Consensus recommendations for the screening, diagnosis, and management of Helicobacter pylori infection in Hong Kong.

Helicobacter pylori infection causes chronic gastric inflammation that contributes to various gastroduodenal diseases, including peptic ulcer and gastric cancer. Despite broad regional variations, the prevalence of resistance to antibiotics used to manage H pylori infection is increasing worldwide; this trend could hinder the success of eradication therapy. To increase awareness of H pylori and improve the diagnosis and treatment of its infection in Hong Kong, our consensus panel proposed a set of guidance statements for disease management. We conducted a comprehensive review of literature published during 2011 and 2021, with a focus on articles from Hong Kong or other regions of China. We evaluated the evidence using the Oxford Centre for Evidence-Based Medicine's 2011 Levels of Evidence and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system and sought consensus through online voting and a subsequent face-to-face meeting, which enabled us to develop and refine the guidance statements. This report consists of 24 statements regarding the epidemiology and burden, screening and diagnosis, and treatment of H pylori. Key guidance statements include a recommendation to use the test-and-treat approach for high-risk individuals, as well as the confirmation that triple therapy with a proton pump inhibitor, amoxicillin, and clarithromycin remains a valid first-line option for adults and children in Hong Kong.

Surgical management of perianal fistula using an ovine forestomach matrix implant.

PURPOSE: Invasive surgical management of cryptoglandular perianal fistulas (PF) is challenging because of high recurrence rates and the potential for injury to the sphincter complex. In the present technical note, we introduce a minimally invasive treatment for PF using a perianal fistula implant (PAFI) comprising ovine forestomach matrix (OFM). METHODS: This retrospective observational case series highlights 14 patients who had undergone a PAFI procedure at a single center between 2020 and 2023. During the procedure, previously deployed setons were removed and tracts were de-epithelialized with curettage. OFM was rehydrated, rolled, passed through the debrided tract, and secured in place at both openings with absorbable suture. Primary outcome was fistula healing at 8 weeks, and secondary outcomes included recurrence or postoperative adverse events. RESULTS: Fourteen patients underwent PAFI using OFM with a mean follow-up period of 37.6 ± 20.1 weeks. In follow-up, 64% (n = 9/14) had complete healing at 8 weeks and all remained healed, except one at last follow-up visit. Two patients underwent a second PAFI procedure and were healed with no recurrence at the last follow-up visit. Of all patients that healed during the study period (n = 11), the median time to healing was 3.6 (IQR 2.9-6.0) weeks. No postprocedural infections nor adverse events were noted. CONCLUSIONS: The minimally invasive OFM-based PAFI technique for PF treatment was demonstrated to be a safe and feasible option for patients with trans-sphincteric PF of cryptoglandular origin.

Psychosocial adjustment mediates impacts of playmate positive support on body mass index and overweight risk in adolescents.

OBJECTIVES: We examined the mediation effects of psychosocial adjustment on the impact of playmate positive support throughout childhood and early adolescence (from age 54 months to 11 years) on later body mass index (BMI) and overweight risk in middle adolescence (age 15 years). STUDY DESIGN: This was a prospective cohort study. METHODS: Among 844 children and their families, positive support between child-playmate dyads was repeatedly assessed from child's age 54 months to Grade 5. Long-term positive support between child-playmate dyads throughout childhood and early adolescence was prospectively linked to child's BMI and overweight/obesity status at age 15 years. The average scores of repeated assessments of internalizing and externalizing behavior problems from Grades 3 to 6 were used as mediators. RESULTS: Significant mediations of internalizing and externalizing behavior problems were observed on pathways from positive support between child-playmate dyads to later BMI and overweight/obesity status at age 15 years. The observed mediations were mainly sustained with pronounced magnitudes in girls, but not in boys. CONCLUSIONS: Our findings demonstrated a significant mediating role of psychosocial adjustment. Future research efforts are highly encouraged to replicate our findings and further explore this underlying mediation mechanism.

Add-on effect of clarithromycin to oral steroids as post- operative therapy for chronic rhinosinusitis with nasal polyps: a randomised controlled trial.

