With interest we read the review article by Brouwer et al. about the neurological complications of a SARS-CoV-2 infection [1]. The authors concluded that headache and taste/smell disturbances are the most frequent neurological symptoms in SARS-CoV-2 infected patients [1] We have the following comments and concerns.

We do not agree that neuro-COVID manifests only with ischemic stroke, headache, acute, hemorrhaghic, necrotising encephalopathy (AHNE), hyposmia, hypogeusia, cerebral hypoxia, and Guillain Barre syndrome (GBS) but also with several other abnormalities of the central or peripheral nervous system (CNS, PNS). CNS disorders associated with COVID-19 other than the ones described in the review include acute disseminated encephalomyelitis (ADEM), transverse myelitis, viral encephalitis, cerebellitis, immune encephalitis, epilepsy, delirium, psychosis, cytokine release syndrome, myoclonus ataxia syndrome, sinus venous thrombosis, sleep disorders, and cerebral vasculitis [Finsterer, submitted]. PNS disorders not addressed in the review are myositis, dermatomyositis, myasthenia, and mononeuropathies of cranial nerves. Additionally, the authors did not mention neurological complications of the treatment applied to COVID-19 patients such as critical ill neuropathy/myopathy, rhabdomyolysis, myasthenic syndrome, or neuroleptic malignant syndrome [Finsterer, submitted].   

We do not agree that only a single patient with AHNE due to COVID-19 has been reported [1]. According to a literature search in PubMed at least 6 further cases with AHNE due to a COVID-19 infection as per November 2020 have been reported.

We do not agree that headache in COVID-19 can be explained by hypoxia, metabolic disturbances, or systemic inflammation alone. Due to the pro-coagulatory state headache could be also due to recurrent thrombosis. Since SARS-CoV-2 affects also the endothelium of arteries it is conceivable that headache may be due to vasculitis in some cases [2]. Headache can be also associated with cerebral vasoconstriction syndrome. Since COVID-19 may also lead to posterior reversible encephalopathy syndrome (PRES) [3], it can be assumed that in some cases PRES is responsible for headache. Since SARS-CoV-2 may cause myositis of skeletal muscle, headache may be attributable to involvement of head muscles in the inflammatory process. Last but not least the infection may be associated with fear and uncertainty, which may secondary to hypertension of muscle and in particular tension headache. 

We do not agree that direct infection of the central nervous system (CNS) by SARS-CoV-2 is unlikely [1]. The authors themselves propose the invasion of the CNS by retrograde axonal migration [1]. Additionally, there is evidence that the virus disrupts the blood brain barrier (BBB) and enters the CNS via the hematogenic pathway. Further evidence for the presence of the virus in the CNS comes from pathoanatomic studies showing the intraneuronal presence of the virus [4]. There are also a number of cases with encephalitis, in which the virus could be documented in the cerebro-spinal fluid (CSF) [5].

Overall, the review by Brewer et al. has several limitations as outlined above which should be met before drawing final conclusions. Neurological manifestations of SARS-CoV-2 are much more widespread than described, the frequency of several manifestations, such as AHNE and GBS, is higher than anticipated, the pathogenesis of headache in COVID-19 is highly variable, and the virus definitively invades the CNS. 

With interest we read the article by Dibue et al. about a literature review of 19 eligible studies reporting 623 patients with sudden unexpected death in epilepsy (SUDEP) of whom 17% had a mild to moderate diffuse cerebral oedema on post-mortem clinical examination (autopsy) or on cerebral computed tomography (CT) [1]. It was concluded that seizures preceding SUDEP may in certain cases elicit acute oedema, which may represent an additional contributing factor in the cascade of events leading to sudden death [1]. We have the following comments and concerns.

