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BackgroundTask-sharing of spinal anaesthesia care by non-specialist graduate physicians, termed medical officers (MOs), is commonly practised in rural Indian healthcare facilities to mitigate workforce constraints. We sought to assess whether spinal anaesthesia failure rates of MOs were non-inferior to those of consultant anaesthesiologists (CA) following a standardised educational curriculum.MethodsWe performed a randomised, non-inferiority trial in three rural hospitals in Tamil Nadu and Chhattisgarh, India. Patients aged over 18 years with low perioperative risk (ASA I & II) were randomised to receive MO or CA care. Prior to the trial, MOs underwent task-based anaesthesia training, inclusive of remotely accessed lectures, simulation-based training and directly observed anaesthetic procedures and intraoperative care. The primary outcome measure was spinal anaesthesia failure with a non-inferiority margin of 5%. Secondary outcome measures consisted of incidence of perioperative and postoperative complications.FindingsBetween 12 July 2019 and 8 June 2020, a total of 422 patients undergoing surgical procedures amenable to spinal anaesthesia care were randomised to receive either MO (231, 54.7%) or CA care (191, 45.2%). Spinal anaesthesia failure rate for MOs (7, 3.0%) was non-inferior to those of CA (5, 2.6%); difference in success rate of 0.4% (95% CI=0.36–0.43%; p=0.80). Additionally, there were no statistically significant differences observed between the two groups for intraoperative or postoperative complications, or patients’ experience of pain during the procedure.InterpretationThis study demonstrates that failure rates of spinal anaesthesia care provided by trained MOs are non-inferior to care provided by CAs in low-risk surgical patients. This may support policy measures that use task-sharing as a means of expanding anaesthesia care capacity in rural Indian hospitals.Trial registration numberNCT04438811.

Innovation ecosystems and emerging technologies can potentially accelerate the access to safe, affordable surgical care in low-resource settings. There is a need to develop localised innovation ecosystems that can establish an initial culture and catalyse the creation, adoption and diffusion of innovation. The surgathon model outlines one approach to seeding surgical innovation ecosystems. International academic institutions collaborated on six global surgery, innovation and ethics-themed hackathons (‘surgathons’) across India and Rwanda between 2016 and 2019. Over 1598 local multidisciplinary students participated, learning about challenges in the delivery of surgical care and ideating solutions that could leverage appropriate technology and resources for impact. Pursuing student ideas and evaluating their implementation past the surgathons continues to be an active effort. Surgathons have unfolded in different permutations based on local faculty, institution and health system context. The surgathon model is a novel method of priority setting challenges in global surgery and utilises locally driven expertise and innovation capacity to derive ethical solutions. The model offers a path for low-resource setting students and faculty to learn, advocate and innovate for improved surgical care.

Background Resection of colorectal liver metastases (CLM) can cure disease, but many patients with extensive disease cannot be fully resected and others recur following surgery. Hepatic arterial infusion (HAI) chemotherapy can convert extensive liver disease to a resectable state or decrease recurrence risk, but response varies and no biomarkers currently exist to identify patients most likely to benefit. Methods We performed a retrospective cohort study of CLM patients receiving HAI chemotherapy whose tumors underwent MSK‐IMPACT sequencing. The frequency of oncogenic alterations and their association with overall survival (OS) and objective response rate were analyzed at the individual gene and signaling pathway levels. Results Three hundred and seventy patients met inclusion criteria: 189 (51.1%) who underwent colorectal liver metastasectomy followed by HAI + systemic therapy (Adjuvant cohort), and 181 (48.9%) with unresectable CLM (Metastatic cohort) who received HAI + systemic therapy, consisting of 63 (34.8%) with extrahepatic disease and 118 (65.2%) with liver‐restricted disease. Genomic alterations were similar in each cohort, and no individual gene or pathway was significantly associated with objective response. Patients in the adjuvant cohort with concurrent Ras/B‐Raf alteration and SMAD4 inactivation had worse prognosis while in the metastatic cohort patients with co‐alteration of Ras/B‐Raf and TP53 had worse OS. Similar findings were observed in a validation cohort. Conclusions Concurrently altered Ras/B‐Raf and SMAD4 mutations were associated with worse survival in resectable patients, while concurrent Ras/B‐Raf and TP53 alterations were associated with worse survival in unresectable patients. The mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 may have prognostic value for CLM patients receiving HAI. Patients with colorectal liver metastases receiving hepatic arterial infusion chemotherapy who have either resectable disease with concurrently altered Ras/B‐Raf and SMAD4 mutations, or unresectable disease with concurrent Ras/B‐Raf and TP53 alterations had worse survival. Mutual exclusivity of Ras/B‐Raf, SMAD4, and TP53 status may be useful for prognostic stratification in these patients.

