Preventative strategies for low anterior resection syndrome.

BACKGROUND: A common and debilitating complication of low anterior resection for rectal cancer is low anterior resection syndrome (LARS). As a multifactorial entity, LARS is poorly understood and challenging to treat. Despite this, prevention strategies are commonly overlooked. Our aim was to review the pathophysiology of LARS and explore current evidence on the efficacy and feasibility of prophylactic techniques. METHODS: A literature review was performed between [1st January 2000 to 1st October 2023] for studies which investigated preventative interventions for LARS. Mechanisms by which LARS develop are described, followed by a review of prophylactic strategies to prevent LARS. Medline, Cochrane, and PubMed databases were searched, 189 articles screened, 8 duplicates removed and 18 studies reviewed. RESULTS: Colonic dysmotility, anal sphincter dysfunction and neorectal dysfunction all contribute to the development of LARS, with the complex mechanism of defecation interrupted by surgery. Transanal irrigation (TAI) and pelvic floor rehabilitation (PFR) have shown benefits in preventing LARS, but may be limited by patient compliance. Intraoperative nerve monitoring (IONM) and robotic-assisted surgery have shown some promise in surgically preventing LARS. Nerve stimulation and other novel strategies currently used in treatment of LARS have yet to be investigated in their roles prophylactically. CONCLUSIONS: To date, there is a limited evidence base for all preventative strategies including IONM, RAS, PFP and TAI. These strategies are limited by either access (IONM, RAS and PFP) or acceptability (PFP and TAI), which are both key to the success of any intervention. The results of ongoing trials will serve to assess acceptability, while technological advancement may improve access to some of the aforementioned strategies.

Mass screening of rice mutant populations at low CO2 for identification of lowered photorespiration and respiration rates.

Introduction: Identifying rice (Oryza sativa) germplasm with improved efficiency of primary metabolism is of utmost importance in order to increase yields. One such approach can be attained through screening genetically diverse populations under altered environmental conditions. Growth or treatment under low carbon dioxide (CO2) concentrations can be used as a means of revealing altered leaf photorespiration, respiration and other metabolic variants. Methods: We developed a pipeline for very high throughput treatment of gamma- and ethyl methanesulfonate- (EMS) induced mutant populations of IR64 rice seedlings at very low CO2 for 7 days. 1050 seedlings per batch at 5th leaf stage were exposed to 60 ppm CO2 for the first day and 30 ppm for the remaining three days. Following this, putative candidates were identified by measuring chlorophyll depletion using SPAD. Screening results showed a distinct difference between the mutants and the WTs. Results and discussion: The mean chlorophyll loss in WTs ranged from 65% to 11% respectively, whereas in the mutant lines chlorophyll loss ranged from 0 to 100%, suggesting considerable phenotypic variation. Rice mutants with a reduced chlorophyll reduction (<10%) were identified as 'Chlorophyll retention mutants' (CRMs) under low CO2 stress. In total, 1909 mutant lines (14,000 seedlings) were screened for chlorophyll content under 30 ppm CO2, with 26 lines selected for detailed screening. These 26 putative candidates were self-seeded to produce an M5 generation, used to determine the genetic control of the altered response to low CO2. Gas exchange of light and CO2 response revealed that there were significant variations among photosynthetic properties in two selected rice mutants. The CO2 compensation points in the absence of photorespiration and leaf respiration rates were lower than the WTs and anatomical analyses showed that CRM 29 had improved mesophyll cell area. We propose that this approach is useful for generating new material for breeding rice with improved primary metabolism.

PROSPECT guideline for tonsillectomy: systematic review and procedure-specific postoperative pain management recommendations.

