Wrist Arthrodesis Using the Medartis Carpometacarpal Joint Sparing Plate.

BACKGROUND: Total wrist arthrodesis is a well-established surgical technique that provides reliable pain relief in patients with advanced wrist disease. Key limitations of existing plating systems include hardware pull-out, hardware failure, and nonunion. There is limited literature on the newer style carpometacarpal joint (CMCJ) sparing plating system, produced by Medartis. The objective of this study was to determine the long-term clinical and radiological outcomes of wrist arthrodesis with a CMCJ sparing wrist plate. METHODS: This study retrospectively identified 23 wrist arthrodeses using the Medartis CMCJ sparing plate for review. This study assessed the outcomes of 18 unilateral wrist fusions and 1 bilateral wrist fusion. The study group consisted of 12 men and 5 women with an average age of 56 years (range: 29-82 years) with a mean follow-up period of 17 months. RESULTS: At the time of follow-up, all patients' wrists had fused without postsurgical complication. The final grip strength in the operative hand was 28.2 kg/cm2, which was 87% of the contralateral side. The mean Quick Disabilities of the Arm, Shoulder, and Hand score at follow-up was 23.9, with all patients returning to daily living activities and work. Patients reported minimal pain (1.3/10), with almost all (17/18) satisfied with the outcome of the surgery and describing that they would recommend this procedure. CONCLUSION: Our case series highlights that the Medartis wrist arthrodesis plate is a newer design that is a well-tolerated option for wrist arthrodesis based on clinical assessment, functional hand assessment, and patient satisfaction, when compared with the existing literature on traditional plating systems.

Bilateral recurrent laryngeal nerve palsy following anterior cervical surgery subsequent to contralateral apical lung radiotherapy.

Unilateral recurrent laryngeal nerve palsy is a potential complication of the anterior approach for cervical surgery. It is a rare complication of radiotherapy to the neck. Only one case has been reported following radiotherapy apical lung cancer. It can result in unilateral vocal cord paralysis. We report a patient who demonstrated bilateral vocal cord paralysis immediately following right-sided anterior cervical surgery, with significant consequences, including aphonia, respiratory distress and subsequent takotsubo cardiomyopathy. She was diagnosed with acute, (temporary) post-operative right recurrent laryngeal nerve palsy, on the background of undetected and previously asymptomatic left recurrent laryngeal nerve palsy following radiotherapy for left apical lung cancer. The possibility of recurrent laryngeal nerve palsy should be considered in patients with previous apical lung cancer and/ or radiotherapy. Patents undergoing subsequent anterior cervical surgery should be considered for the appropriate precautions in the form of same-side surgery or pre-operative investigation for vocal cord paralysis.

Conditional disruption of AMP kinase in dopaminergic neurons promotes Parkinson's disease-associated phenotypes in vivo.

Emerging studies implicate energy dysregulation as an underlying trigger for Parkinson's disease (PD), suggesting that a better understanding of the molecular pathways governing energy homeostasis could help elucidate therapeutic targets for the disease. A critical cellular energy regulator is AMP kinase (AMPK), which we have previously shown to be protective in PD models. However, precisely how AMPK function impacts on dopaminergic neuronal survival and disease pathogenesis remains elusive. Here, we showed that Drosophila deficient in AMPK function exhibits PD-like features, including dopaminergic neuronal loss and climbing impairment that progress with age. We also created a tissue-specific AMPK-knockout mouse model where the catalytic subunits of AMPK are ablated in nigral dopaminergic neurons. Using this model, we demonstrated that loss of AMPK function promotes dopaminergic neurodegeneration and associated locomotor aberrations. Accompanying this is an apparent reduction in the number of mitochondria in the surviving AMPK-deficient nigral dopaminergic neurons, suggesting that an impairment in mitochondrial biogenesis may underlie the observed PD-associated phenotypes. Importantly, the loss of AMPK function enhances the susceptibility of nigral dopaminergic neurons in these mice to 6-hydroxydopamine-induced toxicity. Notably, we also found that AMPK activation is reduced in post-mortem PD brain samples. Taken together, these findings highlight the importance of neuronal energy homeostasis by AMPK in PD and position AMPK pathway as an attractive target for future therapeutic exploitation.

Lessons from the host defences of bats, a unique viral reservoir.

