SARS-CoV-2 Breakthrough Infections among US Embassy Staff Members, Uganda, May-June 2021.

The SARS-CoV-2 Delta variant emerged shortly after COVID-19 vaccines became available in 2021. We describe SARS-CoV-2 breakthrough infections in a highly vaccinated, well-monitored US Embassy community in Kampala, Uganda. Defining breakthrough infection rates in highly vaccinated populations can help determine public health messaging, guidance, and policy globally.

Role of calpains in the injury-induced dysfunction and degeneration of the mammalian axon.

Axonal injury and degeneration, whether primary or secondary, contribute to the morbidity and mortality seen in many acquired and inherited central nervous system (CNS) and peripheral nervous system (PNS) disorders, such as traumatic brain injury, spinal cord injury, cerebral ischemia, neurodegenerative diseases, and peripheral neuropathies. The calpain family of proteases has been mechanistically linked to the dysfunction and degeneration of axons. While the direct mechanisms by which transection, mechanical strain, ischemia, or complement activation trigger intra-axonal calpain activity are likely different, the downstream effects of unregulated calpain activity may be similar in seemingly disparate diseases. In this review, a brief examination of axonal structure is followed by a focused overview of the calpain family. Finally, the mechanisms by which calpains may disrupt the axonal cytoskeleton, transport, and specialized domains (axon initial segment, nodes, and terminals) are discussed.

Calpains mediate axonal cytoskeleton disintegration during Wallerian degeneration.

In both the central nervous system (CNS) and peripheral nervous system (PNS), transected axons undergo Wallerian degeneration. Even though Augustus Waller first described this process after transection of axons in 1850, the molecular mechanisms may be shared, at least in part, by many human diseases. Early pathology includes failure of synaptic transmission, target denervation, and granular disintegration of the axonal cytoskeleton (GDC). The Ca(2+)-dependent protease calpains have been implicated in GDC but causality has not been established. To test the hypothesis that calpains play a causal role in axonal and synaptic degeneration in vivo, we studied transgenic mice that express human calpastatin (hCAST), the endogenous calpain inhibitor, in optic and sciatic nerve axons. Five days after optic nerve transection and 48 h after sciatic nerve transection, robust neurofilament proteolysis observed in wild-type controls was reduced in hCAST transgenic mice. Protection of the axonal cytoskeleton in sciatic nerves of hCAST mice was nearly complete 48 h post-transection. In addition, hCAST expression preserved the morphological integrity of neuromuscular junctions. However, compound muscle action potential amplitudes after nerve transection were similar in wild-type and hCAST mice. These results, in total, provide direct evidence that calpains are responsible for the morphological degeneration of the axon and synapse during Wallerian degeneration.

Calpain mediates proteolysis of the voltage-gated sodium channel alpha-subunit.

Alterations in the expression, molecular composition, and localization of voltage-gated sodium channels play major roles in a broad range of neurological disorders. Recent evidence identifies sodium channel proteolysis as a key early event after ischemia and traumatic brain injury, further expanding the role of the sodium channel in neurological diseases. In this study, we investigate the protease responsible for proteolytic cleavage of voltage-gated sodium channels (NaChs). NaCh proteolysis occurs after protease activation in rat brain homogenates, pharmacological disruption of ionic homeostasis in cortical cultures, and mechanical injury using an in vitro model of traumatic brain injury. Proteolysis requires Ca(2+) and calpain activation but is not influenced by caspase-3 or cathepsin inhibition. Proteolysis results in loss of the full-length alpha-subunits, and the creation of fragments comprising all domains of the channel that retain interaction even after proteolysis. Cell surface biotinylation after mechanical injury indicates that proteolyzed NaChs remain in the membrane before noticeable evidence of neuronal death, providing a mechanism for altered action potential initiation, propagation, and downstream signaling events after Ca(2+) elevation.

Neuroprotection with delayed calpain inhibition after transient forebrain ischemia.

OBJECTIVE: Delayed neurodegeneration after transient global brain ischemia offers a therapeutic window for inhibiting molecular injury mechanisms. One such mechanism is calpain-mediated proteolysis, which peaks 24 to 48 hrs after transient forebrain ischemia in rats. This study tests the hypothesis that delayed calpain inhibitor therapy can reduce brain calpain activity and neurodegeneration after transient forebrain ischemia. DESIGN: Prospective randomized placebo-controlled animal trial. SETTING: University research laboratory. SUBJECTS: Adult male Long-Evans rats. INTERVENTIONS: Rats subjected to 10-min transient forebrain ischemia were randomized to intravenous infusion of calpain inhibitor CEP-3453 or vehicle beginning 22 hrs after injury. MEASUREMENTS AND MAIN RESULTS: In a dose-response study, a 60 mg/kg bolus followed by 30 mg/kg infusion was required to reduce postischemic brain calpain activity measured by Western blot of hippocampal homogenates at 48 hrs after injury. The same dosing protocol decreased degeneration of CA1 pyramidal neurons measured at 72 hrs after injury. CONCLUSIONS: These results suggest a causal role for calpains in delayed postischemic neurodegeneration, and demonstrate a broad therapeutic window for calpain inhibition in this model.

