Development of a chronic compression spinal cord injury model in neonatal and adult rats

Background:Spinal cord injury presents a significant burden globally,with traumatic spinal cord injury being the predominant cause historically.However,nontraumatic spinal cord injury(NTSCI)is emerging as a significant contributor,particularly in devel-oped nations,yet it remains poorly understood due to underreporting and misclassifi-cation.NTSCI,spanning various etiologies such as bony growths,vascular conditions,infections,neoplastic conditions,and immune disorders,poses unique challenges in diagnosis and treatment,often resulting in lifelong morbidity.This study addresses the lack of suitable animal models for NTSCI research,especially in neonatal animals.Methods:Utilizing a solid spacer approach,we developed a compression NTSCI model applicable to both neonatal and adult Sprague-Dawley rats.Results:Through anatomical measurements and in vivo experiments,we confirmed the feasibility and safety of the spacer insertion procedure and observed no acute off-target effects.Conclusion:The versatility of this model lies in its adaptability to different ages of rats,offering a cost-effective and reproducible means to induce graded injuries.Moreover,behavioral assessments demonstrated observable hindlimb function,validating the model's utility for studying functional outcomes.Although challenges persist,par-ticularly in accounting for spinal column growth in neonatal animals,this model fills a crucial gap in pediatric NTSCI research.By providing a platform to investigate patho-physiological mechanisms and test potential treatments,it offers promising avenues for advancing our understanding and management of pediatric NTSCI.

Loss to Specialized Cardiology Follow-Up in Adults Living with Congenital Heart Disease

Background:Much has been written about the loss to follow-up in the transition between pediatric and adult Congenital Heart Disease(CHD)care centers.Much less is understood about the loss to follow-up(LTF)after a successful transition.This is critical too,as patients lost to specialised care are more likely to experience mor-bidity and premature mortality.Aims:To understand the prevalence and reasons for loss to follow-up(LTF)at a large Australian Adult Congenital Heart Disease(ACHD)centre.Methods:Patients with moderate or highly complex CHD and gaps in care of>3 years(defined as LTF)were identified from a comprehensive ACHD data-base.Structured telephone interviews examined current care and barriers to clinic attendance.Results:Overall,407(22%)of ACHD patients(n=1842)were LTF.The mean age at LTF was 31(SD 11.5)years and 54%were male;311(76%)were uncontactable.Compared to adults seen regularly,lost patients were younger,with a greater socio-economic disadvantage,and had less complex CHD(p<0.05 for all).We interviewed 59 patients(14%).The top 3 responses for care absences were“feeling well”(61%),losing track of time(36%),and not needing fol-low-up care(25%).Conclusions:A large proportion of the ACHD population becomes lost to specialised cardiac care,even after a successful transition.This Australian study reports younger age,moderate complexity defects,and socio-economic disadvantage as predictive of loss to follow-up.This study highlights the need for novel approaches to patient-centered service delivery even beyond the age of transition and resources to maintain patient engagement within the ACHD service.

Robotic surgery for multi-visceral resection in locally advanced colorectal cancer:Techniques,benefits and future directions

Colorectal cancer accounts for 10%of diagnosed cancers globally and often presents as advanced disease,necessitating aggressive treatment.With both younger and healthier elderly patients being diagnosed,as well as potentially the need for salvage therapy post total neoadjuvant treatment,surgical options for cure include pelvic exenteration.Whilst typically performed via an open approach,there has been an increased utilisation of minimally invasive techniques including robotic surgery.Offering smaller in-cisions,reduced postoperative pain,and quicker recovery time than open surgery,robotic techniques have demonstrated lower blood loss,shorter hospital stays,and reduced morbidity.Moreover,the er-gonomic design of robotic systems provides surgeons with comfort during long procedures and increased precision.It also offers an increased opportunity for organ preservation and reconstruction whilst maintaining adequate oncological outcomes.As robotic technology continues to evolve and combines with artificial intelligence,it is poised to play an even more significant role in the management of complex colorectal cancer cases,improving survival and long-term outcomes.