Rectal cancer (RC) is a challenging disease to treat that requires chemotherapy, radiation and surgery to optimize outcomes for individual patients. No accurate model of RC exists to answer fundamental research questions relevant to patients. We established a biorepository of 65 patient-derived RC organoid cultures (tumoroids) from patients with primary, metastatic or recurrent disease. RC tumoroids retained molecular features of the tumors from which they were derived, and their ex vivo responses to clinically relevant chemotherapy and radiation treatment correlated with the clinical responses noted in individual patients’ tumors. Upon engraftment into murine rectal mucosa, human RC tumoroids gave rise to invasive RC followed by metastasis to lung and liver. Importantly, engrafted tumors displayed the heterogenous sensitivity to chemotherapy observed clinically. Thus, the biology and drug sensitivity of RC clinical isolates can be efficiently interrogated using an organoid-based, ex vivo platform coupled with in vivo endoluminal propagation in animals. Rectal cancer organoids retain the pathological features of matched patient tumors and recapitulate clinical responses to chemoradiation.

ABSTRACT Introduction: the objective of this study was to evaluate the periodontal effects of fixed retainers in the long term. Methods: a search in electronic databases (PubMed, Cochrane Library, Science Direct, Embase, ProQuest, Ebsco, Biomed Central, Medline, Lilacs, and Google Scholar) and a manual search with no language restrictions. The inclusion criteria were: randomized clinical trials and meta-analysis, prospective and retrospective studies, studies in humans, clinical and radiographical studies evaluating the periodontium, performed during the 1987-2014 period, up to 10 years of follow-up. Four authors extracted data from the selected studies independently. Results: after applying the inclusion criteria, we selected 4 studies in which a total of 405 patients were evaluated. All the studies were longitudinal and retrospective. There was a greater prevalence of gingival recessions, especially in mandibular incisors, which are more vulnerable. There were no significant changes in terms of alveolar bone index or calculus index. The survival rate of fixed retainers was 50% or higher. Due to the heterogeneity of the selected studies, including difference in study population, differences in methods to assess the intervention, and follow-up periods, it was impossible to quantify the variables to perform a meta-analysis. Conclusions: the selected studies had a middle level of evidence. The greatest gingival recessions occurred with the use of fixed retainers in a long time; however, there is no alteration of the alveolar bone level. The studies recommend encouraging patients to maintain good oral hygiene. The findings of this review should be cautiously taken due to the resulting level of evidence, and the general recommendation for clinicians is that, in the long run, these retainers appear to be safe to maintain the alignment of mandibular incisors, although more studies with greater scientific rigor are required. There were no conflicts of interest and this study did not have any kind of financial support.

Truth in Many Tongues examines how the Spanish monarchy managed an empire of unprecedented linguistic diversity. Considering policies and strategies exerted within the Iberian Peninsula and the New World during the sixteenth century, this book challenges the assumption that the pervasiveness of the Spanish language resulted from deliberate linguistic colonization. Daniel I. Wasserman-Soler investigates the subtle and surprising ways that Spanish monarchs and churchmen thought about language. Drawing from inquisition reports and letters; royal and ecclesiastical correspondence; records of church assemblies, councils, and synods; and printed books in a variety of genres and languages, he shows that Church and Crown officials had no single, unified policy either for Castilian or for other languages. They restricted Arabic in some contexts but not in others. They advocated using Amerindian languages, though not in all cases. And they thought about language in ways that modern categories cannot explain: they were neither liberal nor conservative, neither tolerant nor intolerant. In fact, Wasserman-Soler argues, they did not think predominantly in terms of accommodation or assimilation, categories that are common in contemporary scholarship on religious missions. Rather, their actions reveal a highly practical mentality, as they considered each context carefully before deciding what would bring more souls into the Catholic Church. Based upon original sources from more than thirty libraries and archives in Spain, Italy, the United States, England, and Mexico, Truth in Many Tongues will fascinate students and scholars who specialize in early modern Spain, colonial Latin America, Christian-Muslim relations, and early modern Catholicism.