Tonsillectomy is one of the most frequently performed surgical procedures; however, pain management remains challenging. Procedure-specific efficacy as well as specific risks of treatment options should guide selection of pain management protocols based on evidence and should optimise analgesia without harm. The aims of this systematic review were to evaluate the available literature and develop recommendations for optimal pain management after tonsillectomy. A systematic review utilising preferred reporting items for systematic reviews and meta-analysis guidelines with procedure-specific postoperative pain management (PROSPECT) methodology was undertaken. Randomised controlled trials published in the English language up to November 2019 assessing postoperative pain using analgesic, anaesthetic or surgical interventions were identified. Out of the 719 potentially eligible studies identified, 226 randomised controlled trials met the inclusion criteria, excluding the studies examining surgical techniques. Pre-operative and intra-operative interventions that improved postoperative pain were paracetamol; non-steroidal anti-inflammatory drugs; intravenous dexamethasone; ketamine (only assessed in children); gabapentinoids; dexmedetomidine; honey; and acupuncture. Inconsistent evidence was found for local anaesthetic infiltration; antibiotics; and magnesium sulphate. Limited evidence was found for clonidine. The analgesic regimen for tonsillectomy should include paracetamol; non-steroidal anti-inflammatory drugs; and intravenous dexamethasone, with opioids as rescue analgesics. Analgesic adjuncts such as intra-operative and postoperative acupuncture as well as postoperative honey are also recommended. Ketamine (only for children); dexmedetomidine; or gabapentinoids may be considered when some of the first-line analgesics are contra-indicated. Further randomised controlled trials are required to define risk and combination of drugs most effective for postoperative pain relief after tonsillectomy.

A rare presentation of a paediatric patient with acute otomastoiditis media caused by mycobacterium tuberculosis resulting in intracranial complications.

Mastoiditis caused by mycobacterium tuberculosis (TB) has an extremely low incidence in paediatric patients and intracranial complications are even rarer. We report the case of a 2-year-old Caucasian male who presented to a tertiary ENT centre with a left sided mastoid swelling and drowsiness after having been treated unsuccessfully for unresolving ear pain and discharge for 6 weeks. He was subsequently found to have mastoiditis with intracranial complications caused by mycobacterium TB. This report aims to increase awareness of TB as a potential cause of chronic unresolving ear pain in the paediatric age group, as well as the importance of multidisciplinary team management.

Upper airway obstruction assessment: Peak inspiratory flow and clinical COPD Questionnaire.

OBJECTIVES: Spirometric evaluation of upper airway obstruction (UAO) is not commonly performed by Otolaryngologists. In addition, functional evaluation of UAO by flow-volume loops (FVL) is not available in all clinical settings. More recently, peak inspiratory flow (PIF) has proven to be a useful tool to monitor UAO at the patient's bedside. The aim of this work is to assess the role of PIF measured with a simple flow metre (In-Check method) as a standardised, simple, non-invasive tool in quantifying chronic and subacute UAO in a routine clinical practice. In addition, a Clinical COPD Questionnaire (CCQ), previously validated to assess the psychophysical status in patients with laryngotracheal stenosis, was utilised to evaluate respiratory function in UAO. DESIGN: Prospective cohort study. SETTINGS: University teaching hospital. PARTICIPANTS: Seventy 2 subjects, an UAO group of 26 patients and a control group of 46 healthy subjects. MAIN OUTCOME MEASURES: The ability of PIF values to discriminate between the UAO group and the control group was assessed using a ROC curve. A Spearman rank correlation was used to test the relationship between PIF measurements and the global CCQ score. Additionally, an analysis of CCQ at domain and items levels was performed. RESULTS: Peak inspiratory flow values were accurate, with an area under the ROC curve (AUC) of 0.98 (P < .05) for differentiating the control group from the UAO group. A threshold PIF value of 170 L/min was found for diagnosing UAO. An inconclusive negative trend was found (r = -.19; P = .35) between PIF values and CCQ global score. Concerning CCQ, the symptoms domain was the most affected by UAO, higher than mental domains (P < .001) as well as functional domains (P < .01). Exertional dyspnoea and cough were the items that obtained the highest disturbed scores. CONCLUSIONS: Peak inspiratory flow is a non-invasive, quantitative parameter to evaluate the severity of UAO. Testing can be easily performed in a routine clinical setting, with a non-expensive hand-held device, and could help medical follow-up programmes and prevent emergency situations. However, FVL may be necessary for further assessment of UAO diseases. The CCQ confirms that exertional dyspnoea is the main symptom of UAO, but cough remains a common symptom.