Ventricular Arrhythmia in the Fontan Circulation:Prevalence,Risk Factors and Clinical Implications

Objective:Sudden cardiac death(SCD)and malignant ventricular arrhythmia(VA)are increasingly recognized as important issues for people living with a Fontan circulation,but data are lacking.We sought to characterize the cohort who had sudden cardiac death,most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes.Methods:A retrospective cohort study was performed.Inclusion criteria were documented non-sustained ventricular tachycardia,sustained ventricular tachycardia,ventricular fibrillation,resuscitated cardiac arrest or SCD>30 days post-Fontan completion.Results:Of 1611 patients,20(1.2%)had VA;14(1.0%)had VA without SCD and 6(<1%)had SCD(6%of all deaths recorded in Registry;5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated).The median age at first VA was 20.5(14–32)years,10(50%)were females,and the median age at Fontan operation was 8(4–17)years.On univariable analysis,hypoplastic left heart syndrome(p=0.03)and older age Fontan operation(p<0.001)were associated with VA.Earlier Fontan era(p<0.003),atriopulmonary Fontan(p<0.001),pre-Fontan atrioventricular valve repair(p=0.013)pre-or post-Fontan atrial arrhythmia(p=0.010)were associated with SCD.Patients with VA had a 3 times higher risk of death or heart transplant(HR 3.27(1.19,8.98),p=0.02).Conclusions:A proportion of people living with a Fontan circulation have malignant VA.Routine VA screening in this cohort is essential.More data are needed to aid risk stratification.

Aberrant expression of enzymes regulating m^6A mRNA methylation: implication in cancer

N^6-methyladenosine(m^6 A) is an essential RNA modification that regulates key cellular processes, including stem cell renewal,cellular differentiation, and response to DNA damage. Unsurprisingly, aberrant m^6 A methylation has been implicated in the development and maintenance of diverse human cancers. Altered m^6 A levels affect RNA processing, mRNA degradation, and translation of mRNAs into proteins, thereby disrupting gene expression regulation and promoting tumorigenesis. Recent studies have reported that the abnormal expression of m^6 A regulatory enzymes affects m^6 A abundance and consequently dysregulates the expression of tumor suppressor genes and oncogenes, including MYC, SOCS2, ADAM19, and PTEN. In this review, we discuss the specific roles of m^6 A missing space "writers", "erasers", and "readers" in normal physiology and how their altered expression promotes tumorigenesis. We also describe the potential of exploiting the aberrant expression of these enzymes for cancer diagnosis, prognosis, and the development of novel therapies.

Hepatitis B reactivation in the setting of chemotherapy and immunosuppression- prevention is better than cure

Due to the inherent relationship between the immune system and the hepatitis B virus(HBV) in exposed and infected individuals, immunomodulation associated with the treatment of solid tumours, haematological malignancies and inflammatory disorders has been linked to HBV reactivation(HBVr). Reactivation of HBV infection in the setting of chemotherapy and immunosuppression may lead to fulminant liver failure and death, but there is a cumulative body of evidence that these are potentially preventable adverse outcomes. As chronic hepatitis B is largely asymptomatic but also endemic worldwide, clinicians caring for patients requiring chemotherapy or immunosuppression need to be vigilant of the potential for HBVr in susceptible individuals. Serological screening and prophylactic and pre-emptive antiviral treatment with a nucleos(t)ide analogue should be considered in appropriate settings. Hepatitis B prevalence is examined in this review article, as are the risks of HBVr in patients receiving chemo- and immunosuppressive therapy. Recommendations regarding screening, monitoring and the role of antiviral prophylaxis are outlined with reference to current international associations' guidelines and the best available evidence to date.

Update on global epidemiology of viral hepatitis and preventive strategies

Viral hepatitis is one of the major public health concerns around the world but until recently it has drawn little attention or funding from global health policymakers.Every year 1.4 million people die from viral hepatitisrelated cirrhosis and liver cancer.However,the majority of the infected population are unaware of their condition.This population have significant obstacles to overcome such as lack of awareness,vulnerability,increased migration,disease stigma,discrimination,as well as poor health resources,conflict in policy development and program implementation.Despite implementing infection control measures over the last few decades eradication or significant disease reduction remains elusive.This study aims to present the current global prevalence status and examines potential elimination strategies.The information for this research were obtained through a systematic review,published scientific literatures,the official websites of various government organisations,international public health organisations and internationally recognised regulatory bodies over a period of 40 years between 1978 and2018.