Cerebral oedema can be assessed according to various methods. Cerebral oedema can be assessed macroscopically, by the pathologist, or according a formula using intracranial dimensions and cerebral weight [2]. Though rater and the formula show good agreement there is poor agreement between macroscopy and the rater and the formula [3]. A fourth method uses normalised cerebral weight, which relies on putting cerebral weight in relation to the intra-cranial volume [3]. Post-mortem time and cooling time were negligible for this method. We should know according to which method cerebral oedema was assessed in those cases undergoing autopsy. Unfortunately, the authors do not mention how many of the 623 patients underwent autopsy, how many underwent post-mortem imaging, and how many both. Since cerebral oedema may depend on the post-mortem time until autopsy and the cooling time, we should know if these parameters were included in the evaluation. A shortcoming of the normalised cerebral weight is that age at death may confound the oedema classification due to pre-existing cerebral atrophy leading to lower cerebral weights [3]. If post-mortem time, cooling time, and age at death were not considered in the evaluation false positive results may have ensued. 

A further shortcoming of the study is that the pathophysiology of cerebral oedema in the included SUDEP patients remains speculative. How did the authors exclude that cerebral oedema was a post-mortem phenomenon. Fluid re-distribution post mortem has been reported [3]. Cerebral oedema may be also due to ischemic stroke, intracerebral bleeding, sinus venous thrombosis, encephalitis, hyertensive encephalopathy, posterior reversible encephalopathy syndrome (PRES), reversible cerebral vasoconstriction syndrome [4], or hepatic failure [5]. Were all these differentials thoroughly excluded among the 623 included patients?

It is unclear in how many patients focal and in how many patients generalised oedema was found. Knowing the extension of the oedema is crucial as it may help to uncover the underlying cause. 

Overall, the interesting study has a number of limitations in addition to those already mentioned in the article. Criteria for diagnosing cerebral oedema clinically or on imaging should be provided and post-mortem time, cooling time, and age at death should be included in the evaluation to avoid the production of false positive results. 

Study of calcification pattern of costal cartilage is beneficial for sex determination. Rib calcification can be studied radiologically with the help of chest radiographs. The lower ribs in the body shows sexual dimorphism whereas the first rib is not considered. Ossification and mineralization appear at the end of puberty which can be seen on radiographs. Radiological method is easy and simple and is beneficial in forensic medicolegal cases.

Introduction: Crucial property of esthetic restorative materials is their color stability. Aim: to evaluate color stability of Gnathostar Ivoclar Vivadent acrylic artificial teeth in contact with the dark carbonated soft drink, coffee, sage tea and red wine, compared to distilled water. Materials and methods:  a total of 15 samples were monitored, the same type, color and position of the teeth. The samples were divided into 5 groups, 3 teeth in each (n = 3). The artificial teeth were placed in an appropriate liquid at the room temperature. Tooth color was registered after 60 days, using spectrophotometer. Data were analyzed by the Kruskal-Wallis test. Results: dark carbonated beverage had the greatest pigmenting effect (ΔE = 22.1). Conclusion: there was no significant difference in staining ability between the four different fluids (χ² (3) = 4.385, p = 0.223). Each fluid showed perceptible difference in tooth color, compared to the control group.

Pathophysiology of neuro-COVID is more complex than anticipated. The spectrum of central and peripheral nervous system disease triggered by SARS-CoV-2 is more widespread than anticipated. Treatment of neuro-COVID relies on the established treatment of COVID-19 but additionally immunosuppressive treatment may be beneficial in certain cases.