There have been several major outbreaks of emerging viral diseases, including Hendra, Nipah, Marburg and Ebola virus diseases, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS)-as well as the current pandemic of coronavirus disease 2019 (COVID-19). Notably, all of these outbreaks have been linked to suspected zoonotic transmission of bat-borne viruses. Bats-the only flying mammal-display several additional features that are unique among mammals, such as a long lifespan relative to body size, a low rate of tumorigenesis and an exceptional ability to host viruses without presenting clinical disease. Here we discuss the mechanisms that underpin the host defence system and immune tolerance of bats, and their ramifications for human health and disease. Recent studies suggest that 64 million years of adaptive evolution have shaped the host defence system of bats to balance defence and tolerance, which has resulted in a unique ability to act as an ideal reservoir host for viruses. Lessons from the effective host defence of bats would help us to better understand viral evolution and to better predict, prevent and control future viral spillovers. Studying the mechanisms of immune tolerance in bats could lead to new approaches to improving human health. We strongly believe that it is time to focus on bats in research for the benefit of both bats and humankind.

Complementary regulation of caspase-1 and IL-1ß reveals additional mechanisms of dampened inflammation in bats.

Bats have emerged as unique mammalian vectors harboring a diverse range of highly lethal zoonotic viruses with minimal clinical disease. Despite having sustained complete genomic loss of AIM2, regulation of the downstream inflammasome response in bats is unknown. AIM2 sensing of cytoplasmic DNA triggers ASC aggregation and recruits caspase-1, the central inflammasome effector enzyme, triggering cleavage of cytokines such as IL-1ß and inducing GSDMD-mediated pyroptotic cell death. Restoration of AIM2 in bat cells led to intact ASC speck formation, but intriguingly resulted in a lack of caspase-1 or consequent IL-1ß activation. We further identified two residues undergoing positive selection pressures in Pteropus alecto caspase-1 that abrogate its enzymatic function and are crucial in human caspase-1 activity. Functional analysis of another bat lineage revealed a targeted mechanism for loss of Myotis davidii IL-1ß cleavage and elucidated an inverse complementary relationship between caspase-1 and IL-1ß, resulting in overall diminished signaling across bats of both suborders. Thus we report strategies that additionally undermine downstream inflammasome signaling in bats, limiting an overactive immune response against pathogens while potentially producing an antiinflammatory state resistant to diseases such as atherosclerosis, aging, and neurodegeneration.

PGE1 and PGA1 bind to Nurr1 and activate its transcriptional function.

The orphan nuclear receptor Nurr1 is critical for the development, maintenance and protection of midbrain dopaminergic (mDA) neurons. Here we show that prostaglandin E1 (PGE1) and its dehydrated metabolite, PGA1, directly interact with the ligand-binding domain (LBD) of Nurr1 and stimulate its transcriptional function. We also report the crystallographic structure of Nurr1-LBD bound to PGA1 at 2.05 Å resolution. PGA1 couples covalently to Nurr1-LBD by forming a Michael adduct with Cys566, and induces notable conformational changes, including a 21° shift of the activation function-2 helix (H12) away from the protein core. Furthermore, PGE1/PGA1 exhibit neuroprotective effects in a Nurr1-dependent manner, prominently enhance expression of Nurr1 target genes in mDA neurons and improve motor deficits in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned mouse models of Parkinson's disease. Based on these results, we propose that PGE1/PGA1 represent native ligands of Nurr1 and can exert neuroprotective effects on mDA neurons, via activation of Nurr1's transcriptional function.

Effectiveness of telemonitoring-enhanced support over structured telephone support in reducing heart failure-related healthcare utilization in a multi-ethnic Asian setting.

AIMS: Our study aimed to compare the effectiveness of telemonitoring over structured telephone support in reducing heart failure-related healthcare utilization. METHODS: This was a non-randomised controlled study comparing 150 recently discharged heart failure patients enrolled into telemonitoring and 55 patients who only received structured telephone support after rejecting telemonitoring. Patient activation, knowledge and self-management levels were measured at baseline and the one year upon programme completion using the Patient Activation Measure, the Dutch Heart Failure Knowledge Scale and the Self-Care of Heart Failure Index respectively. Differences in heart failure-related and all-cause hospitalization rates, total bed days and mortality rates at 180 days and at one year, knowledge and self-management scores and total cost of care between groups at one year were analysed. RESULTS: Average age of telemonitoring was 57.9 years and 63.9 years for structured telephone support. Significant difference in adjusted 180-day all-cause bed days (telemonitoring: five days versus structured telephone support: 9.8 days), heart failure-related bed days (telemonitoring: 1.2 days versus structured telephone support: six days) and adjusted one-year heart failure-related bed days (telemonitoring: 2.2 days versus structured telephone support: 6.6 days) were observed. Telemonitoring was associated with reduced all-cause one-year mortality (hazard ratio 0.32, p = 0.02). Estimated mean maintenance and confidence scores were significantly higher in the telemonitoring group at one year. No differences in all-cause and HF-related readmission rates and knowledge levels were observed. The one-year total cost of care was predicted to be Singapore dollars (SG$) 2774.4 lower (p = 0.07) in telemonitoring. CONCLUSION: In conclusion, telemonitoring was associated with lower all-cause and heart failure-related total bed days at 180 days, lower heart failure-related total bed days and total cost of care at one year as compared with structured telephone support.

