Extracolonic manifestations of Gardner syndrome: A case report.

Gardner syndrome has head and neck manifestations that may be recognized during dental visits. Features such as multiple gnathic osteomas, impacted supernumerary teeth, and multiple foci of idiopathic osteosclerosis can be easily identified on dental radiographs, prompting the clinician to refer the patient for further investigation. A dental examination and routine radiographs play a vital role in revealing the extracolonic presentation of Gardner syndrome, which facilitates timely screening and detection of colorectal cancer and other malignancies associated with this condition. This report discusses the case of a 50-year-old Caucasian man who presented with a hard swelling of the left angle of the mandible and was diagnosed with Gardner syndrome based on abnormal findings from an oral examination, dental imaging, and medical and family history.

Identifying Factors of Operative Efficiency in Head and Neck Free Flap Reconstruction.

Importance: Head and neck oncological resection and reconstruction is a complex process that requires multidisciplinary collaboration and prolonged operative time. Numerous factors are associated with operative time, including a surgeon's experience, team familiarity, and the use of new technologies. It is paramount to evaluate the contribution of these factors and modalities on operative time to facilitate broad adoption of the most effective modalities and reduce complications associated with prolonged operative time. Objective: To examine the association of head and neck cancer resection and reconstruction interventions with operative time. Design, Setting, and Participants: This large cohort study included all patients who underwent head and neck oncologic resection and free flap-based reconstruction in Calgary (Alberta, Canada) between January 1, 2007, and March 31, 2020. Data were analyzed between November 2021 and May2022. Interventions: The interventions that were implemented in the program were classified into team-based strategies and the introduction of new technology. Team-based strategies included introducing a standardized operative team, treatment centralization in a single institution, and introducing a microsurgery fellowship program. New technologies included use of venous coupler anastomosis and virtual surgical planning. Main Outcomes and Measures: The primary outcome was mean operative time difference before and after the implementation of each modality. Secondary outcomes included returns to the operating room within 30 days, reasons for reoperation, returns to the emergency department or readmissions to hospital within 30 days, and 2-year and 5-year disease-specific survival. Multivariate regression analyses were performed to examine the association of each modality with operative time. Results: A total of 578 patients (179 women [30.9%]; mean [SD] age, 60.8 [12.9] years) undergoing 590 procedures met inclusion criteria. During the study period, operative time progressively decreased and reached a 32% reduction during the final years of the study. A significant reduction was observed in mean operative time following the introduction of each intervention. However, a multivariate analysis revealed that team-based strategies, including the use of a standardized nursing team, treatment centralization, and a fellowship program, were significantly associated with a reduction in operative time. Conclusions: The results of this cohort study suggest that among patients with head and neck cancer, use of team-based strategies was associated with significant decreases in operative time without an increase in complications.

Characteristics of retracted publications related to pain research: a systematic review.

ABSTRACT: Retraction is a mechanism for correcting the scientific record and alerts readers when a study contains unreliable or flawed data. Such data may arise from error or research misconduct. Studies examining the landscape of retracted publications provide insight into the extent of unreliable data and its effect on a medical discipline. We aimed to explore the extent and characteristics of retracted publications in pain research. We searched the EMBASE, PubMed, CINAHL, PsycINFO, and Retraction Watch databases to December 31, 2022. We included retracted articles that (1) investigated mechanisms of painful conditions, (2) tested treatments that aimed to reduce pain, or (3) measured pain as an outcome. Descriptive statistics were used to summarise the included data. We included 389 pain articles published between 1993 and 2022 and retracted between 1996 and 2022. There was a significant upward trend in the number of retracted pain articles over time. Sixty-six percent of articles were retracted for reasons relating to misconduct. The median (interquartile range) time from article publication to retraction was 2 years (0.7-4.3). The time to retraction differed by reason for retraction, with data problems, comprising data falsification, duplication, and plagiarism, resulting in the longest interval (3 [1.2-5.2] years). Further investigations of retracted pain articles, including exploration of their fate postretraction, are necessary to determine the impact of unreliable data on pain research.

Crystal structure of a methyl benzoate quadruple-bonded dimolybdenum complex.

