lower third molar using cone-beam computed tomography (CT) and dental panoramic tomography. In our study of 281 patients, 106 (38%) had bifurcations, and in one quarter, these were classified as large accessory canals. Bifurcations were most commonly found posterior to the lower third molar (n=64, 57%) or within 2mm of the roots of the third molar (n=40, 38%). The sensitivity and specificity of dental panoramic tomography to identify all bifurcations was 11% (95% CI: 5.67 to 17.97) and 91% (95% CI: 85.58 to 94.68), respectively; this was 33% (95% CI: 15.63 to 55.32) and 94% (95% CI: 90.34 to 96.50), respectively, for large bifurcations. Our use of cone-beam CT suggested an incidence of bifid canals of 38%, with a variation in size and distribution in relation to the lower third molar. It also showed that the sensitivity of panoramic radiography to identify them was poor.

Beyond ONJ - A review of the potential uses of bisphosphonates in dentistry.

There is evidence, although limited, for beneficial effects of bisphophonates (BPs) across multiple dental specialties. Within implant dentistry BP coatings have been shown to significantly increase pull out forces and bone density in animal models, and significantly increase implant stability whilst reducing marginal bone loss in humans. Adjunctive topical and systemic application of BPs during conventional periodontal treatment have shown significant improvements in probing depth and clinical attachment level in various forms of periodontal disease. Within orthodontics, BPs have been shown to significantly reduce root resorption and have benefits with respect to anchorage maintenance. Case reports have suggested the use of BPs in the management of diffuse sclerosing osteomylitis. Whilst this review highlights these potential benefits and acknowledges there are no reported cases of osteonecrosis of the jaw associated with locally applied BP, there remains a paucity of human and long-term studies exploring BPs in the context of significant clinical benefit. Further human studies are required to understand the long-term clinical outcomes of these drugs when used as primary therapeutic agents, or adjuncts to conventional treatment.

Identification and characterization of activating ABL1 1b kinase mutations: impact on sensitivity to ATP-competitive and allosteric ABL1 inhibitors.

Although pathologically activated ABL1 fusion kinases represent well-validated therapeutic targets, tumor genomic sequencing has identified numerous point mutations in the ABL1 proto-oncogene of unclear significance. Here we describe ten novel ABL1 1b point mutations, including two from clinical isolates, that cause constitutive kinase activation and cellular transformation. All mutants retained sensitivity to ATP-competitive tyrosine kinase inhibitors (TKIs). Several substitutions cluster near the myristoyl-binding pocket, the target of ABL001, a novel clinically active allosteric kinase inhibitor that mimics the autoinhibitory myristoyl group, and likely activate the kinase by relieving physiologic autoinhibition. In addition, several mutations activate the kinase and confer resistance to allosteric inhibition despite a lack of proximity to this region. We demonstrate that BCR-ABL1 and ABL1 1b point mutations can co-exist in a proportion of clinical cases as a consequence of the chromosome 9 breakpoint location. Collectively, our findings support clinical investigation of ATP-competitive TKIs in malignancies harboring ABL1 point mutations, and sequencing of BCR-ABL1 and ABL1 1b in patients with acquired resistance to allosteric ABL1 inhibitors.

Cross-cover of oral and maxillofacial surgery out-of-hours: an audit of a new adult treatment clinic.

We present our experience of launching the adult treatment clinic - a daytime clinic for semiurgent referrals to oral and maxillofacial surgery (OMFS). This has proved to be an effective way in which cross-covering junior doctors could refer patients for a safe and efficient review in a supervised environment.

Modulation of Intestinal Epithelial Defense Responses by Probiotic Bacteria.

Probiotics are live microorganisms, which when administered in food confer numerous health benefits. In previous studies about beneficial effects of probiotic bacteria to health, particularly in the fields of intestinal mucosa defense responses, specific probiotics, in a strain-dependent manner, show certain degree of potential to reinforce the integrity of intestinal epithelium and/or regulate some immune components. The mechanism of probiotic action is an area of interest. Among all possible routes of modulation by probiotics of intestinal epithelial cell-mediated defense responses, modulations of intestinal barrier function, innate, and adaptive mucosal immune responses, as well as signaling pathways are considered to play important role in the intestinal defense responses against pathogenic bacteria. This review summarizes the beneficial effects of probiotic bacteria to intestinal health together with the mechanisms affected by probiotic bacteria: barrier function, innate, and adaptive defense responses such as secretion of mucins, defensins, trefoil factors, immunoglobulin A (IgA), Toll-like receptors (TLRs), cytokines, gut associated lymphoid tissues, and signaling pathways.

Isolation, Identification and Partial Characterization of a Lactobacillus casei Strain with Bile Salt Hydrolase Activity from Pulque.