Cost Savings and Efficacy in Management of Paracetamol Poisoning in a 23-hours Emergency Department Observation Unit: A Comparison to Inpatient Care.

Introduction Emergency department observation units (EDOU) have been shown to be effective in decreasing hospitalization rates and length of stay (LOS) for various conditions. However, cost savings and efficacy in the management of poisoning in EDOU have not been widely studied. The objective of our study is to compare the costs and effectiveness of managing paracetamol poisoned patients in the EDOU with those treated in the inpatient wards. Methods We conducted a historical controlled observational study comparing paracetamol-poisoned patients (who received at least 21 hours of IV N-acetylcysteine [NAC]) admitted to the EDOU during 2013-2014 with similar patients admitted to inpatient ward during 2011, 2013-2014.  Results We found 136 patients admitted to the inpatient ward and 95 to our EDOU due to paracetamol poisoning but only 78 and 39 patients respectively fulfilled the inclusion criteria. Between the EDOU and inpatient ward groups, we found similar demographics, poisoning presentation, treatment, and adverse event profiles. There were no fatalities and only two patients (one from each group) developed hepatotoxicity. The "medical" length of stay was 31.9 hours shorter in the EDOU group compared to the inpatient ward group (23.3 versus 55.2 hours). EDOU patients have statistically significant savings (comparing bill size) of S$784 per patient. Conclusions Admission to the EDOU resulted in significant cost savings and 58% decreased LOS when compared to inpatient wards. The EDOU is a cost-effective and safe alternative for the management of selected paracetamol poisonings requiring NAC. Further studies would be needed to verify these results.

Economic Evaluation of Nutrition Support in the Prevention and Treatment of Pressure Ulcers in Acute and Chronic Care Settings: A Systematic Review.

BACKGROUND: Recent developments in nutrition intervention indicated clinical effectiveness for pressure ulcer (PU) prevention and treatment, but it is important to assess whether they are cost-effective. The aims of this systematic review are to determine the cost-effectiveness and clinical outcomes of nutrition support in PU prevention and treatment. METHODS: A systematic search of randomized controlled trials, observational studies, and statistical models that investigated cost-effectiveness and economic outcomes for prevention and/or treatment of PUs were performed using standard literature and electronic databases. RESULTS: Fourteen studies met the inclusion criteria, which included 3 randomized controlled trials with their companion economic evaluations, 4 model-based, 2 cohort, 1 pre and post, and 1 prospective controlled trial. Risk of bias assessment for all of the uncontrolled or observational trials revealed high or serious risk of bias. Interventions that incorporated specialized nursing care appeared to be more effective in prevention and treatment of PUs, compared with single intervention studies. There is a trend of improved PU healing when additional energy/protein are provided. PU prevention ($250-$9,800) was less expensive than treatment ($2,500-$16,000). Nutrition intervention for PU prevention was cost-effective in 87.0%-99.99% of the simulation models. CONCLUSIONS: There is potential cost-saving and/or cost-effectiveness of nutrition support in the long term, as predicted by the model-based PU prevention studies in the review. Prevention of PU also appears to be more cost-effective than treatment. A multidisciplinary approach to managing PU is more likely to be cost-effective.

AMP Kinase Activation is Selectively Disrupted in the Ventral Midbrain of Mice Deficient in Parkin or PINK1 Expression.