Quadruple-bond dimolybdenum complexes provide invaluable insight into the two-electron bond, with structural chemistry providing a foundation for examination of bond properties. The synthesis and solid-state structure of the quadruple-bonded dimolybdenum(II) complex tetra-kis-(µ-4-methyl-benzoato-κ 2 O:O')bis[(tetra-hydro-furan-κO)molybdenum(II)] tetra-hydro-furan disolvate, [Mo2(C8H7O2)4(C4H8O)2]·2C4H8O, are presented. This complex crystallizes in a triclinic cell with low-symmetry space group P . The dimolybdenum paddlewheel structure comprises four methyl-benzoate ligands and two axial THF ligands. The dimolybdenum bond distance of 2.1012 (4) Šis exemplary of this class of compounds.

Perspectives on Participation in Clinical Trials Among Individuals With Pain, Depression, and/or Anxiety: An ACTTION Scoping Review.

For individuals experiencing pain, the decision to engage in clinical trials may be influenced by a number of factors including current and past care, illness severity, physical functioning, financial stress, and caregiver support. Co-occurring depression and anxiety may add to these challenges. The aim of this scoping review was to describe perspectives about clinical trial participation, including recruitment and retention among individuals with pain and pain comorbidities, including depression and/or anxiety. We searched PubMed, CINAHL, PsycINFO, and Cochrane CENTRAL databases. Study features, sample demographics, perspectives, barriers and/or motivations were collected and described. A total of 35 assessments were included in this scoping review with 24 focused on individuals with pain (24/35, 68.6%), 9 on individuals with depression and/or anxiety (9/35, 25.7%), and 2 on individuals with pain and co-occurring depression/anxiety (2/35, 5.7%). Barriers among participants with pain and those with depression included: research team's communication of information, fear of interventional risks, distrust (only among respondents with pain), too many procedures, fear of inadequate treatment, disease-life stressors, and embarrassment with study procedures (more commonly reported in participants with depression). Facilitators in both groups included: altruism and supportive staff, better access to care, and the ability to have outcome feedback (more commonly among individuals with depression). Individuals with pain and depression experience challenges that affect trial recruitment and retention. Engaging individuals with pain within research planning may assist in addressing these barriers and the needs of individuals affected by pain and/or depression. PERSPECTIVE: This review highlights the need to address barriers and facilitators to participation in clinical trials, including the need for an assessment of perspectives from underserved or marginalized populations.

Development, implementation and evaluation of a seven-day clinical pharmacy service in a tertiary referral teaching hospital during surge-2 of the COVID-19 pandemic.

BACKGROUND: Seven-day clinical pharmacy services in the acute sector of the National Health Service are limited. There is a paucity of evidential patient benefit. This limits investment and infrastructure, despite United Kingdom wide calls. AIM: To optimise medicines seven-days a week during surge-2 of the COVID-19 pandemic through implementation of a seven-day clinical pharmacy service. This paper describes service development, evaluation and sustainability. SETTING: A tertiary-referral teaching hospital, London, United Kingdom. DEVELOPMENT: The seven-day clinical pharmacy service was developed to critical care, acute and general medical patients. Clinical leads developed the service specification and defined priorities, targeting complex patients and transfer of care. Contributing staff were briefed and training materials developed. IMPLEMENTATION: The service was implemented in January 2021 for 11 weeks. Multidisciplinary team communication brought challenges; strategies were employed to overcome these. EVALUATION: A prospective observational study was conducted in intervention wards over two weekends in February 2021. 1584 beds were occupied and 602 patients included. 346 interventions were reported and rated; 85.6% had high or moderate impact; 56.7% were time-critical. The proportion of medicines reconciliation within 24-h of admission was analysed across the hospital between November 2020 and May 2021. During implementation, patients admitted Friday-Sunday were more likely to receive medicines reconciliation within 24-h (RR 1.41 (95% CI 1.34-1.47), p < 0.001). Rostered services were delivered sustainably in terms of shift-fill rate and medicines reconciliation outcome. CONCLUSION: Seven-day clinical pharmacy services benefit patient outcome through early medicines reconciliation and intervention. Investment to permanently embed the service was sustained.

