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Abstract Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer’s disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women’s increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration.

Dementia refers to an umbrella phenotype of many different underlying pathologies with Alzheimer's disease (AD) being the most common type. Neuropathological examination remains the gold standard for accurate AD diagnosis, however, most that we know about AD genetics is based on Genome-Wide Association Studies (GWAS) of clinically defined AD. Such studies have identified multiple AD susceptibility variants with a significant portion of the heritability unexplained and highlighting the phenotypic and genetic heterogeneity of the clinically defined entity. Furthermore, despite women's increased susceptibility to dementia, there is a lack of sex-specific genetic studies and understanding of sex-specific background for the disorder. Here, we aim to tackle the heterogeneity of AD by specifically concentrating on neuropathological features and pursuing sex-specific analysis. We bring together 14 different genomic and neuropathology datasets (6960 individuals) and we integrate our GWAS findings with transcriptomic and phenotypic data aiming to also identify biomarkers for AD progression. We uncover novel genetic associations to AD neuropathology, including BIN1 and OPCML. Our sex-specific analysis points to a role for BIN1 specifically in women as well as novel AD loci including QRFPR and SGCZ. Post-GWAS analyses illuminate the functional and biological mechanisms underlying AD and reveal sex-specific differences. Finally, through PheWAS and Mendelian Randomization analysis, we identify causal links with AD neuropathology pointing to disrupted lipid metabolism, as well as impaired peripheral immune response and liver dysfunction as part of a vicious cycle that fuels neurodegeneration. [ABSTRACT FROM AUTHOR]

The concept of variable stoichiometry cocrystallization is explored in halogen-bonded systems. Three novel cocrystals of 1,4-diiodotetrafluorobenzene and 3-nitropyridine with molar ratios of 1:1, 2:1, and 1:2, respectively, are prepared by slow evaporation methods. Single-crystal X-ray diffraction analysis reveals key differences between each of the nominally similar cocrystals. For instance, the 1:1 cocrystal crystallizes in the [P2.sub.1]/n space group and features a single chemically and crystallographically unique halogen bond between iodine and the pyridyl nitrogen. The 2:1 cocrystal crystallizes in the P1 space group and features a halogen bond between iodine and one of the nitro oxygens in addition to an iodine--nitrogen halogen bond. The 1:2 cocrystal crystallizes with a large unit cell (V = 9896 [A.sup.3]) in the Cc space group and features 10 crystallographically distinct iodine-nitrogen halogen bonds. Powder X-ray diffraction experiments carried out on the 1:1 and 2:1 cocrystals confirm that gentle grinding does not alter the crystal forms. [.sup.1]H [right arrow] [.sup.13]C and [.sup.19]F [right arrow] [.sup.13]C cross-polarization magic angle spinning (CP/MAS) NMR experiments performed on powdered samples of the 1:1 and 2:1 cocrystals are used as spectral editing tools to select for either the halogen bond acceptor or donor, respectively. Carbon-13 chemical shifts in the cocrystals are shown to change only very subtly relative to pure solid 1,4-diiodotetrafluorobenzene, but the shift of the carbon directly bonded to iodine nevertheless increases, consistent with halogen bond formation (e.g., a shift of +1.6 ppm for the 2:1 cocrystal). This work contributes new examples to the field of variable stoichiometry cocrystal engineering with halogen bonds. Key words: solid-state NMR, X-ray diffraction, halogen bond, cocrystal, polymorphism, stoichiometry, stoichiomorphism. Nous avons etudie le concept de cocristallisation a stoechiometrie variable dans des systemes a liaison halogene. Nous avons prepare par evaporation lente trois nouveaux cocristaux de 1,4-diiodotetrafluorobenzene et de 3-nitropyridine avec des rapports molaires de 1:1, de 2:1 et de 1:2, respectivement. L'analyse par diffraction des rayons X sur monocristal revele des differences importantes entre les cocristaux theoriquement similaires. Par exemple, le cocrystal 1:1 cristallise selon le groupe d'espace [P2.sub.1]/n et presente une seule liaison halogene, sur les plans chimique et cristallographique, entre l'iode et l'azote du groupe pyridyle. Le cocrystal 2:1 cristallise selon le groupe d'espace P1 et presente une liaison halogene entre l'iode et l'un des oxygenes du groupe nitro, en plus de la liaison halogene iode-azote. Le cocristal 1:2 cristallise en formant une grande cellule unitaire (V = 9896 [A.sup.3]) selon le groupe d'espace Cc et presente 10 liaisons halogene iode-azote distinctes sur le plan cristallographique. Des experiences de diffraction des rayons X sur poudre realisees sur les cocristaux 1:1 et 2:1 confirment qu'un broyage leger ne modifie pas les formes cristallines. Nous avons utilise des experiences de RMN [.sup.1]H [right arrow] [.sup.13]C et [.sup.19]F [right arrow] [.sup.13]C a polarisation croisee en rotation a l'angle magique (CP/MAS, cross-polarization/magic angle spinning), realisees sur des echantillons de cocristaux 1:1 et 2:1 sous forme de poudre, comme outils d'edition spectrale pour selectionner l'accepteur ou le donneur de liaison halogene, respectivement. Les deplacements chimiques du carbone-13 dans les cocris-taux ne changent que de facon tres subtile par rapport au 1,4-diiodotetrafluorobenzene solide pur, mais le deplacement du carbone directement lie a l'iode augmente neanmoins, ce qui concorde avec la formation de liaisons halogene (p. ex., un deplacement de +1,6 ppm dans le cas du cocrystal 2:1). Ces travaux apportent de nouveaux exemples au domaine de l'ingenierie des cocristaux a stoechiometrie variable comportant des liaisons halogene. [Traduit par la Redaction] Mots-cles : RMN a l'etat solide, diffraction des rayons X, liaison halogene, cocristal, polymorphisme, stoechiometrie, stoechiomorphisme., Introduction Molecular and ionic solids can adopt a range of forms depending on how they are prepared. (1,2) Such forms include pure crystalline or amorphous phases, hydrates, or solvates. In [...]