Serum cleaved tau does not predict postconcussion syndrome after mild traumatic brain injury.

OBJECTIVES: Our objective was to determine if the biomarker for axonal injury, serum cleaved tau (C-tau), predicts postconcussion syndrome (PCS) in adults after mild traumatic brain injury (mTBI). METHODS: C-tau was measured from blood obtained in the emergency department. Outcome was assessed at 3 months post injury using the Rivermead Postconcussion Symptoms Questionnaire and Acute Medical Outcomes SF-36v2 Health Survey (SF-36). RESULTS: Of 50 patients, there were 15 patients with detectable levels of C-tau, 10 patients with abnormal findings on initial head computed tomography (CT) and 22 patients with PCS. One-third of patients with detectable C-tau and 14.3% of patients without detectable C-tau had abnormal findings on head CT (P = .143). Serum C-tau was not detected more frequently in patients with PCS than those without, neither for all patients (P = .115) nor the subgroup with negative head CT (P = .253). CONCLUSIONS: C-tau is a poor predictor of PCS after mTBI regardless of head CT result.

Ruptured femoral pseudoaneurysm presenting as a lateral abdominal wall hematoma.

Lateral abdominal wall hematomas are rare. We describe a patient with a delayed rupture of a femoral artery pseudoaneurysm, who presented with such a hematoma. In contrast to other types of abdominal wall hematomas, which are often managed conservatively, a ruptured femoral artery pseudoaneurysm frequently requires emergent surgical intervention. Rupture of a pseudoaneurysm can be catastrophic. Due to the rising incidence of femoral artery pseudoaneurysms and shorter hospital stays, it is useful for the emergency physician to be familiar with the diagnosis and management of femoral artery pseudoaneurysms and their potentially life-threatening complications.

Effect of education and guidelines for treatment of uncomplicated dental pain on patient and provider behavior.

STUDY OBJECTIVE: Patients with uncomplicated odontalgia use a significant proportion of emergency department (ED) resources. Some odontalgia patients are unaware that routine dental care is unavailable in most EDs. Using extensive input from regional dentists and oral surgeons, and after reviewing the dental literature, guidelines for the ED management of uncomplicated odontalgia were written for physician and patient use. The guidelines, which emphasize appropriate community dental clinic referrals and the use of nonsteroidal anti-inflammatory drugs, were developed to reflect community standard of care. We hypothesize that patient education and treatment guidelines will decrease the number of ED visits, return visits, and narcotic prescriptions written for odontalgia. METHODS: This retrospective, observational study used primary International Classification of Diseases, Ninth Revision codes to identify visits for odontalgia during the year before and the year after guideline implementation in a tertiary care teaching hospital with 161,181 ED visits during the 2-year period of our study. RESULTS: There were 5,930 visits for odontalgia during the study. The proportion (95% confidence interval [CI]) of visits with odontalgia decreased after guideline implementation from 4.3% (95% CI 4.2% to 4.5%) to 3.1% (95% CI 3.0% to 3.2%). The proportion of patients with return visits decreased from 19.8% (95% CI 18.1% to 21.6%) to 9.2% (95% CI 7.9% to 10.8%). The proportion of patients filling narcotic prescriptions for odontalgia decreased from 29.6% (95% CI 28.1% to 31.2%) to 9.5% (95% CI 8.5% to 10.8%). CONCLUSION: Implementing odontalgia guidelines and providing patients with written information about alternative treatments and a list of dental clinics can reduce the burden of uncomplicated odontalgia on EDs that do not provide routine dental care.

A case of Lemierre's syndrome.

Lemierre's syndrome is a rare but potentially life-threatening entity that follows an oropharyngeal infection. The syndrome is characterized by an antecedent acute oropharyngeal infection, with secondary suppurative thrombophlebitis of the internal jugular vein and septic emboli. In the pre-antibiotic era, it had a 90% mortality rate. Now, with the advent of antibiotics, the prognosis is favorable, but delays in diagnosis may result in increased morbidity and mortality. Its incidence appears to be increasing. We present a case of Lemierre's syndrome, most notable for the patient's essentially benign physical examination and lack of clinical improvement with penicillin.

Calpastatin overexpression protects axonal transport in an in vivo model of traumatic axonal injury.