Extracolonic manifestations of Gardner syndrome: A case report

Gardner syndrome has head and neck manifestations that may be recognized during dental visits. Features such as multiple gnathic osteomas, impacted supernumerary teeth, and multiple foci of idiopathic osteosclerosis can be easily identified on dental radiographs, prompting the clinician to refer the patient for further investigation. A dental examination and routine radiographs play a vital role in revealing the extracolonic presentation of Gardner syndrome, which facilitates timely screening and detection of colorectal cancer and other malignancies associated with this condition. This report discusses the case of a 50-year-old Caucasian man who presented with a hard swelling of the left angle of the mandible and was diagnosed with Gardner syndrome based on abnormal findings from an oral examination, dental imaging, and medical and family history. (Imaging Sci Dent 2023; 53: 169-74)

Caregivers' perspectives on health-related quality of life in young children with TB and respiratory illnesses.

BACKGROUND: There is a lack of holistic health-related quality of life (HRQoL) measures for young children with respiratory disease, especially in low- and middle-income countries (LMICs). We aimed to understand caregivers' perceptions of the relevance of common HRQoL domains for children with respiratory diseases, including TB. METHODS: This study was nested in a prospective observational cohort of children presenting with respiratory symptoms presumptive of pulmonary TB. We conducted 10 semi-structured interviews to explore caregivers' perceptions of the five commonly measured HRQoL domains: physical health, social support, emotional and psychological wellbeing, and schooling. We used case descriptive analysis and thematic coding. RESULTS: Caregivers considered all five domains to be relevant. The socio-economic context framed their responses, with QoL requiring sufficient basic resources for children. HRQoL experiences varied according to the severity of the child's symptoms, but not between TB and non-TB illnesses. Manifestations in the psychological domain were difficult to distinguish from the emotional domain. Social support included broad support for family members, indirectly benefiting the children. Caregivers were concerned about their children's early developmental milestones and future schooling. CONCLUSION: This exploratory study shows that HRQoL domains are relevant but require adaptation to be applicable for young children affected by respiratory illnesses living in LMICs.

CONTEXTE: Il existe un manque de mesures holistiques de la qualité de vie liée à la santé (HRQoL) pour les jeunes enfants atteints de maladies respiratoires, en particulier dans les pays à revenu faible ou intermédiaire (LMIC). Nous avons cherché à comprendre la perception qu'ont les soignants de la pertinence des domaines communs de la HRQoL pour les enfants atteints de maladies respiratoires, dont la TB. MÉTHODES: Cette étude était imbriquée dans une cohorte observationnelle prospective d'enfants présentant des symptômes respiratoires présomptifs de TB pulmonaire. Nous avons mené 10 entretiens semi-structurés pour explorer les perceptions des soignants sur les cinq domaines de la HRQoL communément mesurés : santé physique, soutien social, bien-être émotionnel et psychologique, et scolarité. Nous avons utilisé une analyse descriptive des cas et un codage thématique. RÉSULTATS: Les soignants considèrent que les cinq domaines sont pertinents. Le contexte socio-économique encadrait leurs réponses, la QoL nécessitant des ressources de base suffisantes pour les enfants. Les expériences de QoL variaient en fonction de la gravité des symptômes de l'enfant, mais pas entre les maladies TB et non TB. Les manifestations dans le domaine psychologique étaient difficiles à distinguer du domaine émotionnel. Le soutien social comprenait un large soutien aux membres de la famille, ce qui profitait indirectement aux enfants. Les soignants étaient préoccupés par les premiers stades de développement de leurs enfants et par leur future scolarité. CONCLUSION: Cette étude exploratoire montre que les domaines de la QoL sont pertinents mais nécessitent une adaptation pour être applicables aux jeunes enfants atteints de maladies respiratoires vivant dans les LMIC.

A Qualitative Study of Patient and Healthcare Provider Perspectives on Building Multiphasic Exercise Prehabilitation into the Surgical Care Pathway for Head and Neck Cancer.