BACKGROUND: Evidence is lacking regarding the efficacy of macrolides and oral corticosteroids in chronic rhinosinusitis with nasal polyps (CRSwNP) after endoscopic sinus surgery (ESS). Therefore, we examined the benefits of adding clarithromycin to oral pred- nisolone as post-ESS medical therapy in patients with CRSwNP. METHODS: In this randomised, double-blind, placebo-controlled trial, patients were enrolled and allocated to three study groups receiving different post-ESS medical therapies: group A (placebo for 14 weeks), group B (oral prednisolone [15 mg twice daily] for 2 weeks, followed by placebo for 12 weeks), and group C (oral prednisolone [15 mg twice daily] for 2 weeks, followed by clari- thromycin [500 mg daily] for 12 weeks). All enrolled patients received the perioperative care following a routine protocol, which included oral amoxicillin/clavulanate, and intranasal corticosteroid spray. The baseline and post-operative visual analogue scale (VAS) scores, Sino-nasal Outcome Test (SNOT-22) scores, and Lund-Kennedy endoscopy scores (LKES) were determined as the primary outcomes. RESULTS: One hundred twenty-six patients who received ESS for bilateral CRSwNP were randomised into group A (n=43), B (n=42), or C (n=41). Compared to groups A and B, group C showed greater VAS and SNOT-22 score improvement at 12 weeks after ESS. Group C showed significantly better LKES than did groups A and B at 8, 12, and 24 weeks after ESS. On stratifying the LKES results according to the presence/absence of tissue eosinophilia, greater add-on effects of clarithromycin were observed in the patient subgroup without tissue eosinophilia. CONCLUSIONS: Adding low-dose clarithromycin to oral corticosteroids as post-ESS therapy was well tolerated and showed benefi- cial subjective and objective outcomes in patients with CRSwNP, especially those without tissue eosinophilia.

End-of-life care following leg amputation in patients with peripheral artery disease or diabetes.

BACKGROUND: The aim was to characterize end-of-life care in patients who have had a leg amputated for peripheral artery disease (PAD) or diabetes. METHODS: This was a population-based retrospective cohort study of patients with PAD or diabetes who died in Ontario, Canada, between 2011 and 2017. Those who had a leg amputation within 3 years of death were compared with a control cohort of deceased patients with PAD or diabetes, but without leg amputation. The patients were identified from linked health records within the single-payer healthcare system. Place and cause of death, as well as health services and costs within 90 days of death, were compared between the amputee and control cohorts. Among amputees, multivariable regression models were used to characterize the association between receipt of home palliative care and in-hospital death, as well as time spent in hospital at the end of life. RESULTS: Compared with 213 300 controls, 3113 amputees were less likely to die at home (15·5 versus 24·9 per cent; P < 0·001) and spent a greater number of their last 90 days of life in hospital (median 19 versus 8 days; P < 0·001). Amputees also had higher end-of-life healthcare costs across all sectors. However, receipt of palliative care was less frequent among amputees than controls (inpatient: 13·4 versus 16·8 per cent, P < 0·001; home: 14·5 versus 23·8 per cent, P < 0·001). Among amputees, receipt of home palliative care was associated with a lower likelihood of in-hospital death (odds ratio 0·49, 95 per cent c.i. 0·40 to 0·60) and fewer days in hospital (rate ratio 0·84, 0·76 to 0·93). CONCLUSION: Palliative care is underused after amputation in patients with PAD or diabetes, and could contribute to reducing in-hospital death and time spent in hospital at the end of life.

ANTECEDENTES: Caracterizar la atención al final de la vida en pacientes con amputación de la extremidad inferior por enfermedad arterial periférica (peripheral arterial disease, PAD) o diabetes. MÉTODOS: Se trata de un estudio de cohortes retrospectivo de base poblacional en sujetos fallecidos con PAD o diabetes en Ontario, Canadá (2011-2017). A partir de los registros sanitarios incluidos en un sistema de salud de una sola entidad pagadora, se identificaron los individuos con amputación de la extremidad inferior en los 3 años previos al fallecimiento y una cohorte control de fallecidos con PAD o diabetes sin amputación. Entre las cohortes de amputados y controles se comparó el lugar del fallecimiento y la causa, así como el uso de servicios sanitarios y costes en los últimos 90 días de vida. En el grupo de los amputados, se utilizaron modelos de regresión para caracterizar la asociación entre recibir cuidados paliativos domiciliarios y el fallecimiento en el hospital, así como los días de estancia hospitalaria al final de la vida. RESULTADOS: En comparación con los controles (n = 213.300), los sujetos con amputación (n = 3.113) era menos probable que fallecieran en el domicilio (16% versus 25%, P < 0,001) y pasaron un mayor número de sus últimos 90 días de vida en el hospital (mediana 19 versus 8 días, P < 0,001). Los costes de atención sanitaria al final de la vida en todos los sectores también fueron mayores para los amputados. Sin embargo, recibir cuidados paliativos fue menos frecuente en los amputados que en los controles (en el hospital 13% versus 17%, P < 0,001; domiciliarios 14% versus 24%, P < 0,001). En el grupo de los amputados, recibir cuidados paliativos domiciliarios se asociaba con una menor probabilidad de fallecimiento en el hospital (razón de oportunidades, odds ratio 0,49, i.c. del 95% 0,40-0,60) y menos días de hospitalización (tasa de riesgo 0,84, i.c. del 95% 0,76-0,93). CONCLUSIÓN: Los cuidados paliativos están infrautilizados en pacientes con PAD o diabetes y pueden contribuir a disminuir los fallecimientos en el hospital y los días de hospitalización al final de la vida.