The aim of this study was to isolate, from pulque, Lactobacillus spp. capable of survival in simulated gastrointestinal stress conditions. Nine Gram-positive rods were isolated; however, only one strain (J57) shared identity with Lactobacillus and was registered as Lactobacillus casei J57 (GenBank accession: JN182264). The other strains were identified as Bacillus spp. The most significant observation during the test of tolerance to simulated gastrointestinal conditions (acidity, gastric juice and bile salts) was that L. casei J57 showed a rapid decrease (p ≤ 0.05) in the viable population at 0 h. Bile salts were the stress condition that most affected its survival, from which deoxycholic acid and the mix of bile salts (oxgall) were the most toxic. L. casei J57 showed bile salt hydrolase activity over primary and secondary bile salts as follows: 44.91, 671.72, 45.27 and 61.57 U/mg to glycocholate, taurocholate, glycodeoxycholate and taurodeoxycholate. In contrast, the control strain (L. casei Shirota) only showed activity over tauroconjugates. These results suggest that L. casei J57 shows potential for probiotic applications.

FLT3 D835 mutations confer differential resistance to type II FLT3 inhibitors.

Activating mutations in FLT3 occur in ~30% of adult acute myeloid leukemia, primarily consisting of internal tandem duplication (ITD) mutations (~25%) and point mutations in the tyrosine kinase domain (~5%), commonly at the activation loop residue D835. Secondary kinase domain mutations in FLT3-ITD, particularly at the D835 residue are frequently associated with acquired clinical resistance to effective FLT3 tyrosine kinase inhibitors (TKIs). Molecular docking studies have suggested that D835 mutations primarily confer resistance by stabilizing an active Asp-Phe-Gly in ('DFG-in') kinase conformation unfavorable to the binding of type II FLT3 TKIs, which target a 'DFG-out' inactive conformation. We profiled the activity of active type II FLT3 TKIs against D835 kinase domain mutants that have been clinically detected to date. We found that type II inhibitors (quizartinib, sorafenib, ponatinib and PLX3397) retain activity against specific D835 substitutions. Modeling studies suggest that bulky hydrophobic substitutions (D835Y/V/I/F) at this residue are particularly resistant, whereas mutations that preserve interactions between D835 and S838 are relatively sensitive (D835E/N). All mutants retain sensitivity to the type I inhibitor crenolanib. These results suggest that patients with relatively sensitive D835 mutations should be included in clinical trials of type II FLT3 TKIs.

Infection and medication-related osteonecrosis of the jaw.

Medication-related osteonecrosis of the jaw (MRONJ), although initially believed to be exclusively associated with bisphosphonates, has been implicated in recent reports with additional drugs, especially the bone antiresorptive denosumab. The pathophysiology has not been fully elucidated, and no causal association between bone antiresorptive regimens and MRONJ has yet been established. However, reduced bone turnover and infection, an almost universal finding, are thought to be central to the pathogenesis of MRONJ. Both bisphosphonates and denosumab, through different pathways of action, significantly reduce the rate of bone turnover and potentially reduce the efficacy of the host defense against infection. Recent evidence questions the simplified etiology of low bone turnover causing MRONJ and offers evidence on the prominent role of infection instead. The management of MRONJ remains a significant clinical challenge, with little progress having been made on treatment. The aim of this article is to explore the current theories on the etiology of MRONJ and to emphasize the importance of infection in the development of this devastating pathology.

Brief advice on alcohol: as easy as A...B...I?

Alcohol is widely consumed by the majority of the UK population and alcohol-related harm is estimated to cost society £21 billion per year in healthcare, lost productivity costs, crime and antisocial behaviour. The dental setting offers an ideal opportunity to screen for harmful alcohol consumption; however, current emphasis is on the management of acute complications and risk associated in treating patients with excessive alcohol intake rather than screening and patient education. This article outlines ways in which dentists could improve their recognition of 'at risk' patients and then offer practical advice to help reduce the harmful effects of alcohol.

Phase II study of treatment of advanced ovarian cancer with folate-receptor-targeted therapeutic (vintafolide) and companion SPECT-based imaging agent (99mTc-etarfolatide).