Head and neck cancer (HNC) surgical patients experience a high symptom burden. Multiphasic exercise prehabilitation has the potential to improve patient outcomes, and to implement it into the care pathway, the perspectives of patients and healthcare providers (HCPs) must be considered. The purpose of this study was thus to gather feedback from HNC surgical patients and HCPs on building exercise into the standard HNC surgical care pathway. Methods: Semi-structured interviews were conducted with patients and HCPs as part of a feasibility study assessing patient-reported outcomes, physical function, and in-hospital mobilization. Interview questions included satisfaction with study recruitment, assessment completion, impact on clinical workflow (HCPs), and perceptions of a future multiphasic exercise prehabilitation program. This study followed an interpretive description methodology. Results: Ten patients and ten HCPs participated in this study. Four themes were identified: (1) acceptability and necessity of assessments, (2) the value of exercise, (3) the components of an ideal exercise program, and (4) factors to support implementation. Conclusion: These findings highlight the value of exercise across the HNC surgical timeline from both the patient and the HCP perspective. Results have informed the implementation of a multiphasic exercise prehabilitation trial in HNC surgical patients.

The feasibility of patient-reported outcomes, physical function, and mobilization in the care pathway for head and neck cancer surgical patients.

BACKGROUND: Head and neck cancer (HNC) patients are an understudied population whose treatment often includes surgery, causing a wide range of side effects. Exercise prehabilitation is a promising tool to optimize patient outcomes and may confer additional benefits as a prehabilitation tool. The primary objective of this study was to assess the feasibility of measuring patient-reported outcomes (PROs), physical function, and in-hospital mobilization across the HNC surgical timeline in advance of a future prehabilitation trial. The secondary objective was to examine potential changes in these outcomes across the surgical timeline. METHODS: HNC patients scheduled to undergo oncologic resection with free-flap reconstruction completed assessments of PROs and physical function at three timepoints across the surgical timeline (baseline, in-hospital, and postsurgical/outpatient). Mobilization was measured during the in-hospital period. The feasibility of recruitment and measurement completion was tracked, as were changes in both PROs and physical function. RESULTS: Of 48 eligible patients, 16 enrolled (recruitment rate of 33%). The baseline and in-hospital PROs were completed by 88% of participants, while the outpatient assessments were completed by 81% of participants. The baseline and in-hospital assessment of physical function were completed by 56% of participants, and 38% completed the outpatient assessment. Measuring in-hospital mobilization was completed for 63% of participants. CONCLUSION: Measuring PROs and in-hospital mobilization is feasible across the surgical timeline in HNC; however, the in-person assessment of physical function prior to surgery was not feasible. A multidisciplinary collaboration between exercise specialists and clinicians supported the development of new clinical workflows in HNC surgical care that will aid in the implementation of a future prehabilitation trial for this patient population.

A comparison of registered and published primary outcomes in clinical trials of opioid use disorder: ACTTION review and recommendations.

BACKGROUND AND AIMS: Prospective trial registration can increase research integrity. This Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) review was designed to compare the primary outcomes (PO) reported in registries with associated publications for opioid use disorder (OUD) clinical trials. DESIGN: The World Health Organization's International Clinical Trials Registry Platform (ICTRP) was searched for completed trials (2010 through 2019). Associated publications were identified and paired with trial registry data based on the publication date. MEASUREMENTS: Reviewers independently rated the occurrence of discrepancies between the POs in the registry compared to the publication. An analysis of prospective versus retrospective registration was also completed. FINDINGS: One-hundred and forty trials were identified in the search, and 43 registry-publication pairs evaluated. Only 34 of the 43 pairs could be examined for discrepancies because nine did not report a PO in registry and publication. Of the 34 pairs, only four met rigorous criteria for prospective trial registration and had an exact match of POs. In contrast, the majority of the 34 trials, or 80%, had inconsistent POs (e.g., registered secondary outcomes published as primary; the timing of PO not specified) and/or were retrospectively registered. CONCLUSIONS: Many clinical trials focused on OUD have not met the standards of trial registration, such as consistent reporting of POs and prospective registration. Failure to properly register trial characteristics undermines the validity of research findings and can delay the development of life-saving treatments. Recommendations for improving prospective trial reporting practices are provided.

The prevalence of comorbid chronic pain conditions among patients with temporomandibular disorders: A systematic review.