Synovial fluid cell counts and its role in the diagnosis of paediatric septic arthritis.

PURPOSE: Clinical presentation of paediatric septic arthritis (SA) can be similar to other joint pathologies. Despite potential for infection in all major joints, most diagnostic criteria are based on values from the hip. This study identifies the best joint aspirate values in diagnosing SA in all joints. METHODS: In all, 166 patients who underwent 172 joint aspirations at the authors' institution between 01 September 2004 and 01 September 2014 were retrospectively identified. Recorded measures included age, sex, duration of symptoms, fever history, weight-bearing status, aspiration results, serum results and antibiotic administration. Patients were placed in the following four categories: 'culture confirmed SA' (C-SA), 'suspected SA' (S-SA), 'Other' and 'Other-rheumatologic' (Other-R), a subcategory of 'Other'. RESULTS: Most common sites of aspiration were the knee (55%) and hip (29%). Diagnostic grouping was as follows: C-SA = 44, S-SA = 45, Other = 83 (Other-R = 21). Fever and non-weight-bearing prior to admission were useful predictors of SA, though in C-SA patients, 21% did not have a fever and 23% could weight bear at the time of admission. Aspirate white blood cell (WBC) count was significantly greater in both C-SA (92 000 cells/hpf) and S-SA (54 000) than in Other (10 000) and Other-R (18 000) patients. The percentage of polymorphonuclear (%PMN) was also significantly greater in C-SA (81.1%) and S-SA (80.9%) than in Other (57.9%) and Other-R (63.3%). CONCLUSION: Joint aspirate values, especially %PMN, are valuable in diagnosing SA. Additionally, antibiotics pre-aspiration did not affect %PMN, facilitating subsequent diagnosis of infection. Lastly, while aspirate WBC count was a valuable indicator of SA, this finding is not as definitive as previous research suggests. LEVEL OF EVIDENCE: IV Case Series.

The Unwound Cochlea: A Specific Imaging Marker of Branchio-Oto-Renal Syndrome.

BACKGROUND AND PURPOSE: Branchio-oto-renal syndrome is an important syndromic cause of hearing loss. Our aim was to determine the test characteristics of the unwound cochlea on temporal bone CT for the diagnosis of branchio-oto-renal syndrome in a cohort of children with hearing loss. MATERIALS AND METHODS: Patients were identified retrospectively with a clinical diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. Age-matched controls were also identified with sensorineural hearing loss not related to a diagnosis of branchio-oto-renal syndrome and CT imaging of the temporal bones. All examinations were reviewed by 2 neuroradiologists blinded to the diagnosis of branchio-oto-renal syndrome versus controls for the absence/presence of an unwound cochlea defined as anteromedial rotation and displacement of the middle and apical turns away from the basal turn. RESULTS: The final study group comprised 9 patients with branchio-oto-renal syndrome (age range, 1-14 years; mean age, 8.0 ± 4.3 years) and 50 control patients (age range, 1-16 years; mean age, 7.9 ± 4.1 years). The cochlea was subjectively abnormal in all 9 patients. In 8 patients (89%), imaging demonstrated a typical unwound cochlear morphology. By contrast, none of the control subjects demonstrated an unwound cochlea on either side. Statistically, the unwound cochlea was significantly more frequent in the branchio-oto-renal group compared with controls (P < .001). The unwound cochlea was 89% sensitive and 100% specific for the diagnosis of branchio-oto-renal syndrome. CONCLUSIONS: The unwound cochlea is a specific imaging marker of branchio-oto-renal syndrome. These findings further support the diagnostic accuracy and therefore the utility of temporal bone imaging in the diagnosis of this disorder.