BACKGROUND: This report examines (99m)Tc-etarfolatide imaging to identify the presence of folate receptor (FR) on tumors of women with recurrent/refractory ovarian or endometrial cancer and correlates expression with response to FR-targeted therapy (vintafolide). PATIENTS AND METHODS: In this phase II, single-arm, multicenter study, patients with advanced ovarian cancer were imaged with (99m)Tc-etarfolatide before vintafolide treatment. Up to 10 target lesions (TLs) were selected based on Response Evaluation Criteria In Solid Tumors criteria using computed tomography scans. Single-photon emission computed tomography images of TLs were assessed for (99m)Tc-etarfolatide uptake as either FR positive or negative. Patients were categorized by percentage of TLs positive and grouped as FR(100%), FR(10%-90%), and FR(0%). Lesion and patient response were correlated with etarfolatide uptake. RESULTS: Forty-nine patients were enrolled; 43 were available for analysis. One hundred thirty-nine lesions were (99m)Tc-etarfolatide evaluable: 110 FR positive and 29 FR negative. Lesion disease control rate (DCR = stable or response) was observed in 56.4% of FR-positive lesions versus 20.7% of FR-negative lesions (P < 0.001). Patient DCR was 57%, 36%, and 33% in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. Median overall survival was 14.6, 9.6, and 3.0 months in FR(100%), FR(10%-90%), and FR(0%) patients, respectively. CONCLUSIONS: Overall response to FR-targeted therapy and DCR correlate with FR positivity demonstrated by (99m)Tc-etarfolatide imaging. CLINICAL TRIAL NUMBER: NCT00507741.

A phase 2 trial of ponatinib in Philadelphia chromosome-positive leukemias.

BACKGROUND: Ponatinib is a potent oral tyrosine kinase inhibitor of unmutated and mutated BCR-ABL, including BCR-ABL with the tyrosine kinase inhibitor-refractory threonine-to-isoleucine mutation at position 315 (T315I). We conducted a phase 2 trial of ponatinib in patients with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL). METHODS: We enrolled 449 heavily pretreated patients who had CML or Ph-positive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or who had the BCR-ABL T315I mutation. Ponatinib was administered at an initial dose of 45 mg once daily. The median follow-up was 15 months. RESULTS: Among 267 patients with chronic-phase CML, 56% had a major cytogenetic response (51% of patients with resistance to or unacceptable side effects from dasatinib or nilotinib and 70% of patients with the T315I mutation), 46% had a complete cytogenetic response (40% and 66% in the two subgroups, respectively), and 34% had a major molecular response (27% and 56% in the two subgroups, respectively). Responses were observed regardless of the baseline BCR-ABL kinase domain mutation status and were durable; the estimated rate of a sustained major cytogenetic response of at least 12 months was 91%. No single BCR-ABL mutation conferring resistance to ponatinib was detected. Among 83 patients with accelerated-phase CML, 55% had a major hematologic response and 39% had a major cytogenetic response. Among 62 patients with blast-phase CML, 31% had a major hematologic response and 23% had a major cytogenetic response. Among 32 patients with Ph-positive ALL, 41% had a major hematologic response and 47% had a major cytogenetic response. Common adverse events were thrombocytopenia (in 37% of patients), rash (in 34%), dry skin (in 32%), and abdominal pain (in 22%). Serious arterial thrombotic events were observed in 9% of patients; these events were considered to be treatment-related in 3%. A total of 12% of patients discontinued treatment because of an adverse event. CONCLUSIONS: Ponatinib had significant antileukemic activity across categories of disease stage and mutation status. (Funded by Ariad Pharmaceuticals and others; PACE ClinicalTrials.gov number, NCT01207440 .).

The effect of NaCl substitution with KCl on proteinase activities of cell-free extract and cell-free supernatant at different pH levels and salt concentrations: Lactobacillus acidophilus and Lactobacillus casei.

The aim of this study was to investigate the effect of substitution of NaCl with KCl at different pH levels and salt concentrations on proteinase activity of cell-free extract and cell-free supernatant of the probiotics Lactobacillus acidophilus and Lactobacillus casei. de Man, Rogosa, and Sharpe broth aliquots were mixed with 2 pure salts (NaCl and KCl) and 2 salt concentrations at 2 concentration levels (5 and 10%), inoculated with Lactobacillus acidophilus or Lactobacillus casei, and incubated aerobically at 37°C for 22 h. The cultures were then centrifuged at 4,000×g for 30 min, and the collected cell pellets were used to prepare cell-wall proteinases and the supernatants used as a source of supernatant (extracellular) proteinases. The proteolytic activity and protein content of both portions were determined. After incubation of both portions with 3 milk caseins (α-, ß-, κ-casein), the supernatants were individually subjected to analysis of angiotensin-converting enzyme (ACE)-inhibitory activity and proteolytic activity using the o-phthalaldehyde method. Significant differences were observed in ACE-inhibitory and proteolytic activities between salt substitution treatments of cell-free extract and cell-free supernatant from both probiotic strains at the same salt concentration and pH level.

The effect of NaCl substitution with KCl on Akawi cheese: chemical composition, proteolysis, angiotensin-converting enzyme-inhibitory activity, probiotic survival, texture profile, and sensory properties.