BACKGROUND: This systematic review was designed to evaluate the presence of comorbid conditions among patients with temporomandibular disorders (TMDs). TYPES OF STUDIES REVIEWED: The authors reviewed studies that reported the prevalence or incidence of chronic pain conditions or psychiatric disorders (anxiety, mood, personality disorders) among patients with any type of TMD. The authors calculated sample size-weighted prevalence estimates when data were reported in 2 or more studies for the same comorbid condition. RESULTS: A total of 9 prevalence studies and no incidence studies were eligible for review; 8 of the studies examined chronic pain comorbidities. Weighted estimates showed high prevalence of pain comorbidities across studies, including current chronic back pain (66%), myofascial syndrome (50%), chronic stomach pain (50%), chronic migraine headache (40%), irritable bowel syndrome (19%), and fibromyalgia (14%). A single study examined psychiatric disorders and found that current depression was the most prevalent disorder identified (17.5%). CONCLUSIONS AND PRACTICAL IMPLICATIONS: There is a high prevalence of comorbid chronic pain conditions among patients with TMDs, with more than 50% of patients reporting chronic back pain, myofascial syndrome, and chronic stomach pain. Psychiatric disorders among patients with different types of TMDs were studied less commonly in this pain population. Knowledge of the distribution of these and other comorbid disease conditions among patients with different types of TMDs can help dentists and other health care providers to identify personalized treatment strategies, including the coordination of care across medical specialties.

Patient-Reported Outcomes after Fibula Free Flap Harvest: A Pilot Study.

SUMMARY: Patient-reported outcomes regarding donor-site morbidity and quality of life for the fibula free flap in head and neck reconstruction patients have not been studied. The authors reviewed and identified patients who had undergone head and neck reconstruction using a fibula free flap (2011 to 2016). Patients were assessed via physical examination and two patient-reported outcomes questionnaires: the Foot and Ankle Outcome Score (score range, 0 to 100) and the Pain Disability Questionnaire (score range, 0 to 100). Quantitative data were analyzed with appropriate statistical tests. Semistructured interviews exploring donor-site challenges were performed and analyzed using thematic analysis. Seventeen patients agreed to participate. Their mean age was 62 years (range, 41 to 81 years). Mean follow-up was 38 months (range, 12 to 65 years). Mean perceived level of function compared to baseline was 67 percent. Mean scores for the Foot and Ankle Outcome Score subscales were 84.6 (pain), 80.5 (symptoms), 86.7 (activities of daily living), 67.7 (sport), and 65.6 (quality of life). The mean Pain Disability Questionnaire score was 26.3 (mild/moderate perceived disability). Higher perceived level of function was associated with higher Foot and Ankle Outcome Score values (pain, symptoms, and activities of daily living, p < 0.05). Donor limbs had decreased range of motion and manual muscle testing scores compared with their contralateral limbs (p < 0.05). Lack of ankle support and balance, resulting in limitations and aversions to daily and sporting activities, were the most common themes regarding donor-site challenges. In conclusion, patients who have undergone fibula free flap harvest struggle with ankle support and balance and face functional difficulties that have an impact on their quality of life. Multidisciplinary approaches for targeted rehabilitation after fibula free flap harvest should be explored to determine the impact on patients' quality of life.

Single-dose intravenous ibuprofen for acute postoperative pain in adults.