Articular surface mounted navigated total knee arthroplasty improves the reliability of component alignment.

PURPOSE: The primary aim was to compare the early knee-specific functional outcome after articular surface mounted (ASM) navigation with non-navigated TKA. The secondary aims were to compare general physical and mental health improvement, patient satisfaction, and reliability of component alignment in the sagittal and coronal planes between ASM navigated TKA with that of non-navigated TKA. METHODS: Prospective functional outcome and radiographic data were collect for 123 patients undergoing ASM navigation and 172 patients undergoing non-navigated TKA by a high volume single surgeon. Pre-operative and one-year Oxford knee score (OKS) and short form (SF-) 12 scores were collected. Patient satisfaction was also assessed at one year. Implant position was assessed on post-operative radiographs (alpha, beta, gamma, and sigma angles) by a blinded observer. RESULTS: There was no significant difference for improvement in OKS, SF-12 physical or mental components, or satisfaction between the groups one year following surgery. The non-navigation group was significantly more likely to have outliers (greater than 3 degrees) in femoral varus/valgus coronal alignment [odds ratio (OR) 4.5, 95% confidence interval (CI) 1.0-20.7, p = 0.049] and for posterior tibial slope (OR 8.3, 95% CI 1.1-65.0, p = 0.03). CONCLUSIONS: ASM navigation significantly reduces the number of outliers for the femoral and tibial components when compared to conventional non-navigation alignment. However, the short-term functional outcome is not influenced by the surgical technique used. If the surgeon wants to reduce their number of outliers, then ASM navigation should be considered but the overall functional outcome in the short term is not influenced. LEVEL OF EVIDENCE: III Therapeutic investigation, retrospective cohort study.

The role of canonical and non-canonical Hedgehog signaling in tumor progression in a mouse model of small cell lung cancer.

Hedgehog (Hh) signaling regulates cell fate and self-renewal in development and cancer. Canonical Hh signaling is mediated by Hh ligand binding to the receptor Patched (Ptch), which in turn activates Gli-mediated transcription through Smoothened (Smo), the molecular target of the Hh pathway inhibitors used as cancer therapeutics. Small cell lung cancer (SCLC) is a common, aggressive malignancy with universally poor prognosis. Although preclinical studies have shown that Hh inhibitors block the self-renewal capacity of SCLC cells, the lack of activating pathway mutations have cast doubt over the significance of these observations. In particular, the existence of autocrine, ligand-dependent Hh signaling in SCLC has been disputed. In a conditional Tp53;Rb1 mutant mouse model of SCLC, we now demonstrate a requirement for the Hh ligand Sonic Hedgehog (Shh) for the progression of SCLC. Conversely, we show that conditional Shh overexpression activates canonical Hh signaling in SCLC cells, and markedly accelerates tumor progression. When compared to mouse SCLC tumors expressing an activating, ligand-independent Smo mutant, tumors overexpressing Shh exhibited marked chromosomal instability and Smoothened-independent upregulation of Cyclin B1, a putative non-canonical arm of the Hh pathway. In turn, we show that overexpression of Cyclin B1 induces chromosomal instability in mouse embryonic fibroblasts lacking both Tp53 and Rb1. These results provide strong support for an autocrine, ligand-dependent model of Hh signaling in SCLC pathogenesis, and reveal a novel role for non-canonical Hh signaling through the induction of chromosomal instability.

Removal of a well fixed cemented acetabular component using biomechanical principles.