Surgical management of hepatocellular carcinoma

Hepatocellular carcinoma(HCC) is the second most common cause of death from cancer worldwide. Standard potentially curative treatments are either resection or transplantation. The aim of this paper is to provide an overview of the surgical management of HCC, as well as highlight current issues in hepatic resection and transplantation. In summary, due to the relationship between HCC and chronic liver disease, the management of HCC depends both on tumourrelated and hepatic function-related considerations. As such, HCC is currently managed largely through nonsurgical means as the criteria, in relation to the above considerations, for surgical management is still largelyrestrictive. For early stage tumours, both resection and transplantation offer fairly good survival outcomes(5 years overall survival of around 50%). Selection therefore would depend on the level of hepatic function derangement, organ availability and local expertise. Patients with intermediate stage cancers have limited options, with resection being the only potential for cure. Otherwise, locoregional therapy with transarterial chemoembolization or radiofrequency ablation are viable options. Current issues in resection and transplantation are also briefly discussed such as laparoscopic resection, ablation vs resection, anatomical vs non-anatomical resection, transplantation vs resection, living donor liver transplantation and salvage liver transplantation.

Inhalation of nanoparticle-based drug for lung cancer treatment:Advantages and challenges

Ever since the success of developing inhalable insulin,drug delivery via pulmonary administration has become an attractive route to treat chronic diseases.Pulmonary delivery system for nanotechnology is a relatively new concept especially when applicable to lung cancer therapy.Nano-based systems such as liposome,polymeric nanoparticles or micelles are strategically designed to enhance the therapeutic index of anti-cancer drugs through improvement of their bioavailability,stability and residency at targeted lung regions.Along with these benefits,nano-based systems also provide additional diagnostic advantages during lung cancer treatment,including imaging,screening and drug tracking.Nevertheless,delivery of nanobased drugs via pulmonary administration for lung cancer therapy is still in its infancy and numerous challenges are expected.Pharmacology,immunology,toxicology and largescale manufacturing(stability and activity of drugs)are some aspects in nanotechnology that should be taken into consideration for the development of inhalable nano-based chemotherapeutic drugs.This review will focus on the current inhalable nano-based drugs for lung cancer treatment.

Immune checkpoint inhibitor-related hepatotoxicity:A review

The application of immune checkpoint inhibitors(ICI)in advanced cancer has been a major development in the last decade.The indications for ICIs are constantly expanding into new territory across different cancers,disease stages and lines of therapy.With this increased use,adverse events including immune checkpoint inhibitor-related hepatotoxicity(ICH)have emerged as an important clinical problem.This along with the introduction of ICI as first-and second-line treatments for advanced hepatocellular carcinoma makes ICH very relevant to gastroenterologists and hepatologists.The incidence of ICH varies between 1%-20%depending on the number,type and dose of ICI received.Investigation and management generally involve excluding differential diagnoses and following a stepwise escalation of withholding or ceasing ICI,corticosteroid treatment and adding other immunosuppressive agents depending on the severity of toxicity.The majority of patients with ICH recover and some may even safely recommence ICI therapy.Guideline recommendations are largely based on evidence derived from retrospective case series which highlights a priority for future research.

Update on the natural history of intracranial atherosclerotic disease: A critical review

Intracranial atherosclerotic disease (ICAD) contributes to a significant number of ischemic strokes. There is debate in the recent literature concerning the impact of the location of stenosis in ICAD on outcome. Some reports have suggested that disease processes and outcomes vary by vessel location, potentially altering the natural history and indications for intervention. Here we have performed a comprehensive, critical review of the natural history of ICAD by vessel in an attempt to assess the differences in disease specific to each of the vascular territories. Our assessment concludes that only minor differences exist between patients with different vessels affected in vessel-specific ICAD. We have found that middle cerebral artery disease confers a lower mortality than vessel-specific ICAD in other intracranial vessels, asymptomatic disease follows a more benign course than symptomatic disease, andthat plaque progression or the detection of microemboli on transcranial Doppler may predict poor outcome. Given the expanding indications for treatment of ICAD and rapidly developing endovascular techniques to confront this disease, a thorough understanding of the natural history of ICAD aids the interventional neuroradiologist in determining when to treat and how to predict outcome in this patient population.