Obwohl periphere Neuropathien insgesamt mit einer Prävalenz von 2-3% häufige Erkrankungen darstellen, hat die überwiegende Zahl der Unterformen einen Orphan-Status. Die Prävalenz ist dabei stark von der untersuchten Region abhängig. Unter den primären hereditären Neuropathien (hNP) sind bis auf jene bedingt durch Mutationen in PMP22, MPZ, MFN2, GJB1 oder SH3TC2 selten bis ultra-selten (d.h. die meisten HMSN, alle HSAN, alle dHMN). Selten sind auch hereditäre Plexopathien, hereditäre „small-fiber“ Neuropathien und die „giant axonal neuropathy“. Unter den sekundären hNP werden seltene Neuropathien bei mitochondrialen Erkrankungen (z.B. NARP, MNGIE, SANDO), bei hereditären spastischen Paraplegien (SPG1-7, SPG9-11, SPG14-15, SPG25, SPG27, SPG30-31, SPG36, SPG38-39, SPG43. SPG47. SPG49. SPG55-57, und SPG76), bei spino-cerebellären Ataxien (SCA1, SCA2, SCA3, SCA4, SCA6, SCA7, SCA10, SCA11, SCA18), bei Porphyrien wie der DOSS Porphyrie (ALAD1), akuten intermittierenden Porphyrie (HMBS), der hereditären Coproporphyrie (CPOX CPOX), oder der variegaten Porphyrie (PPOX), bei lysosomalen Speicher-Erkrankungen (z.B. M. Fabry, Krabbe, Sandhoff), ûnd bei Tangier Krankheit beobachtet. Auch unter den erworbenen peripheren Neuropathien (metabolisch, toxisch, infektiös, immun-mediiert, neoplastisch/paraneoplastisch) gibt es eine Fülle von Neuropathien mit Orphan-Status. Unter den metabolischen Neuropathien sind Neuropathien bei Hypo- oder Hyperthyreose und bei Vitamin-Mangel (B1, Folsäure, B6, B12, D, E) als selten zu betrachten. Seltene toxische Neuropathien sind jene bei Vergiftung mit Metallen (Kupfer, Lithium, Blei, Arsen, Thallium, Quecksilber, Kobalt). Zu den vielen Medikamenten die seltene Neuropathien verursachen zählen z.B. L-DOPA, Vitamin-B6, die „immune checkpoint“ Inhibitoren Pembrolizumap, Nivolumab, und Ipilimumab, sowie Eribulin. Chemikalien die selten Neuropathien verursachen sind beispielsweise Nitric-Oxid, Vinyl-Benzen, Di-Ethylen-Glykol, Hexa-Carbon, Acryl-Amid, und Carbon-Disulfid. Seltene infektiöse Neuropathien werden durch Erreger wie C. diphterie, Varicella-Zoster, Lepra, Zika, HIV, Influenza-A, Dengue, oder andere Arboviren verursacht. Unter den immun-mediierten Neuropathien gibt es seltene Unterformen des Guillain-Barre Syndroms (GBS) (z.B. AMAN, AMSAN, Bickkerstaff Enzephalitis). Seltene infektiöse Trigger eines GBS sind M. pneumoniae, EBV, CMV, Influenza-A, Hepatitis-E, „scrub typhus“, Chikungunya, Rubella, oder Zika. Seltene nicht-infektiöse Trigger eines GBS sind Hyponatriämie, bariatrische Operationen, Lupus, bakterielle Meningitis, oder    Paranodopathien.   Zwei   bis   sechs Prozent der CIDPs sind durch Antikörper gegen paranodale Proteine (contactin-1,  neurofascin-155) verursacht (Paranodopathien). Bindegewebserkrankungen die selten mit einer Neuropathie vergesellschaftet sein können sind der Lupus, die rheumatoide Arthritis, die Sarkoidose, das Sjögren Syndrom, und die Sklerodermie. Unter den monoklonalen Gammopathien (Paraproteinämien) sind Neuropathien selten bei der Waldenström‘schen Makroglobulinemie, POEMS Syndrom, und bei CANOMAD. Unter den Vaskulitiden kommen Neuropathien selten bei systemischen Vaskulitiden (Panarteriitis nodosa, „microscopic polyangitis“, „eosinophilic granulomatosis with polyangitis“ (Churg-Strauss), „granulomatosis with polyangitis“ (Wegener), Hennoch-Schönlein purpura, Riesenzellarteriitis, und bei „essential mixed cryoglobulinemia“) und häufiger bei isolierter Vaskulitis des PNS vor. Selten treten Neuropathien auch in Zusammenhang mit neoplastischen und paraneoplastischen Erkrankungen auf. Generell gilt, dass bei     hereditären und metabolischen Neuropathien mehrheitlich eine symmetrische und distale Verteilung vorliegt, während die infektiösen, immun-mediierten, und paraneoplastischen Neuropathien eher asymmetrisch, als Mononeuropathie, oder Schwerpunkt-Neuropathie manifestieren. Demyelinisierend sind vor allem die HMSN1, die Paraproteinämien, und das GBS/CIDP. Die übrigen Formen zeigen meist eine axonale Schädigung. Orphan Neuropathien sollten aus logistischen, Experise, und finanziellen Gründen in spezialisierten Zentren gemanaget werden.