BACKGROUND: Removal of well fixed components can be a complex problem facing an orthopaedic surgeon during revision hip arthroplasty. As the burden of revision hip surgery increases, techniques have been described to enable safe and reliable removal of well fixed components. Removal of well fixed cemented components requires different considerations to the removal of cemented components. Polymethylmethacrylate bone cement and polyethylene have unique biomechanical properties. METHOD: We present a step-by-step technique to reliably and safely remove a well fixed cemented acetabular component and underlying cement during revision hip arthroplasty. RESULTS: This reproducible technique is presented with intra-operative photography and a detailed description of the necessary steps to remove a well fixed cemented acetabular component. CONCLUSION: Consideration of important underlying biomechanical principles of polymethylmethacrylate bone cement and polyethylene can aid the safe removal of a well fixed cemented acetabular component in revision hip surgery, reducing risk to underlying bone.

Intravenous acetaminophen for the treatment of intrapartum fever and resolution of fetal tachycardia: a novel use for an old medication.

This case series demonstrates a potential new role for the use of intravenous (IV) acetaminophen. The authors reviewed two cases, whereby patients that developed intrapartum fever leading to fetal tachycardia were effectively treated with IV acetaminophen, leading to rapid reduction of maternal temperature and resolution of fetal tachycardia. Both patients had an uncomplicated vaginal delivery of healthy neonates. Intravenous acetaminophen, with its increased bioavailability and more rapid onset of action, may have benefit in the intrapartum setting by reducing adverse neonatal and maternal outcomes associated with febrile morbidity.

Scedosporium apiospermum causing otomycosis in an immunocompetent child with tympanostomy tubes: Management of this rare entity.

Infection following a tympanostomy tube insertion is a common occurrence. Scedosporium apiospermum is a filamentous fungus mainly isolated in water and soil. There have been no reported cases of S. apiospermum infection of an immunocompetent individual with a tympanostomy tube in situ. A child was referred with unilateral otorrhoea failing to respond to conventional treatment in the community. S. apiospermum was identified following specialist testing. An extended course of anti-fungal treatment led to complete resolution. Due to the rare occurrence of aural S. apiospermum and unreported nature, it should be managed in a multidisciplinary setting.

Gene delivery to the spinal cord using MRI-guided focused ultrasound.

Non-invasive gene delivery across the blood-spinal cord barrier (BSCB) remains a challenge for treatment of spinal cord injury and disease. Here, we demonstrate the use of magnetic resonance image-guided focused ultrasound (MRIgFUS) to mediate non-surgical gene delivery to the spinal cord using self-complementary adeno-associated virus serotype 9 (scAAV9). scAAV9 encoding green fluorescent protein (GFP) was injected intravenously in rats at three dosages: 4 × 10(8), 2 × 10(9) and 7 × 10(9) vector genomes per gram (VG g(-1)). MRIgFUS allowed for transient, targeted permeabilization of the BSCB through the interaction of focused ultrasound (FUS) with systemically injected Definity lipid-shelled microbubbles. Viral delivery at 2 × 10(9) and 7 × 10(9) VG g(-1) leads to robust GFP expression in FUS-targeted regions of the spinal cord. At a dose of 2 × 10(9) VG g(-1), GFP expression was found in 36% of oligodendrocytes, and in 87% of neurons in FUS-treated areas. FUS applications to the spinal cord could address a long-term goal of gene therapy: delivering vectors from the circulation to diseased areas in a non-invasive manner.

Colonoscopy after spinal cord injury: a case-control study.

DESIGN: An age- and gender-matched case-control study. OBJECTIVE: To compare colonoscopy after spinal cord injury (SCI) with the general population in terms of indications, bowel preparation, technical success and disease detection. SETTING: Victoria, Australia. METHODS: Consecutive SCI colonoscopies between January 1998 and February 2013 were compared with a randomly selected age- and gender-matched control group. Injury level, indication for procedure and demographics were collected. Outcome measures included quality of bowel preparation, completion rates, procedural duration and benign and malignant disease detection. RESULTS: A total of 440 colonoscopies were assessed, comprising 148 SCI patients and 292 age- and gender-matched controls. Both the groups were of similar age (54.7 years vs 54.5 years, P=0.906) and comprised predominantly males (87.1% vs 86.3%, P=0.919). SCI colonoscopies were more often performed to investigate abnormalities (85.1% vs 58.2%, P<0.001) than for screening or surveillance (18.2% vs 40.8%, P<0.001). Unsatisfactory bowel preparation was recorded more often in the SCI group (36.0% vs 13.0%, P<0.001) and completion rates were lower (75.7% vs 93.1%, P<0.001). Overall disease detection was lower in the SCI group (45.3% vs 59.6%, P<0.006). The polyp detection rate was lower for SCI (11.4% vs 25.3%, P=0.001). The rate of diagnosis of malignancy was equivalent (2.7% vs 3.0%, P=0.904). CONCLUSION: SCI patients have the same risk of malignancy as the general population and are less likely to undergo screening colonoscopy. Colonoscopy is then limited by poor bowel preparation and lower completion rates with a subsequent lower polyp detection rate.