Indications and surgical options for small bowel, large bowel and perianal Crohn's disease

Despite advancements in medical therapy of Crohn's disease(CD), majority of patients with CD will eventually require surgical intervention, with at least a third of patients requiring multiple surgeries. It is important to understand the role and timing of surgery, with the goals of therapy to reduce the need for surgery without increasing the odds of emergency surgery and its associated morbidity, as well as to limit surgical recurrence and avoid intestinal failure. The profile of CD patients requiring surgical intervention has changed over the decades with improvements in medical therapy with immunomodulators and biological agents. The most common indication for surgery is obstruction from stricturing disease, followed by abscesses and fistulae. The risk of gastrointestinal bleeding in CD is high but the likelihood of needing surgery for bleeding is low. Most major gastrointestinal bleeding episodes resolve spontaneously, albeit the risk of re-bleeding is high. The risk of colorectal cancer associated with CD is low. While current surgical guidelines recommend a total proctocolectomy for colorectal cancer associated with CD, subtotal colectomy or segmental colectomy with endoscopic surveillance may be a reasonable option. Approximately 20%-40% of CD patients will need perianal surgery during their lifetime. This review assesses the practice parameters and guidelines in the surgical management of CD, with a focus on the indications for surgery in CD(and when not to operate), and a critical evaluation of the timing and surgical options available to improve outcomes and reduce recurrence rates.

Colorectal cancer in the young,many questions,few answers

At a time where the incidence of colorectal cancer,a disease predominantly of developed nations,is showing a decline in those 50 years of age and older,data from the West is showing a rising incidence of this cancer in young individuals.Central to this has been the 75% increase in rectal cancer incidence in the last four decades.Furthermore,predictive data based on mathematical modelling indicates a 124 percent rise in the incidence of rectal cancer by the year 2030-a statistic that calls for collective global thought and action.While predominance of colorectal cancer(CRC) is likely to be in that part of the large bowel distal to the splenic flexure,which makes flexible sigmoidoscopic examination an ideal screening tool,the cost and benefit of mass screening in young people remain unknown.In countries where the incidence of young CRC is as high as 35% to 50%,the available data do not seem to indicate that the disease in young people is one of high red meat consuming nations only.Improvement in our understanding of genetic pathways in the aetiology of CRC,chiefly of the MSI,CIN and CIMP pathway,supports the notion that up to 30% of CRC is genetic,and may reflect a familial trait or environmentally induced changes.However,a number of other germline and somatic mutations,some of which remain unidentified,may play a role in the genesis of this cancer and stand in the way of a clear understanding of CRC in the young.Clinically,a proportion of young persons with CRC die early after curative surgery,presumably from aggressive tumour biology,compared with the majority in whom survival after operation will remain unchanged for five years or greater.The challenge in the future will be to determine,by genetic fingerprinting or otherwise,those at risk of developing CRC and the determinants of survival in those who develop CRC.Ultimately,prevention and early detection,just like for those over 50 years with CRC,will determine the outcome of CRC in young persons.At present,aside from those with an established familial tendency,there is no consensus on screening young persons who may be at risk.However,increasing awareness of this cancer in the young and the established benefit of prevention in older persons,must be a message that should be communicated with medical students,primary health care personnel and first contact doctors.The latter constitutes a formidable challenge.