Blood clotting and traumatic injury with shock mediates complement-dependent neutrophil priming for extracellular ROS, ROS-dependent organ injury and coagulopathy.

Polymorphonuclear (PMN) leucocytes participate in acute inflammatory pathologies such as acute respiratory distress syndrome (ARDS) following traumatic injury and shock, which also activates the coagulation system systemically. Trauma can prime the PMN nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex for an enhanced respiratory burst, but the relative role of various priming agents in this process remains incompletely understood. We therefore set out to identify mediators of PMN priming during coagulation and trauma-shock and determine whether PMN reactive oxygen species (ROS) generated in this manner could influence organ injury and coagulation. Initial experiments demonstrated that PMN are primed for predominantly extracellular ROS production by products of coagulation, which was abrogated by CD88/C5a receptor(C5aR) inhibition. The importance of this was highlighted further by demonstrating that known PMN priming agents result in fractionally different amounts of extracellular versus intracellular ROS release depending on the agent used. Plasma from trauma patients in haemodynamic shock (n = 10) also primed PMN for extracellular ROS in a C5a-dependent manner, which correlated with both complement alternative pathway activation and thrombin generation. Furthermore, PMN primed by preincubation with products of blood coagulation directly caused loss of endothelial barrier function in vitro that was abrogated by C5aR blockade or NADPH oxidase inhibition. Finally, we show in a murine model of trauma-shock that p47phox knock-out (KO) mice with PMN incapable of generating ROS were protected from inflammatory end-organ injury and activated protein C-mediated coagulopathy. In summary, we demonstrate that trauma-shock and coagulation primes PMN for predominantly extracellular ROS production in a C5a-dependent manner that contributes to endothelial barrier loss and organ injury, and potentially enhances traumatic coagulopathy.

A pathogenic role for tumor necrosis factor-related apoptosis-inducing ligand in chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a life-threatening inflammatory respiratory disorder, often induced by cigarette smoke (CS) exposure. The development of effective therapies is impaired by a lack of understanding of the underlining mechanisms. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a cytokine with inflammatory and apoptotic properties. We interrogated a mouse model of CS-induced experimental COPD and human tissues to identify a novel role for TRAIL in COPD pathogenesis. CS exposure of wild-type mice increased TRAIL and its receptor messenger RNA (mRNA) expression and protein levels, as well as the number of TRAIL(+)CD11b(+) monocytes in the lung. TRAIL and its receptor mRNA were also increased in human COPD. CS-exposed TRAIL-deficient mice had decreased pulmonary inflammation, pro-inflammatory mediators, emphysema-like alveolar enlargement, and improved lung function. TRAIL-deficient mice also developed spontaneous small airway changes with increased epithelial cell thickness and collagen deposition, independent of CS exposure. Importantly, therapeutic neutralization of TRAIL, after the establishment of early-stage experimental COPD, reduced pulmonary inflammation, emphysema-like alveolar enlargement, and small airway changes. These data provide further evidence for TRAIL being a pivotal inflammatory factor in respiratory diseases, and the first preclinical evidence to suggest that therapeutic agents that target TRAIL may be effective in COPD therapy.

Lower Respiratory Tract Adenoid Cystic Carcinoma: Its Management in the Past Decades.