Traumatic brain injury (TBI) causes substantial morbidity and mortality worldwide. A key component of both mild and severe TBI is diffuse axonal injury. Except in cases of extreme mechanical strain, when axons are torn at the moment of trauma, axonal stretch injury is characterized by early cytoskeletal proteolysis, transport disruption, and secondary axotomy. Calpains, a family of Ca(2+)-dependent proteases, have been implicated in this pathologic cascade, but direct in vivo evidence is lacking. To test the hypothesis that calpains play a causal role in axonal stretch injury in vivo, we used our rat optic nerve stretch model following adeno-associated viral (AAV) vector-mediated overexpression of the endogenous calpain inhibitor calpastatin in optic nerve axons. AAV vectors were designed for optimal expression of human calpastatin (hCAST) in retinal ganglion cells (RGCs). Calpain inhibition by the expressed protein was then confirmed in primary cortical cultures. Finally, we performed bilateral intravitreal injections of AAV vectors expressing hCAST or the reporter protein ZsGreen 3 weeks prior to unilateral optic nerve stretch. Immediately after stretch injury, Fluoro-Gold was injected into the superior colliculi for assessment of retrograde axonal transport. Rats were euthanized 4 days after stretch injury. Both hCAST and ZsGreen were detected in axons throughout the optic nerve to the chiasm. Calpastatin overexpression partially preserved axonal transport after stretch injury (58.3±15.6% reduction in Fluoro-Gold labeling relative to uninjured contralateral controls in ZsGreen-expressing RGCs, versus 33.8±23.9% in hCAST-expressing RGCs; p=0.038). These results provide direct evidence that axonal calpains play a causal role in transport disruption after in vivo stretch injury.

Short-duration treatment with the calpain inhibitor MDL-28170 does not protect axonal transport in an in vivo model of traumatic axonal injury.

Traumatic axonal injury is characterized by early cytoskeletal proteolysis and disruption of axonal transport. Calpain inhibition has been shown to protect axons in rodent models of traumatic brain injury. However, in these models, both white and gray matter are injured, making it difficult to determine if calpain inhibitors are directly protecting injured axons. To address this issue, we used our rat optic nerve stretch model to test the hypothesis that early calpain inhibition directly protects central nervous system (CNS) axons following stretch injury. Rats were given an intravenous bolus of the calpain inhibitor MDL-28170 (30 mg/kg) 30 min prior to unilateral optic nerve stretch, followed by a 15 mg/kg/h intravenous infusion over the next 2.5 h. Immunohistochemical analysis of optic nerves 30 min after stretch injury revealed variable increases of calpain-cleaved α-spectrin that appeared less evident in stretched nerves from drug-treated rats, although this difference was not statistically significant. Retrograde axonal transport measured by Fluorogold® labeling of retinal ganglion cells was significantly impaired after stretch injury. However, there was no difference in the number of Fluorogold-labeled cells in the vehicle vs. drug treatment groups. These results suggest that early short-duration calpain inhibitor therapy with MDL-28170 is not an effective strategy to prevent disruption of axonal transport following isolated axonal stretch injury in the CNS.

Immediate short-duration hypothermia provides long-term protection in an in vivo model of traumatic axonal injury.

A prospective, multicenter, randomized trial did not demonstrate improved outcomes in severe traumatic brain injured patients treated with mild hypothermia [Clifton, G.L., Miller, E.R., Choi, S.C., Levin, H.S., McCauley, S., Smith, K.R., Jr., Muizelaar, J.P., Wagner, F.C., Jr., Marion, D.W., Luerssen, T.G., Chesnut, R.M., Schwartz, M., 2001. Lack of effect of induction of hypothermia after acute brain injury. N. Engl. J. Med. 344, 556-563.]. However, the mean time to target temperature was over 8 h and patient inclusion was based on Glasgow Coma Scale score so brain pathology was likely diverse. There remains significant interest in the benefits of hypothermia after traumatic brain injury (TBI) and, in particular, traumatic axonal injury (TAI), which is believed to significantly contribute to morbidity and mortality of TBI patients. The long-term beneficial effect of mild hypothermia on TAI has not been established. To address this issue, we developed an in vivo rat optic nerve stretch model of TAI. Adult male Sprague-Dawley rats underwent unilateral optic nerve stretch at 6, 7 or 8 mm piston displacement. The increased number of axonal swellings and bulbs immunopositive for non-phosphorylated neurofilament (SMI-32) seen four days after injury was statistically significant after 8 mm displacement. Ultrastructural analysis 2 weeks after 8 mm displacement revealed a 45.0% decrease (p<0.0001) in myelinated axonal density in the optic nerve core. There was loss of axons regardless of axon size. Immediate post-injury hypothermia (32 degrees C) for 3 h reduced axonal degeneration in the core (p=0.027). There was no differential protection based on axon size. These results support further clinical investigation of temporally optimized therapeutic hypothermia after traumatic brain injury.

Fatal myocarditis due to Clostridium novyi type B in a previously healthy woman: case report and literature review.

Clostridium novyi is a Gram-positive anaerobe, which is commonly a pathogen of domestic and wild animals. Disease in humans typically presents as myonecrosis. C. novyi has not previously been reported as a cause of myocarditis. We report a fatal case with infection of the myocardium by C. novyi type B.