Today ‘Health is wealth’ is not merely a platitude but something that time demands we constantly revisit in innovative ways. While the news of Covid-19 had kept popping up in the background in the months of March-April 2020, town were replaced by barren roads, deserted markets, and never experienced zone of deafening silence. The subsequent announcement of lockdown made the students realize that this will be a long-drawn battle for them and had markedly impacted the life of medical students and explained further.

This study was carried out to investigate the application of pumpkin seed flour as composite flour with the aim of improving the nutritional quality and reducing the burden on economy especially with importation of wheat. Wheat flour was blended with pumpkin seed flour in ratio 100%:0, 95%: 5%, 90%: 10%, 85%:15% and 80%:20% to produce cookies. The proximate composition, mineral, phytochemical, antioxidant, physical properties and consumer acceptability of wheat-pumpkin seed cookies were determined. It was observed that the protein content of cookies increased from 17.95%-21.02%, fat 17.33%-23.08% while there were reductions in carbohydrate 49.32%-43.22% and moisture content 4.95%-3.05% of cookies. Phosphorus 53.48 mg/100g-189.43 mg/100g was the predominant mineral, followed by sodium 56.11 mg/100g-91.20 mg/100g and zinc 0.41 mg/100g-1.06 mg/100g was the least. The physical properties of the cookies include; weight 3.04 g-3.27 g, diameter 22.06 mm-31.33 mm, thickness 7.33 mm-8.30 mm and spread ratio 0.24-0.36. The flavonoid content of cookies ranged from 0.01mg/100g-0.14 mg/100g while the ability of wheat-pumpkin cookies to scavenge free radicals 5.03 mg/100g-10.84 mg/100g was found to decrease with increase in pumpkin seed flour. Result of the consumer acceptability of cookies revealed that there were no significant differences in the overall acceptability of cookies from wheat flour and wheat-pumpkin seed flour. Based on this study, pumpkin seed flour may be considered as composite flour in cookies production.

Children are the most vulnerable and always at increased risk of some infectious diseases in human society; thus, it is vital to monitor the occurrence of these health concerns to be able to provide appropriate medical attention and management. The Philippines, being an archipelagic country, has shown that for the past several years, based on records of the Department of Health, occurrences of both communicable and non-communicable diseases vary from region to region, and from communities to communities. To be able to have information at the local level, conditions affecting children admitted in hospitals in Iligan City, Philippines, was data-mined to be able to determine the frequencies of communicable and non-communicable diseases affecting the different age groups. Given a list of medical records available from the hospital for a period of nine years (2005 to 2013), patients ranging from 1 to 12 years old were divided into three categories: 1 to 3 years old (toddler), 4 to 5 years old (pre-school), and 6 to 12 years old (grade school). Results of the evaluation of patients’ records show thirty diseases are commonly the cause of hospital admissions. The list based on tabulated data, the number of patients that were diagnosed by these diseases concerning age and gender show the distribution of the diseases for every year shown through stacked bar graphs. Across all the years, it was found out that the most prevalent diseases among children were pneumonia, acute gastroenteritis with dehydration, and urinary tract infection. The number of incidences per year of the mentioned diseases, however, showed some variations in frequencies. Urinary tract infection and acute gastroenteritis were almost similar, while cases of pneumonia varied and were the highest in three years 2008, 2009, and 2012. These findings may be useful in making preventive measures against these diseases from occurring in the succeeding years by the government’s Department of Health and provide appropriate measures to be done by the communities in the city to avoid the incidence of high admissions due to these diseases.

