BNT162b vaccines protect rhesus macaques from SARS-CoV-2.

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

Surgical considerations in a paediatric case of a large skull-base epithelioid haemangioendothelioma.

Intracranial epithelioid haemangioendothelioma (EHE) is a rare intermediate grade vascular tumour with heterogeneous clinical and histopathological behaviour. We present the surgical considerations of an exceptionally large skull-based EHE in an 11-year old female who presented to our institution with headaches and a protuberance over the left parietal area. Magnetic resonance imaging (MRI) demonstrated a left sided 10.5 × 6.6 × 11.1 cm extra-axial tumour arising from the parieto-temporaloccipital region which was continuous with the calvarium. An initial biopsy confirmed EHE. Staged treatment involved preoperative angiography and embolization. The patient underwent an extensive tumour excision and acrylic cranioplasty. Residual tumour persists in the petrous temporal bone. No neurological deficit was sustained. Postoperatively, we proceeded to tumour surveillance rather than adjuvant therapies, and follow-up imaging up to 36 months postoperatively has shown no tumour progression. We illustrate our surgical management of this large EHE and review the literature of this rare pathological entity with variable tumour behaviour and potential role for adjuvant therapy.

Long-term follow-up for keystone design perforator island flap for closure of myelomeningocele.

PURPOSE: We have previously reported a small series on the closure of large myelomeningocele (MMC) defects with a keystone design perforator island flap (KDPIF) in a paediatric neurosurgical centre in Australia. We are now presenting an updated longer term follow-up of an expanded series demonstrating longer term durability of this vascularized flap for large myelomeningocele defects. METHODS: The prospective data from the Monash Neurosurgical Database were used to select all cases of MMC between December 2008 and September 2016. Retrospective analysis of the neurosurgical database revealed an additional three patients who underwent KDPIF closure at the Monash Medical Centre for MMC repair at birth. RESULTS: Wound healing was satisfactory in all six cases. With delayed follow-up, there was no associated skin flap separation, skin flap dehiscence, skin flap necrosis, cerebro-spinal fluid leak, however two infections were encountered, both resolved with conservative management including antibiotics and simple washout. CONCLUSION: In this expanded case series with increased longevity of follow-up, the keystone design perforator island flap remains a robust alternative for closure of large myelomeningocele defects.

Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals.

We present two cases of recurrent progressive multifocal leukoencephalopathy (PML) in patients with long standing virally suppressed human immunodeficiency virus (HIV) and normal CD4+ T cell count who were taking stable regimens of highly active antiretroviral therapy (HAART). This has significant implications for other patients with a past history of PML, not just those with HIV but also those on medications such as natalizumab or fumarates.

Posterior Reversible Encephalopathy Syndrome and Subarachnoid Hemorrhage After Lumboperitoneal Shunt for Fulminant Idiopathic Intracranial Hypertension.

A 33-year-old woman presented with severe visual loss from fulminant idiopathic intracranial hypertension. Her lumbar puncture opening pressure was 97 cm H2O. Soon after lumboperitoneal shunt surgery, she had a generalized tonic-clonic seizure. Magnetic resonance imaging demonstrated frontal subarachnoid hemorrhage (SAH) and neuroimaging findings consistent with posterior reversible encephalopathy syndrome (PRES). We hypothesize that an abrupt drop in intracranial pressure after lumboperitoneal shunting led to maladjustment of cerebral vascular autoregulation, which caused SAH and PRES.

Intrauterine fetal death with subsequent quill exfoliation and dissemination in a North American porcupine (Erethizon dorsatum).

An adult female, wild North American porcupine (Erethizon dorsatum) presented with bilateral cataracts and naso-ocular discharge. A pregnancy was identified by radiography with a near-full-term fetus, which was delivered stillborn 4 wk later with hard, developed quills. At that time, a repeated examination and further imaging, including computed tomography, demonstrated a uterine mass that was identified as a choriocarcinoma following ovariohysterectomy. Additionally, numerous exfoliated quills were discovered throughout the abdomen, most of which were removed during the surgical procedure. Ultimately, development of peritonitis despite medical care led to the porcupine's death. Necropsy confirmed a wide migration of the quills with extensive serosal adhesions and granulomas affecting liver, lungs, urinary bladder, kidneys, and gastrointestinal tract.

Intraoperative overlay of optic radiation tractography during anteromesial temporal resection: a prospective validation study.