Parkinson's disease (PD) is a prevalent neurodegenerative movement disorder that is characterized pathologically by the progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) of the midbrain. Despite intensive research, the etiology of PD remains poorly understood. Interestingly, recent studies have implicated neuronal energy dysregulation as one of the key perpetrators of the disease. Supporting this, we have recently demonstrated that pharmacological or genetic activation of AMP kinase (AMPK), a master regulator of cellular energy homeostasis, rescues the pathological phenotypes of Drosophila models of PD. However, little is known about the role of AMPK in the mammalian brain. As an initial attempt to clarify this, we examined the expression of AMPK in rodent brains and found that phospho-AMPK (pAMPK) is disproportionately distributed in the adult mouse brain, being high in the ventral midbrain where the SN resides and relatively lower in regions such as the cortex-reflecting perhaps the unique energy demands of midbrain DA neurons. Importantly, the physiologically higher level of midbrain pAMPK is significantly reduced in aged mice and also in Parkin-deficient mice; the loss of function of which in humans causes recessive Parkinsonism. Not surprisingly, the expression of PGC-1α, a downstream target of AMPK activity, and a key regulator of mitochondrial biogenesis, mirrors the expression pattern of pAMPK. Similar observations were made with PINK1-deficient mice. Finally, we showed that metformin administration restores the level of midbrain pAMPK and PGC-1α expression in Parkin-deficient mice. Taken together, our results suggest that the disruption of AMPK-PGC-1α axis in the brains of individuals with Parkin or PINK1 mutations may be a precipitating factor of PD, and that pharmacological AMPK activation may represent a neuroprotective strategy for the disease.

Dampened STING-Dependent Interferon Activation in Bats.

Compared with terrestrial mammals, bats have a longer lifespan and greater capacity to co-exist with a variety of viruses. In addition to cytosolic DNA generated by these viral infections, the metabolic demands of flight cause DNA damage and the release of self-DNA into the cytoplasm. However, whether bats have an altered DNA sensing/defense system to balance high cytosolic DNA levels remains an open question. We demonstrate that bats have a dampened interferon response due to the replacement of the highly conserved serine residue (S358) in STING, an essential adaptor protein in multiple DNA sensing pathways. Reversing this mutation by introducing S358 restored STING functionality, resulting in interferon activation and virus inhibition. Combined with previous reports on bat-specific changes of other DNA sensors such as TLR9, IFI16, and AIM2, our findings shed light on bat adaptation to flight, their long lifespan, and their unique capacity to serve as a virus reservoir.

Barriers to dispatcher-assisted cardiopulmonary resuscitation in Singapore.

BACKGROUND: Dispatcher-assisted cardiopulmonary resuscitation (DA-CPR) is effective in increasing bystander CPR in out-of-hospital cardiac arrests (OHCA). Singapore has recently implemented a DA-CPR program. We aimed to characterize barriers to commencement of chest compressions by callers in Singapore. METHODS: We analyzed dispatch recordings of OHCA cases received by the ambulance call center between July 2012 and March 2015. Audio recordings of poor quality were excluded. Trained reviewers noted the sequential stages of the dispatcher's recognition of CPR, delivering CPR instructions and caller performing CPR. Time taken to reach these milestones was noted. Barriers to chest compressions were identified. RESULTS: A total of 4897 OHCA occurred during the study period, overall bystander CPR rate was 45.7%. 1885 dispatch recordings were reviewed with 1157 cases qualified for dispatcher CPR. In 1128 (97.5%) cases, the dispatcher correctly recognized the need for CPR. CPR instructions were delivered in 1056 (91.3%) cases. Of these, 1007 (87.0%) callers performed CPR to instruction. One or more barriers to chest compressions were identified in 430 (37.2%) cases. The commonest barrier identified was "could not move patient" (27%). Cases where barriers were identified were less likely to have the need for CPR recognized by the dispatcher (94.9% vs. 99.0%, p<0.001), CPR instructions given (79.3% vs. 98.3%, p<0.001) and CPR started (67.9% vs. 98.3%, p<0.001), while the time taken to reach each of these stages were significantly longer (p<0.001). CONCLUSION: Barriers were present in 37% of cases. They were associated with lower proportion of CPR started and longer delay to CPR.

Radiological and histopathological examination of apparent lytic lesions in allograft long bones-No cause for concern.

OBJECTIVE: Identify the nature of apparent lytic lesions within human allograft specimens from patients with no known malignancy, using radiological and histopathological analysis. METHODS: 123 Post-retrieval radiographs from 23 donors were examined. Sixty-seven radiographs were noted to show apparent lytic lesions. The number, size, character and position of the apparent lesions were recorded. RESULTS: CT scanning of 9 specimens confirmed the lesions to be of air pockets causing artefact. Histopathological analysis showed no malignant or pathological process. CONCLUSIONS: Apparent lesions were not pathological. PRACTICE IMPLICATIONS: Specimens with similar appearances, in donors with no malignancy, can be safely used in donation.