BACKGROUND: Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous (IV) ibuprofen, compared with placebo or an active comparator, for moderate-to-severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 10 June 2021. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: We included randomized trials that compared a single postoperative dose of intravenous (IV) ibuprofen with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. Two review authors independently considered trials for review inclusion, assessed risk of bias, and extracted data. Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a 4- and 6-hour period. Our secondary outcomes were time to, and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants reporting or experiencing any AE, serious AEs (SAEs), and specific NSAID-related or opioid-related AEs. We were not able to carry out any planned meta-analysis. We assessed the certainty of the evidence using GRADE. MAIN RESULTS: Only one study met our inclusion criteria, involving 201 total participants, mostly female (mean age 42 years), undergoing primary, unilateral, distal, first metatarsal bunionectomy (with osteotomy and internal fixation). Ibuprofen 300 mg, placebo or acetaminophen 1000 mg was administered intravenously to participants reporting moderate pain intensity the day after surgery. Since we identified only one study for inclusion, we did not perform any quantitative analyses. The study was at low risk of bias for most domains. We downgraded the certainty of the evidence due to serious study limitations, indirectness and imprecision. Ibuprofen versus placebo Findings of the single study found that at both the 4-hour and 6-hour assessment period, the proportion of participants with at least 50% pain relief was 32% (24/76) for those assigned to ibuprofen and 22% (11/50) for those assigned to placebo. These findings produced a risk ratio (RR) of 1.44 (95% confidence interval (CI) 0.77 to 2.66 versus placebo for at least 50% of maximum pain relief over the 4-hour and 6-hour period (very low-certainty evidence). Median time to rescue medication was 101 minutes for ibuprofen and 71 minutes for placebo (1 study, 126 participants; very low-certainty evidence). The number of participants using rescue medication was not reported within the included study. During the study (1 study, 126 participants), 58/76 (76%) of participants assigned to ibuprofen and 39/50 (78%) assigned to placebo reported or experienced any adverse event (AE), (RR 0.98, 95% CI 0.81 to 1.19; low-certainty evidence). No serious AEs (SAEs) were experienced (1 study, 126 participants; very low-certainty evidence). Ibuprofen versus active comparators Ibuprofen (300 mg) was similar to the active comparator, IV acetaminophen (1000 mg) at 4 hours and 6 hours (1 study, 126 participants). For those assigned to active control (acetaminophen), the proportion of participants with at least 50% pain relief was 35% (26/75) at 4 hours and 31% (23/75) at 6 hours. At 4 hours, these findings produced a RR of 0.91 (95% CI 0.58 to 1.43; very low-certainty evidence) versus active comparator (acetaminophen). At 6 hours, these findings produced a RR of 1.03 (95% CI 0.64 to 1.66; very low-certainty evidence) versus active comparator (acetaminophen). Median time to rescue medication was 101 minutes for ibuprofen and 125 minutes for the active comparator, acetaminophen (1 study, 151 participants; very low-certainty evidence). The number of participants using rescue medication was not reported within the included study. During the study, 8/76 (76%) of participants assigned to ibuprofen and 45/75 (60%) assigned to active control (acetaminophen) reported or experienced any AE, (RR 1.27, 95% CI 1.02 to 1.59; very low-certainty evidence). No SAEs were experienced (1 study, 151 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: There is insufficient evidence to support or refute the suggestion that IV ibuprofen is effective and safe for acute postoperative pain in adults.

Single-dose intravenous ketorolac for acute postoperative pain in adults.