It's indeed striking to read these excerpts on tuberculosis (TB) at the beginning of the third millennium, highlighting the ongoing challenges and urgent need for action in TB control. Despite significant progress in medicine and technology, TB remains a major global health concern, especially in vulnerable populations such as prisoners, military personnel and those living in crowded conditions. The statistics on TB's impact are sobering, with millions of deaths and infections projected if immediate action is not taken. The development of laser systems for TB treatment represents a promising approach, with different types of lasers offering varying levels of effectiveness and safety considerations. Excimer lasers and solid-state diode-pumped lasers are two approaches being explored for TB treatment. The wavelength of 265 to 266nm is considered optimal for bacteriostatic activity, with excimer lasers emitting at 248nm and solid-state Nd: YAG lasers at 266nm. However, careful consideration must be given to pulse energy and exposure time to avoid tissue damage and ensure effectiveness.

With interest we read the review article by Hassett et al. about neurological complications of an infection with SARS-CoV-2 [1]. It was concluded that clinicians should develop high clinical suspicion of neurological complications of a SARS-CoV-2 infection [1]. We have the following comments and concerns.

In addition to acute encephalopathy, acute cerebrovascular disease (acute ischemic stroke, venous thromboembolism), infections (encephalitis, meningitis, post-infections demyelination, acute, hemorrhaghic, necrotizing encephalopathy), seizures, critical ill neuropathy, critical ill myopathy, Guillain-Barre syndrome, and olfactory neuropathy, SARS-CoV-2 may cause intracerebral bleeding, myalgia, ataxia from cerebellitis [2], transverse syndrome due to transverse myelitis [3], spasticity [4], myoclonus [4], subarachnoid bleeding, neurogenic dysphagia [4], dysexecutive syndrome [4], memory impairment [4], psychosis [5], and hypogeusia. Recently, several patients with posterior, reversible, encephalopathy syndrome (PRES) due to infection with SARS-CoV-2 have been reported.     

We appreciate that the authors mention critical ill neuropathy and myopathy. A number of neurological complications in association with SARS-CoV-2 may not be due to a direct viral attack or the immune response to the virus, but rather due to side effects of the treatment applied to SARS-CoV-2-infected patients. Steroids, chloroquine, and nucleoside, reverse transcriptase inhibitors may cause myopathy, and azithromycine may trigger seizures. Additionally, chloroquine may induce supra- and ventricular arrhythmias, which may lead to secondary cerebrovascular events.

The term encephalopathy is misleading. If the authors mean “altered mental status”, we suggest to use “altered mental status” instead of encephalopathy, as encephalopathy is a general term, which just means cerebral disease. 

Overall, the article by Hassett et al. has shortcomings, as outlined above, which should be addressed before drawing final conclusions. The spectrum of neurological complications from a SARS-CoV-2 infection is much broader than anticipated. The virus itself may directly damage brain tissues or the immune response to the virus may cause secondary cerebral disease.

We appreciated to read the review article by Galassi et al. about neuromuscular implications of infections with SARS-CoV-2 (COVID-19) [1]. The authors collected 13 cases with polyradiculitis affecting the peripheral nerves, cranial nerves, or both [1]. It was concluded that Guillain-Barre syndrome (GBS) is the only neuromuscular disorder (NMD) triggered by SARS-CoV-2 [1]. We have the following comments and concerns.

The first shortcoming of the study is that GBS is not the only NMD triggered by SARS-CoV-2. In addition to polyradiculitis, myositis [2,3], myalgia [4], rhabdomyolysis [5-7], mononeuropathy of the facial nerve [8,9], myasthenia, and polyneuropathy [10] have been reported as neuromuscular manifestations of COVID-19. The low prevalence of NMD caused by SARS-CoV-2 may be due to the dominance of pulmonary compromise in COVID-19 patients, which may give rise to missing manifestations of the peripheral nervous system (PNS). A further reason could be that NMD in severely ill, intubated, and artificially ventilated patients may be missed, particularly if it the NMD is transient and present only at the intensive care unit. 

Another shortcoming is that it was not differentiated between primary and secondary NMD triggered by SARS-CoV-2. Primary NMD may be due to the viral attack. Secondary NMD may be due to the immunological response against the virus or due to side effects of the treatment applied for COVID-19. 