Background: Depression and anxiety occur more frequently in women and are associated with an increased risk of cardiovascular disease. Objectives: Data on the association between these psychiatric conditions and the incidence of acute heart failure (HF) and how they influence heart failure outcomes in women are lacking. We investigated this potential relationship using data from the National Inpatient Sample. Methods: We used ICD-10 codes to extract encounters for acute heart failure and/or the acute exacerbation of chronic heart failure, anxiety, and depression from the discharge data of the NIS from 2019 to 2020. We compared baseline characteristics and length of stay (LOS), cost of care (COC) and acute HF by depression/anxiety status for males and females and employed regression models to assess the influence of these psychiatric conditions on the outcomes. Results: There were 6,394,136 encounters involving females, which represented 56.6% of the sample. The prevalence of depression and anxiety were 15.7% and 16.8%, respectively. Among females, the occurrence of acute CHF did not differ by depression or anxiety status. However, Takostubo cardiomyopathy was more prevalent in those with depression (0.3% vs. 0.2%, p = 0.003) and anxiety (0.3% vs. 0.2%, p = 0.03) compared to those without these conditions. Among those with depression, LOS was significantly longer (3 days IQR: 2–6, vs. 3 days IQR:2–5 days, p < 0.001). The COC was USD 1481 more in patients with depression. On the contrary, LOS and COC were significantly lower in those without anxiety. Conclusions: Depression was associated with an increased LOS among both men and women and an increased cost of care among women. Anxiety was associated with a decreased LOS and cost of care among women, which may be related to an increased rate of against medical advice (AMA) discharges among this population. Further research is necessary to identify optimal management strategies for depression and anxiety among patients hospitalized with HF.

Users of the microbond test assume that a microbond resin droplet's properties are equivalent to a macroscale specimen. However, there is currently no standardised methodology for determining the cure state of droplet specimens used in the microbond test. In this paper, we present a technique for microbond test users to better understand the properties of thermoset droplet specimens. Utilising a conventional benchtop spectrometer, a novel sample preparation technique involving curing epoxy droplets on thin-steel filaments allowed for high-throughput determination of the microbond droplet cure state. The parity between steel filament and glass fibre microbond samples was confirmed by infrared microspectroscopy. It is shown that cure schedules used in manufacturing composite parts produced microbond droplets with degrees of cure lower than that of bulk matrix specimens subjected to an identical thermal history. Testable microbond droplets could only be prepared for commercial resin systems when introducing a room temperature pre-curing time of at least 2 h. It is concluded that microbond testing should be supported by some droplet cure state characterisation methods to ensure that interfacial effects are not artefacts of droplet sample preparation. [ABSTRACT FROM AUTHOR]