Role of endoplasmic reticulum stress induction by the plant toxin, persin, in overcoming resistance to the apoptotic effects of tamoxifen in human breast cancer cells.

BACKGROUND: Persin is a plant toxin that displays synergistic cytotoxicity with tamoxifen in human breast cancer cell lines. Here, we examined the ability of persin to circumvent tamoxifen resistance and delineated the intracellular signalling pathways involved. METHODS: The induction of apoptosis in tamoxifen-resistant and -sensitive breast cancer cells was measured by flow cytometry following treatment with persin±tamoxifen. Markers of endoplasmic reticulum stress (ERS) were analysed following treatment, and their causal role in mediating persin-induced apoptosis was determined using chemical inhibitors and RNA interference. RESULTS: Cells that were resistant to an apoptotic concentration of tamoxifen maintained an apoptotic response to persin. Persin-induced apoptosis was associated with an increase in markers of ERS, that is, CHOP expression and XBP-1 splicing and was decreased by CHOP siRNA. The CASP-4 inhibitor Z-YVAD-FMK markedly inhibited persin-induced apoptosis in both tamoxifen-sensitive and -resistant cells. CONCLUSION: The cytotoxic effects of persin are CASP-4 dependent and mediated by CHOP-dependent and -independent ERS signalling cascades. Increased ERS signalling contributes to persin-induced reversal of tamoxifen resistance.

Vestibular function after vestibular neuritis.

OBJECTIVE: To measure horizontal semicircular canal function over days, weeks, and months after an acute attack of vestibular neuritis. DESIGN: The video head impulse test (vHIT) was used to measure the eye movement response to small unpredictable passive head turns at intervals after the attack. STUDY SAMPLE: Two patients diagnosed with acute right unilateral vestibular neuritis. RESULTS: There was full restoration of horizontal canal function in one patient (A) as shown by the return of the slow phase eye velocity response to unpredictable head turns, while in the other patient (B) there was little or no recovery of horizontal canal function. Instead this second patient generated covert saccades during head turns. CONCLUSION: Despite the objective evidence of their very different recovery patterns, both patients reported, at the final test, being happy and feeling well recovered, even though in one of the patients there was clear absence of horizontal canal function. The results indicate covert saccades seem a successful way of compensating for loss of horizontal canal function after unilateral vestibular neuritis. Factors other than recovery of the slow phase eye velocity are significant for patient recovery.

Serum concentrations of brain-derived neurotrophic factor (BDNF) are decreased in colorectal cancer patients.