AIMS: Adenoid cystic carcinoma of the lower respiratory tract is a rare indolent neoplasm with prolonged survival, propensity for recurrences and metastasis years after initial therapy. We aim to study a 1,700-bed single tertiary academic hospital's long-term experience with ACC of the lower respiratory tract from the larynx to the lungs and review published literature on this subject. MATERIALS AND METHODS: We analysed the clinicopathology, treatment options and outcome in 33 patients and reviewed the published literature over the last five decades. RESULTS: The tumour has no gender predilection, a peak incidence in the fifth decade and is not related to smoking. Insidious symptoms are often treated as benign obstructive airway disease and infection; negative signs and normal chest X-rays delayed diagnosis. The tumour was distributed most commonly in the trachea followed by main bronchi, lobar bronchi and larynx. About 22% of patients required emergent bronchoscopic intervention to secure airway patency before definitive therapy with surgery or/and radiotherapy. A high proportion of resected specimens had positive margins. Overall survival and disease-free survival rates at 5 years were 81 and 62%, respectively, and at 10 years 70 and 54%, respectively. Prolonged good palliation was achieved for patients with unresectable lesions with radiation and wide armamentarium of endoscopic therapy. CONCLUSIONS: In time, many patients eventually succumb to this disease. However, advances in medical skill and technology have prolonged survival while maintaining a good quality of life. Adenoid cystic carcinoma of the respiratory tract is a chronic life-long disease that may require interval intensive therapy. The challenge is to find the best therapeutic regimen aiming for a 'true' cure. Further study on the mutational landscape of adenoid cystic carcinoma may provide potential avenues for novel treatments to address a chemoresistant cancer.

Quantifying renal allograft loss following early antibody-mediated rejection.

Unlike antibody-mediated rejection (AMR) with clinical features, it remains unclear whether subclinical AMR should be treated, as its effect on allograft loss is unknown. It is also uncertain if AMR's effect is homogeneous across donor (deceased/live) and (HLA/ABO) antibody types. We compared 219 patients with AMR (77 subclinical, 142 clinical) to controls matched on HLA/ABO-compatibility, donor type, prior transplant, panel reactive antibody (PRA), age and year. One and 5-year graft survival in subclinical AMR was 95.9% and 75.7%, compared to 96.8% and 88.4% in matched controls (p = 0.0097). Subclinical AMR was independently associated with a 2.15-fold increased risk of graft loss (95% CI: 1.19-3.91; p = 0.012) compared to matched controls, but not different from clinical AMR (p = 0.13). Fifty three point two percent of subclinical AMR patients were treated with plasmapheresis within 3 days of their AMR-defining biopsy. Treated subclinical AMR patients had no difference in graft loss compared to matched controls (HR 1.73; 95% CI: 0.73-4.05; p = 0.21), but untreated subclinical AMR patients did (HR 3.34; 95% CI: 1.37-8.11; p = 0.008). AMR's effect on graft loss was heterogeneous when stratified by compatible deceased donor (HR = 4.73; 95% CI: 1.57-14.26; p = 0.006), HLA-incompatible deceased donor (HR = 2.39; 95% CI: 1.10-5.19; p = 0.028), compatible live donor (no AMR patients experienced graft loss), ABO-incompatible live donor (HR = 6.13; 95% CI: 0.55-67.70; p = 0.14) and HLA-incompatible live donor (HR = 6.29; 95% CI: 3.81-10.39; p < 0.001) transplant. Subclinical AMR substantially increases graft loss, and treatment seems warranted.

Cementless total knee replacement fixation: a contemporary durable solution--affirms.

A retrospective review was performed of patients undergoing primary cementless total knee replacement (TKR) using porous tantalum performed by a group of surgical trainees. Clinical and radiological follow-up involved 79 females and 26 males encompassing 115 knees. The mean age was 66.9 years (36 to 85). Mean follow-up was 7 years (2 to 11). Tibial and patellar components were porous tantalum monoblock implants, and femoral components were posterior stabilised (PS) in design with cobalt-chromium fibre mesh. Radiological assessments were made for implant positioning, alignment, radiolucencies, lysis, and loosening. There was 95.7% survival of implants. There was no radiological evidence of loosening and no osteolysis found. No revisions were performed for aseptic loosening. Average tibial component alignment was 1.4° of varus (4°of valgus to 9° varus), and 6.2° (3° anterior to 15° posterior) of posterior slope. Mean femoral component alignment was 6.6° (1° to 11°) of valgus. Mean tibiofemoral alignment was 5.6° of valgus (7° varus to 16° valgus). Patellar tilt was a mean of 2.4° lateral (5° medial to 28° lateral). Patient satisfaction with improvement in pain was 91%. Cementless TKR incorporating porous tantalum yielded good clinical and radiological outcomes at a mean of follow-up of seven-years.

TLR3 and MDA5 signalling, although not expression, is impaired in asthmatic epithelial cells in response to rhinovirus infection.