Congenital peritoneal encapsulation: A review and novel classification system

Congenital peritoneal encapsulation(CPE) is a very rare, congenital condition characterised by the presence of an accessory peritoneal membrane which encases a variable extent of the small bowel. It is unclear how CPE develops,however it is currently understood to be a result of an aberrant adhesion in the peritoneal lining of the physiological hernia in foetal mid-gut development. The condition was first described in 1868, and subsequently there have been only 45 case reports of the phenomenon. No formal, systematised review of CPE has yet been performed, meaning the condition remains poorly understood,underdiagnosed and mismanaged. Diagnosis of CPE remains clinical with important adjuncts provided by imaging and diagnostic laparoscopy. Two thirds of patients present with abdominal pain, likely secondary to sub-acute bowel obstruction. A fixed, asymmetrical distension of the abdomen and differential consistency on abdominal palpation are more specific clinical features present in approximately 10% of cases. CPE is virtually undetectable on plain imaging, and is only detected on 40% of patients with computed tomography scan. Most patients will undergo diagnostic laparotomy to confirm the diagnosis.Management of CPE includes both medical management of the critically-unstable patient and surgical laparotomy, partial peritonectomy and adhesiolysis.Prognosis following prompt surgical treatment is excellent, with a majority of patients being symptom free at follow up. This review summarises the current literature on the aetiology, diagnosis and treatment of this rare disease. We also introduce a novel classification system for encapsulating bowel diseases, which may distinguish CPE from the commoner, more morbid conditions of abdominal cocoon and encapsulating peritoneal sclerosis.

Diagnosis of gastrointestinal bleeding: A practical guide for clinicians

Gastrointestinal bleeding is a common problem encountered in the emergency department and in the primary care setting. Acute or overt gastrointestinal bleeding is visible in the form of hematemesis, melena or hematochezia. Chronic or occult gastrointestinal bleeding is notapparent to the patient and usually presents as positive fecal occult blood or iron deficiency anemia. Obscure gastrointestinal bleeding is recurrent bleeding when the source remains unidentified after upper endoscopy and colonoscopic evaluation and is usually from the small intestine. Accurate clinical diagnosis is crucial and guides definitive investigations and interventions. This review summarizes the overall diagnostic approach to gastrointestinal bleeding and provides a practical guide for clinicians.

Sleep disordered breathing in interstitial lung disease: A review

Patients with interstitial lung disease commonly exhibit abnormal sleep architecture and increased sleep fragmentation on polysomnography. Fatigue is a frequent complaint, and it is likely that poor sleep quality is a significant contributor. A number of studies have shown that sleep disordered breathing is prevalent in this population, particularly in the idiopathic pulmonary fibrosis subgroup. The factors that predispose these patients to obstructive sleep apnoea are not well understood, however it is believed that reduced caudal traction on the upper airway can enhance collapsibility. Ventilatory control system instability may also be an important factor, particularly in those with increased chemo-responsiveness, and in hypoxic conditions. Transient, repetitive nocturnal oxygen desaturation is frequently observed in interstitial lung disease, both with and without associated obstructive apnoeas. There is increasing evidence that sleep-desaturation is associated with increased mortality, and may be important in the pathogenesis of pulmonary hypertension in this population.

Influence of HLA gene polymorphisms on susceptibility and outcome post infection with the SARS-CoV virus

Dear Editor,Severe Acute Respiratory Syndrome(SARS)has beendescribed as the first pandemic of the 21st century andbetween November 2002 and July 2003,over 8000 peo-ple were infected with the SARS-associated coronavirus(SARS-CoV).Polymorphisms in the human leukocyteantigen(HLA)system have been shown to influencesusceptibility to SARS-CoV but here we were unable

Relationship between depression and diabetes in pregnancy: A systematic review

AIM To systematically review the literature on women with both diabetes in pregnancy(DIP) and depression during or after pregnancy. METHODS In this systematic literature review, PubM ed/MEDLINE and EMBASE were searched(13 November 2015) using terms for diabetes(type 1, type 2, or gestational), depression, and pregnancy(no language or date restrictions). Publications that reported on women who had both DIP(any type) and depression or depressive symptoms before, during, or within one year after pregnancy were considered for inclusion. All study types were eligible for inclusion; conference abstracts, narrative reviews, nonclinical letters, editorials, and commentaries were excluded, unless they provided treatment guidance.RESULTS Of 1189 articles identified, 48 articles describing women with both DIP and depression were included(sample sizes 36 to > 32 million). Overall study quality was poor; most studies were observational, and only 12 studies(mostly retrospective database studies) required clinical depression diagnosis. The prevalence of concurrent DIP(any type) and depression in general populations of pregnant women ranged from 0% to 1.6%(median 0.61%; 12 studies). The prevalence of depression among women with gestational diabetes ranged from 4.1% to 80%(median 14.7%; 16 studies). Many studies examined whether DIP was a risk factor for depression or depression was a risk factor for DIP. However, there was no clear consensus for either relationship. Importantly, we found limited guidance on the management of women with both DIP and depression. CONCLUSION Given the increasing prevalence of diabetes and depression, high-quality research and specific guidance for management of pregnant women with both conditions are warranted.