OBJECTIVE: To determine the usefulness of brain-derived neurotrophic factor (BDNF) as a diagnostic biomarker for colorectal cancer (CRC). MATERIALS AND METHODS: ELISA immunoassay was used to examine BDNF concentrations in the sera of two different retrospective cohorts consisting of CRC patients and age/gender matched controls. Cohort 1 consisted of 99 controls and 97 CRC patients, whereas cohort 2 consisted of 47 controls and 91 CRC patients. RESULTS: In cohort 1, the median concentration of BDNF was significantly (p< 0.0001) lower in CRC patient samples (18.8 ng/mL, range 4.0-56.5 ng/mL) than control samples (23.4 ng/mL, range 3.0-43.1 ng/mL). This finding was validated in an independent patient cohort (CRC patients: 23.0 ng/mL, range 6.0-45.9 ng/mL; control patients: 32.3 ng/mL, range 14.2-62.4 ng/mL). BDNF concentrations did not differ significantly between Dukes' staging in the patient cohort, however patients with Stages A, B, C and D (p< 0.01 for each stage) tumours had significantly reduced BDNF levels compared to healthy controls. Receiver operating characteristic analysis was performed to determine the ability of BDNF to discriminate between healthy controls and those with CRC. At 95% specificity, BDNF concentrations distinguished CRC patients with 25% and 18% sensitivity, respectively, in cohorts 1 and 2 (cohort 1: AUC=0.79, 95% CI 0.70-0.87; cohort 2: AUC =0.69, 95% CI 0.61-0.76). CONCLUSION: The serum levels of BDNF were significantly lower in colorectal cancer patients when compared to a control population, and this did not differ between different Dukes' stages.

Different APC genotypes in proximal and distal sporadic colorectal cancers suggest distinct WNT/ß-catenin signalling thresholds for tumourigenesis.

Biallelic protein-truncating mutations in the adenomatous polyposis coli (APC) gene are prevalent in sporadic colorectal cancer (CRC). Mutations may not be fully inactivating, instead producing WNT/ß-catenin signalling levels 'just-right' for tumourigenesis. However, the spectrum of optimal APC genotypes accounting for both hits, and the influence of clinicopathological features on genotype selection remain undefined. We analysed 630 sporadic CRCs for APC mutations and loss of heterozygosity (LOH) using sequencing and single-nucleotide polymorphism microarrays, respectively. Truncating APC mutations and/or LOH were detected in 75% of CRCs. Most truncating mutations occurred within a mutation cluster region (MCR; codons 1282-1581) leaving 1-3 intact 20 amino-acid repeats (20AARs) and abolishing all Ser-Ala-Met-Pro (SAMP) repeats. Cancers commonly had one MCR mutation plus either LOH or another mutation 5' to the MCR. LOH was associated with mutations leaving 1 intact 20AAR. MCR mutations leaving 1 vs 2-3 intact 20AARs were associated with 5' mutations disrupting or leaving intact the armadillo-repeat domain, respectively. Cancers with three hits had an over-representation of mutations upstream of codon 184, in the alternatively spliced region of exon 9, and 3' to the MCR. Microsatellite unstable cancers showed hyper-mutation at MCR mono- and di-nucleotide repeats, leaving 2-3 intact 20AARs. Proximal and distal cancers exhibited different preferred APC genotypes, leaving a total of 2 or 3 and 0 to 2 intact 20AARs, respectively. In conclusion, APC genotypes in sporadic CRCs demonstrate 'fine-tuned' interdependence of hits by type and location, consistent with selection for particular residual levels of WNT/ß-catenin signalling, with different 'optimal' thresholds for proximal and distal cancers.

Unusual presentation of cervical spine metastases to the ENT surgeon.

OBJECTIVE: Cervical spine metastases account for 10 per cent of all spinal metastases. We report three cases of cervical spine metastases whose unusual primary presentation was with ENT-related symptoms. METHODS: The three patients reported herein did not have a confirmed diagnosis of malignancy at presentation. The first patient presented with stridor, the second presented with dysphagia and the third presented with dysphonia. All patients complained of significant neck pain that preceded and was concomitant to the other symptoms. Clinical suspicion of cervical spine involvement led to radiological investigation with computed tomography, which showed metastatic lesions in the craniovertebral junction and cervical spine region. Histological confirmation of malignancy was obtained for two of the three patients. The condition proved uniformly fatal in the weeks following diagnosis. A review of the literature on this condition was conducted using PubMed and Medline databases. CONCLUSION: Cervical spine pathology may present initially to the ENT surgeon. A high degree of suspicion of cervical spine involvement should be maintained in elderly patients with persistent or progressive neck pain, with or without other ENT symptoms. Adequate radiological imaging will usually confirm the diagnosis.