ABSTRACT Introduction: stability is one of the main goals of orthodontic treatment, and circumferential supracrestal fiberotomy is an alternative to prevent relapse in cases of tooth rotation, crowding and inclined teeth. However, there are no studies demonstrating the effectiveness of this treatment and its effects on the periodontal condition. The aim of this systematic review (SR) was to evaluate the effectiveness of circumferential supracrestal fiberotomy (CSF) as an adjuvant in the stability of orthodontic treatment during retention and its effects on the periodontal condition once it has been performed. Methods: the search for topic-related studies was conducted on the PubMed and EMBASE databases until October 2018. The studies were considered eligible if they covered the use of CSF during the retention period and reported the periodontal condition in a follow-up period longer than or equal to 1 year. For bias-risk assessment in the chosen studies, the Newcastle-Ottawa Scale was applied to observational studies, and the Cochrane Collaboration tool for Randomized Clinical Trials (RCTs) and Controlled Clinical Trials (CCTs). Results: the search strategy yielded 85 potential eligible articles, of which 5 were included in the SR. Four of the five studies reported a lower irregularity rate in patients who had CSF when compared to a control group. No changes in plaque index, gingival index, insertion levels, probe depth and keratinized gingiva amount were reported. Conclusions: fiberotomy is an effective method to prevent relapse of previously rotated teeth and does not cause periodontal alterations. However, it is important to note that the studies’ methodological quality was low.

IntroductionTo improve the standard treatment paradigm for glioblastoma (GBM), efforts have been made to explore the efficacy of epigenetic agents as chemosensitizers. Recent data suggest possible synergy between decitabine (DAC), a DNA hypomethylating agent, and temozolomide (TMZ) in GBM, but the mechanism remains unclear. The objective of this study was to determine the effects of DAC on TMZ sensitization in a consecutively derived set of primary GBM cultures, with a focus on mismatch repair (MMR) proteins.MethodsHalf maximal inhibitory concentrations (IC50) of TMZ were calculated in eleven consecutive patient-derived GBM cell lines before and after preconditioning with DAC. MMR protein expression changes were determined by quantitative immunoblots and qPCR arrays. Single-molecule real-time (SMRT) sequencing of bisulfite (BS)-converted PCR amplicons of the MLH1 promoter was performed to determine methylation status.ResultsTMZ IC50 significantly changed in 6 of 11 GBM lines of varying MGMT promoter methylation status in response to DAC preconditioning. Knockdown of MLH1 after preconditioning reversed TMZ sensitization. SMRT-BS sequencing of the MLH1 promoter region revealed higher levels of baseline methylation at proximal CpGs in desensitized lines compared to sensitized lines.ConclusionsDAC enhances TMZ cytotoxicity in a subset of GBM cell lines, comprising lines both MGMT methylated and unmethylated tumors. This effect may be driven by levels of MLH1 via E2F1 transcription factor binding. Using unbiased long-range next-generation bisulfite-sequencing, we identified a region of the proximal MLH1 promoter with differential methylation patterns that has potential utility as a clinical biomarker for TMZ sensitization.

ABSTRACT Introduction: orthodontic tooth movement with open apices which have not completed root formation has not been sufficiently studied. There is controversy about the risks associated to this movement, such as root resorption and decreased root length. The goal of this systematic review is to determine the possible effects of lengthening, shortening, or root resorption possibly occurring during orthodontic movement in teeth that have not completed root formation. Methods: electronic search (PubMed, Cochrane, Dentistry and Oral Sciences Source, Science Direct, Google Scholar, IdeA, ProQuest, Embase, Medline, Lilacs, TRIP) and manual search at Universidad El Bosque Juan Roa Vázquez Library since 1990 to 2014. Articles meeting the inclusion criteria, such as randomized clinical trials, prospective and retrospective studies, and studies in early mixed dentition with 2 x 4 system, were evaluated and methodologically qualified by four researchers. Results: this study involved a custom methodological rating taken from Lagravere et al (2005). Four articles were finally selected, three of which were retrospective: Amlani et al (2007), with 26 patients, found root resorption in 8% of the sample, with no statistical significance. Mavragani et al (2002), with a sample of 146 patients, found longer roots in younger teeth, and Kim & Park (2004), with 59 patients, found higher resorption in maxillary lateral incisors. Da Silva et al (2005), with 46 patients, reported a prevalence of 4.4% in root resorption in central incisors. Conclusions: this systematic review must be taken cautiously due to the low and moderate level of evidence found. In general terms, there were no alterations in terms of root length or shape when teeth with open apices were subjected to fixed orthodontic forces. The risk of apical resorption was more related to treatment duration in teeth with both open and closed apexes.