BACKGROUND: Postoperative pain is common and may be severe. Postoperative administration of non-steroidal anti-inflammatory drugs (NSAIDs) reduces patient opioid requirements and, in turn, may reduce the incidence and severity of opioid-induced adverse events (AEs). OBJECTIVES: To assess the analgesic efficacy and adverse effects of single-dose intravenous ketorolac, compared with placebo or an active comparator, for moderate to severe postoperative pain in adults. SEARCH METHODS: We searched the following databases without language restrictions: CENTRAL, MEDLINE, Embase and LILACS on 20 April 2020. We checked clinical trials registers and reference lists of retrieved articles for additional studies. SELECTION CRITERIA: Randomized double-blind trials that compared a single postoperative dose of intravenous ketorolac with placebo or another active treatment, for treating acute postoperative pain in adults following any surgery. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane.  Our primary outcome was the number of participants in each arm achieving at least 50% pain relief over a four- and six-hour period. Our secondary outcomes were time to and number of participants using rescue medication; withdrawals due to lack of efficacy, adverse events (AEs), and for any other cause; and number of participants experiencing any AE, serious AEs (SAEs), and NSAID-related or opioid-related AEs. For subgroup analysis, we planned to analyze different doses of parenteral ketorolac separately and to analyze results based on the type of surgery performed. We assessed the certainty of evidence using GRADE. MAIN RESULTS: We included 12 studies, involving 1905 participants undergoing various surgeries (pelvic/abdominal, dental, and orthopedic), with 17 to 83 participants receiving intravenous ketorolac in each study. Mean study population ages ranged from 22.5 years to 67.4 years. Most studies administered a dose of ketorolac of 30 mg; one study assessed 15 mg, and another administered 60 mg. Most studies had an unclear risk of bias for some domains, particularly allocation concealment and blinding, and a high risk of bias due to small sample size. The overall certainty of evidence for each outcome ranged from very low to moderate. Reasons for downgrading certainty included serious study limitations, inconsistency and imprecision. Ketorolac versus placebo Very low-certainty evidence from eight studies (658 participants) suggests that ketorolac results in a large increase in the number of participants achieving at least 50% pain relief over four hours compared to placebo, but the evidence is very uncertain (risk ratio (RR) 2.81, 95% confidence interval (CI) 1.80 to 4.37). The number needed to treat for one additional participant to benefit (NNTB) was 2.4 (95% CI 1.8 to 3.7). Low-certainty evidence from 10 studies (914 participants) demonstrates that ketorolac may result in a large increase in the number of participants achieving at least 50% pain relief over six hours compared to placebo (RR 3.26, 95% CI 1.93 to 5.51). The NNTB was 2.5 (95% CI 1.9 to 3.7). Among secondary outcomes, for time to rescue medication, moderate-certainty evidence comparing intravenous ketorolac versus placebo demonstrated a mean median of 271 minutes for ketorolac versus 104 minutes for placebo (6 studies, 633 participants). For the number of participants using rescue medication, very low-certainty evidence from five studies (417 participants) compared ketorolac with placebo. The RR was 0.60 (95% CI 0.36 to 1.00), that is, it did not demonstrate a difference between groups. Ketorolac probably results in a slight increase in total adverse event rates compared with placebo (74% versus 65%; 8 studies, 810 participants; RR 1.09, 95% CI 1.00 to 1.19; number needed to treat for an additional harmful event (NNTH) 16.7, 95% CI 8.3 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from eight studies (703 participants) did not demonstrate a difference in rates between ketorolac and placebo (RR 0.62, 95% CI 0.13 to 3.03). Ketorolac versus NSAIDs  Ketorolac was compared to parecoxib in four studies and diclofenac in two studies. For our primary outcome, over both four and six hours there was no evidence of a difference between intravenous ketorolac and another NSAID (low-certainty and moderate-certainty evidence, respectively). Over four hours, four studies (337 participants) produced an RR of 1.04 (95% CI 0.89 to 1.21) and over six hours, six studies (603 participants) produced an RR of 1.06 (95% CI 0.95 to 1.19). For time to rescue medication, low-certainty evidence from four studies (427 participants) suggested that participants receiving ketorolac waited an extra 35 minutes (mean median 331 minutes versus 296 minutes). For the number of participants using rescue medication, very low-certainty evidence from three studies (260 participants) compared ketorolac with another NSAID. The RR was 0.90 (95% CI 0.58 to 1.40), that is, there may be little or no difference between groups.   Ketorolac probably results in a slight increase in total adverse event rates compared with another NSAID (76% versus 68%, 5 studies, 516 participants; RR 1.11, 95% CI 1.00 to 1.23; NNTH 12.5, 95% CI 6.7 to infinite, moderate-certainty evidence). Serious AEs were rare. Low-certainty evidence from five studies (530 participants) did not demonstrate a difference in rates between ketorolac and another NSAID (RR 3.18, 95% CI 0.13 to 76.99). Only one of the five studies reported a single serious AE. AUTHORS' CONCLUSIONS: The amount and certainty of evidence for the use of intravenous ketorolac as a treatment for postoperative pain varies across efficacy and safety outcomes and amongst comparators, from very low to moderate. The available evidence indicates that postoperative intravenous ketorolac administration may offer substantial pain relief for most patients, but further research may impact this estimate. Adverse events appear to occur at a slightly higher rate in comparison to placebo and to other NSAIDs. Insufficient information is available to assess whether intravenous ketorolac has a different rate of gastrointestinal or surgical-site bleeding, renal dysfunction, or cardiovascular events versus other NSAIDs. There was a lack of studies in cardiovascular surgeries and in elderly populations who may be at increased risk for adverse events.

Stem cells for the treatment of glioblastoma: a 20-year perspective.

Glioblastoma, the deadliest form of primary brain tumor, remains a disease without cure. Treatment resistance is in large part attributed to limitations in the delivery and distribution of therapeutic agents. Over the last 20 years, numerous preclinical studies have demonstrated the feasibility and efficacy of stem cells as antiglioma agents, leading to the development of trials to test these therapies in the clinic. In this review we present and analyze these studies, discuss mechanisms underlying their beneficial effect and highlight experimental progress, limitations and the emergence of promising new therapeutic avenues. We hope to increase awareness of the advantages brought by stem cells for the treatment of glioblastoma and inspire further studies that will lead to accelerated implementation of effective therapies.