BACKGROUND: Rhinoviruses (RV) are the most common acute triggers of asthma, and airway epithelial cells are the primary site of infection. Asthmatic bronchial epithelial cells (BECs) have been found to have impaired innate immune responses to RV. RV entry and replication is recognized by pathogen recognition receptors (PRRs), specifically toll-like receptor (TLR)3 and the RNA helicases; retinoic acid-inducible gene I (RIG-I) and melanoma differentiation-associated gene 5 (MDA5). OBJECTIVE: Our aim was to assess the relative importance of these PRRs in primary bronchial epithelial cells (pBEC) from healthy controls and asthmatics following RV infection and determine whether deficient innate immune responses in asthmatic pBECs were due to abnormal signalling via these PRRs. METHODS: The expression patterns and roles of TLR3 and MDA5 were investigated using siRNA knock-down, with subsequent RV1B infection in pBECs from each patient group. We also used BX795, a specific inhibitor of TBK1 and IKKi. RESULTS: Asthmatic pBECs had significantly reduced release of IL-6, CXCL-8 and IFN-λ in response to RV1B infection compared with healthy pBECs. In healthy pBECs, siMDA5, siTLR3 and BX795 all reduced release of IL-6, CXCL-10 and IFN-λ to infection. In contrast, in asthmatic pBECs where responses were already reduced, there was no further reduction in IL-6 and IFN-λ, although there was in CXCL-10. CONCLUSION AND CLINICAL RELEVANCE: Impaired antiviral responses in asthmatic pBECs are not due to deficient expression of PRRs; MDA5 and TLR3, but an inability to later activate types I and III interferon immune responses to RV infection, potentially increasing susceptibility to the effects of RV infection.

Quality standards for DNA sequence variation databases to improve clinical management under development in Australia.

Despite the routine nature of comparing sequence variations identified during clinical testing to database records, few databases meet quality requirements for clinical diagnostics. To address this issue, The Royal College of Pathologists of Australasia (RCPA) in collaboration with the Human Genetics Society of Australasia (HGSA), and the Human Variome Project (HVP) is developing standards for DNA sequence variation databases intended for use in the Australian clinical environment. The outputs of this project will be promoted to other health systems and accreditation bodies by the Human Variome Project to support the development of similar frameworks in other jurisdictions.

Generalized verrucosis in a patient with GATA2 deficiency.

Generalized verrucosis is a characteristic of several genetic and immunodeficiency disorders including epidermodysplasia verruciformis; warts, hypogammaglobulinaemia, infections and myelokathexis (WHIM) syndrome; warts, immunodeficiency, lymphoedema and anogenital dysplasia (WILD) syndrome; severe combined immune deficiency and HIV, among others. In recent years, it has been consistently recognized in patients with GATA2 deficiency, a novel immunodeficiency syndrome characterized by monocytopenia, B-cell and natural killer-cell lymphopenia, and a tendency to develop myeloid leukaemias and disseminated mycobacterial, human papillomavirus (HPV) and opportunistic fungal infections. Mutations in GATA2 cause haploinsufficiency and track in families as an autosomal dominant immunodeficiency. GATA2 is a transcription factor involved in early haematopoietic differentiation and lymphatic and vascular development. We describe a case of generalized verrucosis with HPV type 57 presenting in a young man with GATA2 deficiency. GATA2 deficiency is a novel dominant immunodeficiency that is often recognized later in life and should be considered in the differential diagnosis of patients with generalized verrucosis.

Critical airway obstruction by mediastinal masses in the intensive care unit.

Critical airway obstruction is a dreaded complication of a mediastinal mass. The acute management is difficult and catastrophic outcomes have been reported. A total of 19 patients, aged between 13 and 69 years, who had critical major airway obstruction due to mediastinal mass requiring mechanical ventilation were reviewed. Three patients had benign pathologies (retrosternal goitre, bronchogenic cyst, giant left atrium) and three had lymphoma. The remaining patients had advanced malignancies: metastatic mediastinal lymphadenopathy (n=6), thyroid carcinoma (n=1) and oesophageal carcinoma (n=6). Three patients underwent surgery, three received chemotherapy and 15 had airway stenting under deep intravenous sedation. Apart from one patient who had brain haemorrhage and nosocomial infection after cardiac surgery, all other patients were successfully weaned off ventilation within five days after the interventions to alleviate the major airway obstruction without major complications. All patients were discharged from hospital without supplemental oxygen. Patients who had benign pathologies and lymphoma (n=6, 32%) were still alive after a mean follow-up period of six years (range 3 to 10) and those with metastatic disease died after a mean survival period of 3.3 months (range 1 to 9). In summary, critical major airway obstruction is caused by a heterogeneous group of mediastinal pathologies, and the definitive treatment and long-term prognosis of these patients are highly dependent on the underlying aetiology. Combining various therapeutic modalities can lead to successful separation of these patients from mechanical ventilation within a short period of time.