Secondary myopathy may be the consequence of a side effect of anti-viral agents (lopinavir/ritonavir), of chloroquine, or of steroids, frequently given for COVID-19. Secondary myopathy may be also due to critical ill myopathy in patients on the intensive care unit. Secondary neuropathy includes GBS and critical-ill neuropathy. Chloroquine has been also reported to trigger myasthenic syndrome [11].

Immunological disorders affecting the PNS may be GBS, myasthenia, or myositis. Neuromuscular complications of treatment include critical ill neuropathy/myopathy, or myopathy due to steroids, anti-viral agents, or chloroquine.

A recently reported complication of COVID-19 may be myasthenia gravis. The first cases of myasthenia triggered by SARS-CoV-2 were reported by Restivo et al. [12]. Myasthenia triggered by SARS- CoV-2 has been also reported in a Turkish patient [13].

Whether hypogeusia/hyposomia is due to affection of the cranial nerves or due to other causes, remains speculative.

A third point that should be considered in COVID-19 patients is that the infection may worsen already pre-existing NMD, such as myasthenia [14]. In several patients with myasthenia, SARS-CoV-2 led to exacerbation of myasthenia [14] or even myasthenic crisis [15]. 

Overall, SARS-CoV-2 may cause direct damage of muscle/nerve by the virus or the immune reaction against the virus, there may be muscle/nerve damage due to side effects of the anti-viral treatment, and SARS-CoV-2 may worsen a pre-existing NMD. The spectrum of NMDs due to infection with SARS-CoV-2 is more variegated than anticipated. Primary and secondary NMD due to SARS-CoV-2 infection should be delineated as treatment may vary between these entities, and it is helpful to differentiate between NMD caused by direct attack of the virus and a NMD caused by the secondary immune response.

With interest we read the article by Fay et al. about a large Venezuelan family with Charcot-Marie-Tooth disease, being attributed to the mtDNA variant m.1661A>G in tRNA(Val) [1]. The variant was detected in homoplasmy in one clinically affected and one clinically unaffected family member [1]. We have the following comments and concerns.

A main shortcoming of the study is that only limited clinical information about the mutation carriers was provided and that they were not prospectively investigated for multisystem involvement. Mitochondrial disorder (MIDs) are usually multisystem diseases, either already at onset of the disease or become a multisystem problem with progression of the condition [2]. Frequently, organs are subclinically or only mildly affected, giving rise to overlooking these abnormalities. Thus, it is crucial to investigate mtDNA mutation carriers prospectively for cerebral, ocular, otologic, endocrine, cardiac, gastro-intestinal; renal, hematologic, pulmonary, immunological, or dermal involvement. 

MIDs are frequently associated with lactic acidosis, or even elevated cerebral lactate [3]. Thus, we should know the serum and cerebrospinal fluid (CSF) lactate values. Knowing the lactate values is crucial as elevated lactate values may strongly determine the phenotype and may have therapeutic implications [3]. 

Pathogenicity of mtDNA tRNA variants should be assessed by application of the modified Yarham score [4]. Applying the score to the m.1661A>G variant and the reported data gives a score of only 5 points (>1 independent report: 0, heteroplasmy: 0, biochemical defect in complex-I, -III, or IV: 2, disease segregation with the variant: 2, variant segregation in single fiber studies: 0, tRNA steady-state or cybrid studies: 0, evidence of normality in cybrid studies: 0, evolutionary conservation: 0, histopathological evidence: 1). Thus, the variant m.1661A>G has to be assessed as “neutral” and not pathogenic. According to the modified Smith gene-disease association scoring system the score is 3 and thus the correlation is of “limited evidence” [4]. 

Hyperreflexia and a positive Babinski sign in 28 of 44 patients does not comply with a CMT phenotype. This discrepancy should be explained. 

Overall, this interesting study has a number of shortcomings, which need to be addressed before drawing final conclusions. As long as the affected and unaffected mutation carriers are not prospectively investigated and as long as the pathogenicity of the m.1661A>G variant is not confirmed upon appropriate investigations, not only the CMT phenotype but also the pathogenicity of the m.1661A>G variant remains unproven.