Chalcogen bonds (ChB) are moderately strong, directional, and specific non‐covalent interactions that have garnered substantial interest over the last decades. Specifically, the presence of two σ‐holes offers great potential for crystal engineering, catalysis, biochemistry, and molecular sensing. However, ChB applications are currently hampered by a lack of methods to characterize and control chalcogen bonds. Here, we report on the influence of various substituents (halogens, cyano, and methyl groups) on the observed self‐complementary ChB networks of 2,1,3‐benzoselenadiazoles. From molecular electrostatic potential calculations, we show that the electrostatic surface potentials (ESP) of the σ‐holes on selenium are largely influenced by the electron‐withdrawing character of these substituents. Structural analyses via X‐ray diffraction reveal a variety of ChB geometries and binding modes that are rationalized via the computed ESP maps, although the structure of 5,6‐dimethyl‐2,1,3‐benzoselenadiazole also demonstrates the influence of steric interactions. 77Se solid‐state magic‐angle spinning NMR spectroscopy, in particular the analysis of the selenium chemical shift tensors, is found to be an effective probe able to characterize both structural and electrostatic features of these self‐complementary ChB systems. We find a positive correlation between the value of the ESP maxima at the σ‐holes and the experimentally measured 77Se isotropic chemical shift, while the skew of the chemical shift tensor is established as a metric which is reflective of the ChB binding motif. [ABSTRACT FROM AUTHOR]

Cerebral artery aneurysms are present in up to 10% of ischemic stroke patients, often within or adjacent to the occluded vessel. In some cases, the approach to intervention may need to be modified based on the size and location of the aneurysm. We describe a 99-year-old female with a known history of cerebral aneurysm who underwent successfully mechanical thrombectomy of a right middle cerebral artery thrombus; an 8-mm aneurysm involving the right M1 bifurcation was identified only on post-procedural digital subtraction angiography. In addition, we discuss strategies to reduce the risk of iatrogenic aneurysm rupture in the setting of endovascular thrombectomy.

Background: Molluscum contagiosum is a benign viral infection of the skin. Lesions typically present as dome-shaped, flesh-colored, umbilicated papules that range in size from 1 to 5 millimeters in diameter. They are usually asymptomatic, but can become tender or pruritic. Children and immunocompromised adults, including individuals being treated with immunosuppressive drugs, are most susceptible to infection. Single or multiple lesions most commonly appear on the extremities, face, genitals, and trunk. However, albeit rarely, molluscum contagiosum may also develop at other sites, including the eyelids.Purpose: We describe the clinical and pathologic findings of a man who developed molluscum contagiosum of the eyelid while receiving methotrexate. We also review the characteristics of other patients with molluscum contagiosum acquired either during treatment with methotrexate or associated with human immunodeficiency virus (HIV) infection and summarize the unusual sites of presentation for the viral lesions in these individuals.Materials and methods: The features of a man receiving methotrexate who developed molluscum contagiosum of the eyelid are presented. Using PubMed, the following terms were searched and relevant citations assessed: adalimumab, contagiosum, Enbrel, etanercept, Humira, infliximab, methotrexate, molluscum, Remicade, TNF alpha, and tumor necrosis factor alpha. In addition, the literature on methotrexate treatment and molluscum contagiosum is reviewed.Results:  Several small papules were observed on the eyelid of a 24-year-old man who had been receiving methotrexate and adalimumab (Humira) for the treatment of Crohn disease. The lesions were removed by shave biopsy. Microscopic examination revealed epidermal hyperplasia composed of keratinocytes filled with large eosinophilic intracytoplasmic inclusions. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of molluscum contagiosum was established. The patient applied mupirocin 2% ointment to the biopsy sites, which subsequently healed without complication or recurrence.Conclusion: Molluscum contagiosum is a benign viral papular eruption that frequently affects children and immunocompromised adults. Patients treated with immunosuppressive agents, such as methotrexate, have a heightened risk of developing molluscum contagiosum lesions. It remains to be determined whether adjunct therapy with a tumor necrosis factor alpha inhibitor increasesthe risk of this viral infection. Diagnosis can usually be established by clinical presentation, although a biopsy is sometimesrequired to exclude other conditions. Molluscum contagiosum is generally self-limiting and often resolves spontaneously within18 months. However, topical (cantharidin) or locally destructive (curettage, cryotherapy, and/or laser) therapy may be indic tedfor patients who are concerned about persistent lesions and for children who are particularly susceptible to autoinoculation.