Ampullary cancer of intestinal origin and duodenal cancer-A logical clinical and therapeutic subgroup in periampullary cancer

Periampullary cancers include pancreatic, ampullary, biliary and duodenal cancers. At presentation, the majority of periampullary tumours have grown to involve the pancreas, bile duct, ampulla and duodenum. This can result in difficulty in defining the primary site of origin in all but the smallest tumors due to anatomical proximity and architectural distortion. This has led to variation in the reported proportions of resected periampullary cancers. Pancreatic cancer is the most common cancer resected with a pancreaticoduodenectomy followed by ampullary(16%-50%), bile duct(5%-39%), and duodenal cancer(3%-17%). Patients with resected duodenal and ampullary cancers have a better reported median survival(29-47 mo and 22-54 mo) compared to pancreatic cancer(13-19 mo). The poorer survival with pancreatic cancer relates to differences in tumour characteristics such as a higher incidence of nodal, neural and vascular invasion. While small ampullary cancers can present early with biliary obstruction, pancreatic cancers need to reach a certain size before biliary obstruction ensues. This larger size at presentation contributes to a higher incidence of resection margin involvement in pancreatic cancer. Ampullary cancers can be subdivided into intestinal or pancreatobiliary subtype cancers with histomolecular staining. This avoids relying on histomorphology alone, as even some poorly differentiated cancers preserve the histomolecular profile of their mucosa of origin. Histomolecular profiling is superior to anatomic location in prognosticating survival. Ampullary cancers of intestinal subtype and duodenal cancers are similar in their intestinal origin and form a logical clinical and therapeutic subgroup of periampullary cancers. They respond to 5-FU based chemotherapeutic regimens such as capecitabine-oxaliplatin. Unlike pancreatic cancers, KRAS mutation occurs in only approximately a third of ampullary and duodenal cancers. Future clinical trials should group ampullary cancers of intestinal origin and duodenal cancers together given their similarities and their response to fluoropyrimidine therapy in combination with oxaliplatin. The addition of anti-epidermal growth factor receptor therapy in this group warrants study.

Rationale and Design of the Randomized Controlled Trial of Intensive Versus Usual ECG Screening for Atrial Fibrillation in Elderly Chinese by an Automated ECG System in Community Health Centers in Shanghai(AF-CATCH)

Objective:The randomized controlled trial(ClinicalTrials.gov identifier NCT02990741)will investigate whether more frequent electrocardiographic(ECG)recordings and analyses with an automated ECG system would improve detection of atrial fibrillation compared with a single annual ECG screen in elderly Chinese in community health centers.Design:Men and women(≥65 years)will be randomized into intensive(n=3500)and usual(n=3500)screening groups,and within the intensive screening group into intensive screening(n=2625)and more intensive screening(n=875)subgroups.ECG recordings will be performed with an automated ECG analysis system(AliveCor heart monitor)at 1 year in the usual screening group,at 3,6,9,and 12 months in the intensive screening subgroup,and at 1,2,3,and 4 weeks and 3,6,9,and 12 months in the more intensive screening subgroup.The primary outcome is the detection rate of atrial fibrillation between the usual screening group and the intensive screening group.Sample size estimation was based on a projected detection rate of atrial fibrillation of 2.0% by a single ECG recording at 12 months,an improvement of 50% with more frequent ECG recordings,α=0.05,power of 80%,and a one-sided test.Conclusions:The trial will provide evidence on the clinical effectiveness of more frequent ECG recordings by a handheld automated analysis system in the detection of atrial fibrillation.