Physiologic load-bearing characteristics of autografts, allografts, and polymer-based scaffolds in a critical sized segmental defect of long bone: an experimental study.

BACKGROUND: To address the challenge of treating critical sized intercalary defects, we hypothesized that under physiologic cyclic loading, autografts, allografts, and scaffolds loaded with and without human mesenchymal stem cells (hMSCs) would have different biomechanical characteristics. METHODS: Using a rat femoral defect model, 46 rats were assigned to four groups, ie, autograft (n = 12), allograft (n = 10), scaffold (n = 13), and scaffold with hMSCs (n = 11). The scaffold groups used a 5 mm segment of scaffold composed of 80% poly-ε-caprolactone and 20% hydroxyapatite. Rats were sacrificed 4 months postoperatively, and the repairs were assessed radiographically and biomechanically. RESULTS: Autograft and allograft groups exhibited the most bridging callus, while the scaffold/hMSCs group had more callus than the scaffold repairs. Although signs of radiographic healing did not accurately reflect restoration of mechanical properties, addition of hMSCs on the scaffold enhanced bone formation. The scaffold alone group had significantly lower elastic and viscous stiffness and higher phase angles than other repairs and the contralateral controls. Addition of hMSCs increased the elastic and viscous stiffness of the repair, while decreasing the phase angle. CONCLUSION: Further comparative analysis is needed to optimize clinical use of scaffolds and hMSCs for critical sized defect repairs. However, our results suggest that addition of hMSCs to scaffolds enhances mechanical simulation of native host bone.

Interferon alpha treatment of patients with impaired interferon gamma signaling.

Patients with deficiency in the interferon gamma receptor (IFN-γR) are unable to respond properly to IFN-γ and develop severe infections with nontuberculous mycobacteria (NTM). IFN-γ and IFN-α are known to signal through STAT1 and activate many downstream effector genes in common. Therefore, we added IFN-α for treatment of patients with disseminated mycobacterial disease in an effort to complement their IFN-γ signaling defect. We treated four patients with IFN-γR deficiency with adjunctive IFN-α therapy in addition to best available antimicrobial therapy, with or without IFN-γ, depending on the defect. During IFN-α treatment, ex vivo induction of IFN target genes was detected. In addition, IFN-α driven gene expression in patients' cells and mycobacteria induced cytokine response were observed in vitro. Clinical responses varied in these patients. IFN-α therapy was associated with either improvement or stabilization of disease. In no case was disease exacerbated. In patients with profoundly impaired IFN-γ signaling who have refractory infections, IFN-α may have adjunctive anti-mycobacterial effects.

Thalidomide-analogue biology: immunological, molecular and epigenetic targets in cancer therapy.

Thalidomide and its analogues (lenalidomide and pomalidomide) are small molecule glutamic acid derivatives of the immunomodulatory drug (IMiD) class. In addition to the immuno-adjuvant and anti-inflammatory properties that define an IMiD, the thalidomide analogues demonstrate an overlapping and diverse range of biological activities, including anti-angiogenic, teratogenic and epigenetic effects. Importantly, the IMiDs possess anti-cancer activity with selectivity for molecularly defined subgroups of hematological malignancies, specifically mature B-cell neoplasms and myelodysplasia with deletion of chromosome 5q. Emerging insight into the pathophysiological drivers of these IMiD-responsive disease states can now be synthesized using previously disclosed IMiD activities and recently discovered thalidomide targets to build unifying models of IMiD mechanism of action. Attention to mechanisms of IMiD-induced clinical toxicities, in particular the recently identified association of lenalidomide with second primary malignancies, provides an additional tool for determination of drug mechanism. This review seeks to define the molecular IMiD targets and biological outputs that underpin their anti-neoplastic activity. It is anticipated that elucidation of important IMiD targets will allow the rational development of new-generation therapeutics with the potential to separate thalidomide-analogue efficacy from clinical toxicity.