Lay abstract Glioblastoma is the deadliest and most common form of brain tumor, for which there is no cure. It is very difficult to deliver medicine to the tumor cells, because they spread out widely into the normal brain, and local blood vessels represent a barrier that most medicines cannot cross. It was shown, in many studies over the last 20 years, that stem cells are attracted toward the tumor and that they can deliver many kinds of therapeutic agents directly to brain cancer cells and shrink the tumor. In this review we analyze these studies and present new discoveries that can be used to make stem cell therapies for glioblastoma more effective to prolong the life of patients with brain tumors.

Efficacy of Multimodal Analgesia for Postoperative Pain Management in Head and Neck Cancer Patients.

Postoperative opioid use has been linked to the subsequent development of opioid dependency. Multimodal analgesia (MMA) can reduce the use of opioids in the postoperative period, but MMA has not been well-studied after major head and neck surgery. Our goal is to explore the association between MMA and postoperative opioid use and pain control in patients undergoing major head and neck surgery. We performed a retrospective study in adult (age ≥ 18 years) patients undergoing primary head and neck cancer resection with free-flap reconstruction. All patients were treated using an established care pathway. The baseline group was treated between January 2015-December 2015 (n = 41), prior to the implementation of MMA, and were compared to an MMA-treated cohort treated between December 2017-June 2019 (n = 97). The primary outcome was the proportion of opioids prescribed and oral morphine equivalents (OMEs) consumed during the hospitalization. The secondary outcome was pain control. We found that the post-MMA group consumed fewer opioids in the postoperative period compared to the pre-MMA group. Prior to post-operative day (POD) 6, pain control was better in the post-MMA group; however, the pain control lines intersect on POD 6 and the pre-MMA group appeared to have better pain control from PODs 7-10. In conclusion, our data suggest MMA is an effective method of pain control and opioid reduction in patients undergoing surgery for head and neck cancer with free flap reconstruction. MMA use was associated with a significant decrease in the quantity of opioids consumed postoperatively. The MMA protocol was associated with improved pain management early in the postoperative course. Finally, the MMA protocol is a feasible method of pain control and may reduce the adverse side effects associated with opioid use.

A Multi-Omics Study Revealing the Metabolic Effects of Estrogen in Liver Cancer Cells HepG2.

Hepatocellular carcinoma (HCC) that is triggered by metabolic defects is one of the most malignant liver cancers. A much higher incidence of HCC among men than women suggests the protective roles of estrogen in HCC development and progression. To begin to understand the mechanisms involving estrogenic metabolic effects, we compared cell number, viability, cytotoxicity, and apoptosis among HCC-derived HepG2 cells that were treated with different concentrations of 2-deoxy-d-glucose (2-DG) that blocks glucose metabolism, oxamate that inhibits lactate dehydrogenase and glycolysis, or oligomycin that blocks ATP synthesis and mitochondrial oxidative phosphorylation. We confirmed that HepG2 cells primarily utilized glycolysis followed by lactate fermentation, instead of mitochondrial oxidative phosphorylation, for cell growth. We hypothesized that estrogen altered energy metabolism via its receptors to carry out its anticancer effects in HepG2 cells. We treated cells with 17ß-estradiol (E2), 1,3,5-tris(4-hydroxyphenyl)-4-propyl-1H-pyrazole (PPT) an estrogen receptor (ER) α (ERα) agonist, or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN), an ERß agonist. We then used transcriptomic and metabolomic analyses and identified differentially expressed genes and unique metabolite fingerprints that are produced by each treatment. We further performed integrated multi-omics analysis, and identified key genes and metabolites in the gene-metabolite interaction contributed by E2 and ER agonists. This integrated transcriptomic and metabolomic study suggested that estrogen acts on estrogen receptors to suppress liver cancer cell growth via altering metabolism. This is the first exploratory study that comprehensively investigated estrogen and its receptors, and their roles in regulating gene expression, metabolites, metabolic pathways, and gene-metabolite interaction in HCC cells using bioinformatic tools. Overall, this study provides potential therapeutic targets for future HCC treatment.