BackgroundLocalized cutaneous argyria is a rare skin condition caused by direct contact with silver or silver particles. It presents as asymptomatic gray or blue-gray macules that appear similar to blue nevi. Histologic features include brown-colored or black-colored silver granules in the basement membrane and dermis, most commonly surrounding eccrine glands, elastic fibers, and collagen fibrils. The condition is most frequently observed in individuals who are regularly exposed to small silver particles, such as silversmiths and welders. However, localized cutaneous argyria has also been associated with acupuncture needles, silver earrings, and topical medications containing silver nitrate. Although the condition is benign, patients who are concerned about the cosmetic features of localized cutaneous argyria may benefit from laser therapy.PurposeWe describe the clinical and pathologic findings of two women who developed localized cutaneous argyria. We also review the characteristics of other patients with localized cutaneous argyria and summarize the differential diagnosis and treatment options for this condition.Materials and methodsThe features of two women with localized cutaneous argyria are presented. Using PubMed, the following terms were searched and relevant citations assessed: acquired localized argyria, acupuncture, argyria, argyrosis, colloidal silver, cutaneous argyria, and localized cutaneous argyria. In addition, the literature on localized cutaneous argyria is reviewed.ResultsTwo women presented with small, asymptomatic blue-gray macules appearing at sites directly adjacent to ear piercings. A punch biopsy was performed on one woman. Microscopic examination revealed a yellowish-brown colored granular material found adjacent to elastic fibers. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of localized cutaneous argyria was established. The second woman did not undergo a biopsy. However, the clinical presentation was highly suggestive of localized cutaneous argyria. Both women were reassured of the benign nature of the condition and agreed to return for clinical follow-up if they observed any changes in the appearance of the lesions.

Background: Intravascular papillary endothelial hyperplasia -- also known as Masson tumor -- is a rare, benign vascular condition that manifests on the skin as a firm, blue-black colored nodule or papule. Lesions range in size from 0.25 to 5 centimeters in diameter and may be tender or painless. In some individuals, nodules appear red colored, mimicking hemangioma or pyogenic granuloma. Histologically, intravascular papillary endothelial hyperplasia is characterized by the presence of an organizing thrombus in the vascular lumen with accompanying hyperplastic endothelial cell proliferation. Common sites of presentation include the head, neck, and extremities. However, albeit rarely, lesions may also appear in the genital region.Purpose: We describe the clinical and pathologic findings of a woman who developed intravascular papillary endothelial hyperplasia of the vulva. We also review the characteristics of other patients with intravascular papillary endothelial hyperplasia of the vulva and summarize the differential diagnosis and treatment options for this condition.Materials and methods: The features of a woman with intravascular papillary endothelial hyperplasia of the vulva are presented. Using PubMed, the following terms were searched and relevant citations assessed: intravascular papillary endothelial hyperplasia, IPEH, labia majora, Masson hemangioma, Masson pseudoangiosarcoma, Masson tumor, and vulva. In addition, the literature on intravascular papillary endothelial hyperplasia is reviewed.Results: A 32-year-old woman presented with a 3 x 2 millimeter painless, black colored submucosal papule on her left labia majora. The lesion was removed by excisional biopsy. Microscopic examination revealed a re-canalizing thrombus and a proliferation of erythrocytes within a dilated vascular structure. Based on correlation of the clinical presentation and histopathologic findings, a diagnosis of intravascular papillary endothelial hyperplasia was established. The patient applied mupirocin 2% ointment to the biopsy site, which subsequently healed without complication or recurrence.Conclusion: Intravascular papillary endothelial hyperplasia -- also known as Masson tumor -- is a rare, benign vascular eruption. Cutaneous lesions typically present as red colored or blue-black colored nodules ranging in size from 0.25 to 5 centimeters in diameter. The most common sites of presentation include the head, neck, and extremities. However, albeit rarely, lesions may also appear in the genital region. The histologic hallmark of intravascular papillary endothelial hyperplasia is an organizing thrombus in the vascular lumen with associated hyperplastic endothelial cell proliferation. Lesions often appears similar to other neoplastic and non-neoplastic cutaneous tumors, including hemangiomas, pyogenic granulomas, and cutaneous angiosarcomas. Therefore, pathologic examination is required to confirm the suspected diagnosis and exclude malignancy. The condition can usually be treated with simple local excision.