OBJECTIVE: Anteromesial temporal lobe resection (ATLR) results in long-term seizure freedom in patients with drug-resistant focal mesial temporal lobe epilepsy (MTLE). There is significant anatomical variation in the anterior projection of the optic radiation (OR), known as Meyer's loop, between individuals and between hemispheres in the same individual. Damage to the OR results in contralateral superior temporal quadrantanopia that may preclude driving in 33%-66% of patients who achieve seizure freedom. Tractography of the OR has been shown to prevent visual field deficit (VFD) when surgery is performed in an interventional MRI (iMRI) suite. Because access to iMRI is limited at most centers, the authors investigated whether use of a neuronavigation system with a microscope overlay in a conventional theater is sufficient to prevent significant VFD during ATLR. METHODS: Twenty patients with drug-resistant MTLE who underwent ATLR (9 underwent right-side ATLR, and 9 were male) were recruited to participate in this single-center prospective cohort study. Tractography of the OR was performed with preoperative 3-T multishell diffusion data that were overlaid onto the surgical field by using a conventional neuronavigation system linked to a surgical microscope. Phantom testing confirmed overlay projection errors of < 1 mm. VFD was quantified preoperatively and 3 to 12 months postoperatively by using Humphrey and Esterman perimetry. RESULTS: Perimetry results were available for all patients postoperatively, but for only 11/20 (55%) patients preoperatively. In 1/20 (5%) patients, a significant VFD occurred that would prevent driving in the UK on the basis of the results on Esterman perimetry. The VFD was identified early in the series, despite the surgical approach not transgressing OR tractography, and was subsequently found to be due to retraction injury. Tractography was also used from this point onward to inform retractor placement, and no further significant VFDs occurred. CONCLUSIONS: Use of OR tractography with overlay outside of an iMRI suite, with application of an appropriate error margin, can be used during approach to the temporal horn of the lateral ventricle and carries a 5% risk of VFD that is significant enough to preclude driving postoperatively. OR tractography can also be used to inform retractor placement. These results warrant a larger prospective comparative study of the use of OR tractography-guided mesial temporal resection.

Keystone design perforator island flap for closure of myelomeningocele.

OBJECT: We present a series of three infants who underwent keystone design perforator island flap (KDPIF) closure for myelomeningocele in a paediatric neurosurgical centre in Australia. This is the first recorded utilization of this flap for primary closure of myelomeningocele (MMC). METHODS: The prospective data from the Monash Neurosurgical Database were used to select all cases of MMC between December 2008 and September 2010. Retrospective analysis of these cases revealed three patients who underwent KDPIF at Monash Medical Centre for MMC repair at birth. RESULTS: Wound healing was prompt and satisfactory in all three cases. No minor or major complications were noted. In particular, there was no associated skin flap separation, skin flap dehiscence, skin flap necrosis, infection, cerebrospinal fluid leak, or need for return to theatre for further intervention to the wound. This keystone design perforator island flap is based on random perforating musculo/fasciocutaneous perforators. In our experience, this robust flap provides better tissue bulk, more reliable vascularity and a wider geometrical versatility than traditional random 1:1 cutaneous flaps. CONCLUSION: Whilst primary closure remains an option for myelomeningocele closure, primary repair of larger defects can lead to closure site tension, stretching of inelastic scar tissue and inadequate soft tissue cover. In this small series, we have demonstrated the use of keystone design perforator island flap closure as an alternative for larger and more complex lesions.

The floating anchored craniotomy.

BACKGROUND: The "floating anchored" craniotomy is a technique utilized at our tertiary neurosurgery institution in which a traditional decompressive craniectomy has been substituted for a floating craniotomy. The hypothesized advantages of this technique include adequate decompression, reduction in the intracranial pressure, obviating the need for a secondary cranioplasty, maintained bone protection, preventing the syndrome of the trephined, and a potential reduction in axonal stretching. METHODS: The bone plate is re-attached via multiple loosely affixed vicryl sutures, enabling decompression, but then ensuring the bone returns to its anatomical position once cerebral edema has subsided. RESULTS: From the analysis of 57 consecutive patients analyzed at our institution, we have found that the floating anchored craniotomy is comparable to decompressive craniectomy for intracranial pressure reduction and has some significant theoretical advantages. CONCLUSIONS: Despite the potential advantages of techniques that avoid the need for a second cranioplasty, they have not been widely adopted and have been omitted from trials examining the utility of decompressive surgery. This retrospective analysis of prospectively collected data suggests that the floating anchored craniotomy may be applicable instead of decompressive craniectomy.

Early improvement in cardiac tissue perfusion due to mesenchymal stem cells.

The underlying mechanism(s) of improved left ventricular function (LV) due to mesenchymal stem cell (MSC) administration after myocardial infarction (MI) remains highly controversial. Myocardial regeneration and neovascularization, which leads to increased tissue perfusion, are proposed mechanisms. Here we demonstrate that delivery of MSCs 3 days after MI increased tissue perfusion in a manner that preceded improved LV function in a porcine model. MI was induced in pigs by 60-min occlusion of the left anterior descending coronary artery, followed by reperfusion. Pigs were assigned to receive intramyocardial injection of allogeneic MSCs (200 million, approximately 15 injections) (n = 10), placebo (n = 6), or no intervention (n = 8). Resting myocardial blood flow (MBF) was serially assessed by first-pass perfusion magnetic resonance imaging (MRI) over an 8-wk period. Over the first week, resting MBF in the infarct area of MSC-treated pigs increased compared with placebo-injected and untreated animals [0.17 +/- 0.03, 0.09 +/- 0.01, and 0.08 +/- 0.01, respectively, signal intensity ratio of MI to left ventricular blood pool (LVBP); P < 0.01 vs. placebo, P < 0.01 vs. nontreated]. In contrast, the signal intensity ratios of the three groups were indistinguishable at weeks 4 and 8. However, MSC-treated animals showed larger, more mature vessels and less apoptosis in the infarct zones and improved regional and global LV function at week 8. Together these findings suggest that an early increase in tissue perfusion precedes improvements in LV function and a reduction in apoptosis in MSC-treated hearts. Cardiac MRI-based measures of blood flow may be a useful tool to predict a successful myocardial regenerative process after MSC treatment.