The effect of partial substitution of NaCl with KCl on Akawi cheese with probiotic bacteria was investigated during 30 d of storage at 4 °C. Chemical composition, the survival of probiotic and lactic acid bacteria, proteolytic activity, and texture profile analysis were analyzed and sensory analysis was carried out to determine the effects of substitution. No significant differences were observed in moisture, protein, fat, and ash contents among the experimental Akawi cheeses at the same storage period. Significant differences were observed in water-soluble nitrogen and phosphotungstic-soluble nitrogen between experimental cheeses at the same of storage period. No significant difference was observed in the growth of Lactobacillus delbrueckii ssp. bulgaricus between experimental cheeses at the same storage period. However, the growth of Streptococcus thermophilus, Lactobacillus casei, and Lactobacillus acidophilus was significantly affected among experimental cheeses. A significant difference was observed in soluble Ca among experimental cheeses at the same storage period. In general, no significant differences existed in hardness and adhesiveness among experimental cheeses at the same storage period. No significant differences existed in sensory attributes, including creaminess, bitterness, saltiness, sour-acid, and vinegar taste among experimental Akawi cheeses at the same storage period.

The impact of NaCl substitution with KCl on proteinase activities cell-free extract and cell-free supernatant at different pH levels and salt concentrations: Lactobacillus delbrueckii ssp. bulgaricus and Streptococcus thermophilus.

UNLABELLED: The effect of NaCl substitution with KCl at different pH levels (6.0, 5.5, and 5.0) and salt concentrations on proteinase activities of cell-free and supernatant of Lactobacillus delbrueckii ssp. bulgaricus 11824 (L. bulgaricus) and Streptococcus thermophilus MS (ST) was investigated. MRS broths were separately mixed with 4 salt treatments (NaCl only, 1NaCl:1KCl, 1NaCl:3KCl, and KCl only) at 2 different concentrations (5% and 10%) and incubated at 37 °C for 22 h. The cell pellets were used to prepare proteinase of cell-free extract and the cell-free supernatants were used as source of extracellular proteinases. The proteolytic activities and protein contents of both fractions were determined. The supernatants after incubation of both fractions with 3 milk caseins (α-, ß-, κ-casein) were subjected to angiotensin-converting-enzyme inhibitory (ACE-inhibitory) activity and proteolytic activity by ortho-phthalaldehyde (OPA) method. Significant differences were observed in ACE-inhibitory activities and proteolytic (OPA) between salt treatments of cell-free extract and cell-free supernatant of L. bulgaricus and S. thermophilus at same salt concentration and same pH level. There was a significant effect of pH level and salt treatments interaction on ACE-inhibitory activity, OPA activity and azocasein activity. PRACTICAL APPLICATION: To reduce sodium concentration in cheese by substituting of NaCl with KCl, it was important to study the effect on starter culture proteinases which play a vital role in ripening and texture profile of cheese.

The effect of substitution of NaCl with KCl on chemical composition and functional properties of low-moisture Mozzarella cheese.

The effect of NaCl substitution with KCl on chemical composition, organic acids profile, soluble calcium, and functionality of low-moisture Mozzarella cheese (LMMC) was investigated. Functionality (meltability and browning), organic acids profile, and chemical composition were determined. Chemical composition showed no significant difference between experimental cheeses at same storage period, and same salt treatment. Meltability of LMMC salted with 3NaCl:1KCl, 1NaCl:1KCl, and 1NaCl:3KCl was higher compared with only NaCl (control). The amount of soluble Ca and P increased significantly during storage, with no significant difference between salt treatments. Organic acids profile did not differ between salt treatments at the same storage time.

Proteolysis of low-moisture Mozzarella cheese as affected by substitution of NaCl with KCl.

The proteolytic and ACE inhibitory activities of low-moisture Mozzarella cheese (LMMC) as affected by partial substitution of NaCl with KCl were investigated. Experimental LMMC were made and salted with 4 salt mixtures: NaCl only (control), 3NaCl:1KCl, 1NaCl:1KCl, and 1NaCl:3KCl, and then proteolytic activity and angiotensin-converting enzyme inhibitory activity were determined. Salt treatment significantly affected angiotensin-converting enzyme inhibitory activity and phosphotungstic acid-soluble N of LMMC during storage. Water-soluble N, trichloroacetic acid-soluble N, lactic acid bacteria population, and total free amino acids were unaffected during storage. Nonetheless, water-soluble N and trichloroacetic acid-soluble N increased significantly during storage within a salt treatment. Peptide profiles and urea-PAGE gels did not differ between experimental cheeses at the same storage time.