Background: Cryotherapy-induced milia is a rarely described cutaneous reaction that may occur in patients who have received cryotherapy with liquid nitrogen. Cryotherapy-induced milia is characterized by 1-2 millimeter white dermal cysts that develop at the healed cryotherapy site. Milia en plaque, an erythematous plaque containing numerous milia, has not previously been described following treatment of a skin lesion with liquid nitrogen cryotherapy.Purpose:  We describe a man who developed cryotherapy-induced milia en plaque after receiving cryotherapy to his dorsal hand for the treatment of an actinic keratosis. We also summarize the potential complications of cryotherapy, the differential diagnosis of milia en plaque, and therapeutic interventions for this lesion.Materials and methods:  The features of a man with cryotherapy-induced milia en plaque are presented. Using PubMed, the following terms were searched and relevant citations assessed: cryosurgery, cryotherapy, hypothermia, milia, milia en plaque, and Wolf's isotopic response. In addition, the literature on cryotherapy-induced milia and cryotherapy-induced milia en plaque is reviewed.Results:  Our patient developed cryotherapy-induced milia en plaque shortly after his cryotherapy site had healed. Some of the asymptomatic cystic dermal lesions had spontaneously resolved when a lesional biopsy was performed to confirm the diagnosis. The diagnosis, natural course, and potential treatments were discussed with the patient. Subsequent management was to observe the area; at follow-up examination, the remainder of the milia had also spontaneously resolved. Conclusion:  Cryotherapy-induced milia is a benign condition characterized by the development of small white dermal cystic lesions that develop at a healed liquid nitrogen cryotherapy site. The lesions may appear individually or as milia en plaque. While the mechanism of pathogenesis is unknown, we postulate that the condition is an example of Wolf's isotopic response, in which a new, unrelated skin disease develops at the site of a previously healed dermatosis - in this circumstance, following cryotherapy which created an immune compromised zone. The diagnosis of milia en plaque can usually be established by clinical presentation; if necessary, a biopsy can be performed to provide pathologic confirmation of the suspected diagnosis. Treatment options include manual extraction, topical retinoids, or observation. Similar to our patient, the milia may resolve spontaneously.

Abstract Diffuse large B‐cell lymphoma often presents with extranodal manifestations involving the musculoskeletal system. Shoulder pain is particularly worrisome for malignancy. Individuals presenting with refractory upper extremity complaints should undergo a prompt and thorough evaluation for cancer, as a delay in diagnosis can result in an unfavorable outcome.

Lithium salts continue to find pharmaceutical applications, particularly as psychiatric medications. As with any active pharmaceutical ingredient, structural polymorphism is an important concern for lithium-based medications that can influence solubility and other physicochemical properties. Here we report a 13C, 1H, and 7Li magic-angle spinning solid-state nuclear magnetic resonance (MAS SSNMR) study of two 1:1 polymorphic ionic cocrystals of lithium 4-methoxybenzoate and L-proline (L4MPRO(α) and L4MPRO(β)). One-dimensional 13C cross-polarization MAS and two-dimensional heteronuclear correlation NMR spectra hint at differential mobilities of the proline and benzoate moieties for the two polymorphs. Five key resonances differ in 13C chemical shift by more than 1 ppm between the two polymorphs, clearly distinguishing between them. Gauge-including projector-augmented-wave density functional theory calculations of 13C and 1H magnetic shielding constants correlate strongly with the experimental chemical shifts for both polymorphs. R2 and root-mean-square deviation metrics are shown to be insufficient in the case of 13C, but sufficient in the case of 1H, for differentiating between the polymorphs. 7Li satellite-transition MAS NMR of both polymorphs are identical, as are the computed lithium magnetic shielding constants, demonstrating the insensitivity of 7Li NMR to polymorphism in these samples. This work highlights the utility of solid-state NMR spectroscopy for examining ionic salt cocrystals and also highlights some caveats in this regard. [ABSTRACT FROM AUTHOR]