The role of surgical disconnection for posterior fossa pial arteriovenous fistulas and dural fistulas with pial supply: an illustrative case series.

BACKGROUND: Pial arteriovenous fistulas (pAVFs) are rare vascular malformations characterized by high-flow arteriovenous shunting involving a cortical arterial supply directly connecting to venous drainage without an intermediate nidus. Dural arteriovenous fistulas (dAVFs) can infrequently involve additional pial feeders which can introduce higher flow shunting and increase the associated treatment risk. In the posterior fossa, arteriovenous fistula (AVF) angioarchitecture tends to be particularly complex, involving either multiple arterial feeders-sometimes from both dural and pial origins-or small caliber vessels that are difficult to catheterize and tend to be intimately involved with functionally critical brainstem or upper cervical cord structures. Given their rarity, published experience on microsurgical or endovascular treatment strategies for posterior fossa pAVFs and dAVFs with pial supply remains limited. METHODS: Retrospective chart review from 2019-2023 at a high-volume center identified six adult patients with posterior fossa pAVFs that were unable to be fully treated endovascularly and required microsurgical disconnection. These cases are individually presented with a technical emphasis and supported by comprehensive angiographic and intraoperative images. RESULTS: One vermian (Case 1), three cerebellopontine angle (Cases 2-4) and two craniovertebral junction (Cases 5-6) posterior fossa pAVFs or dAVFs with pial supply are presented. Three cases involved mixed dural and pial arterial supply (Cases 1, 4, and 6), and one case involved a concomitant microAVM (Case 2). Endovascular embolization was attempted in four cases (Cases 1-4): The small caliber and tortuosity of the main arterial feeder prevented catheterization in two cases (Cases 1 and 3). Partial embolization was achieved in Cases 2 and 4. In Cases 5 and 6, involvement of the lateral spinal artery or anterior spinal artery created a prohibitive risk for endovascular embolization, and surgical clip ligation was pursued as primary management. In all cases, microsurgical disconnection resulted in complete fistula obliteration without evidence of recurrence on follow-up imaging (mean follow-up 27.1 months). Two patients experienced persistent post-treatment sensory deficits without significant functional limitation. CONCLUSIONS: This illustrative case series highlights the technical difficulties and anatomical limitations of endovascular management for posterior fossa pAVFs and dAVFs with pial supply and emphasizes the relative safety and utility of microsurgical disconnection in this context. A combined approach involving partial preoperative embolization-when the angioarchitecture is permissive-can potentially decrease surgical morbidity. Larger studies are warranted to better define the role for multimodal intervention and to assess associated long-term AVF obliteration rates in the setting of pial arterial involvement.

Pituitary metastases: a case series and scoping review.

PURPOSE: To understand the natural history and optimal treatment strategy for pituitary gland metastasis. METHODS: We performed both a retrospective chart review of patients treated at our institution and a scoping review of the topic. RESULTS: The retrospective review identified seven patients with an average age of 59.6 years. Primary histologies included breast cancer (4), melanoma (1), renal cell carcinoma (1), and sarcoma (1). Two patients had anterior pituitary endocrine dysfunction, one of whom was the only patient with visual symptoms. All patients were treated with radiosurgery and two also underwent surgical resection. Overall survival ranged from 6.5 to 117 months. Literature review identified 166 patients from 71 studies. The most common primary cancer was lung (27.7%), followed by breast (18.7%) and renal (14.5%) cancer. 107 presented with endocrine dysfunction, including 41 cases of diabetes insipidus and 55 cases of hypopituitarism. 110 presented with visual compromise. 107 patients received radiotherapy, 96 underwent surgical resection and 44 received systemic chemotherapy/immunotherapy. Surgery was significantly associated with an increased likelihood of vision improvement and a decreased likelihood of endocrine normalization. Radiographic regression predicted visual improvement. Median overall survival was 9.9 months (range: 0.2-96). CONCLUSIONS: This scoping review showed that both radiosurgery and surgical resection have been frequently used to treat pituitary metastases with good response. Vision improvement is more likely to happen following surgical resection, likely at the expense of endocrine dysfunction. Despite treatment and radiographic response, patient survival remains less than a year.

Long-term outcomes of surgical clipping of saccular middle cerebral artery aneurysms: a consecutive series of 92 patients.

Despite advances in endovascular treatment, microsurgical clipping of middle cerebral artery (MCA) aneurysms remains appropriate. We review the high occlusion rate and treatment durability seen with surgical clipping of MCA aneurysms. We retrospectively reviewed patients who underwent microsurgical clipping of saccular MCA aneurysms by a single surgeon. Outcomes included aneurysm occlusion rate and durability, modified Rankin scale (mRS), and postoperative neurological morbidities. Ninety-two patients with 92 saccular MCA aneurysms were included, 50% of which were ruptured aneurysms. The mean follow-up period was 59 months. Complete aneurysm occlusion was achieved in all except one patient (99%) with near-complete occlusion. MCA aneurysm clipping was durable, with only one patient (1%) requiring retreatment after 4 years due to regrowth. Of the cohort, 79.3% achieved mRS 0-2 at last follow-up, including all with unruptured aneurysms. Poor outcome at discharge was associated with age > 65 (p = .03), postoperative neurological morbidities (p = .006), and aneurysm rupture (p < .001). Older age remained the single correlate for poor long-term outcome (p = .04). For ruptured aneurysms, predictors of poor long-term outcome included hemiparesis on presentation (p = .017), clinical vasospasm requiring treatment (p = .026), and infarction related to vasospasm (p = .041). Older age (p = .046) and complex anatomy (p = .036) were predictors of new postoperative neurological morbidities in the unruptured group. MCA aneurysm clipping is safe, durable, and should be considered first-line treatment for patients with saccular MCA aneurysms, especially in centers with abundant surgical experience.

The Effect of Derotational Kirschner Wires on Fracture Gap Reduction With Variable-Pitch Headless Screws.

PURPOSE: We evaluated the impact of angled derotational Kirschner wires (K-wires) on fracture gap reduction with variable-pitch headless screws. METHODS: Fully threaded variable-pitch headless screws (20 and 28 mm) were inserted into "normal" bone models of polyurethane blocks. In separate trials, derotational K-wires were inserted at predetermined angles of 0°, 15°, 30°, and 40° and compared with each other, with no K-wire as a control. Fluoroscopic images taken after each screw turn were analyzed. The optimal fracture gap closure, initial screw push-off, and screw back-out gap creation were determined and compared at various derotational K-wire angles. RESULTS: Initial screw push-off due to screw insertion and screw back-out gap creation were not significantly affected by the angle of the derotational K-wire. With a 20-mm screw, only a 40° derotational K-wire led to significantly less gap closure compared with control and with 0°, 15°, and 30° derotational K-wires. It led to an approximately 60% decrease in gap closure compared with no K-wire. With the 28-mm screw, compared with no K-wire, 15° and 30° derotational K-wires led to statistically significant decreases in gap closure (approximately 25%), whereas a 40° derotational K-wire led to an approximately 60% decrease. With the 28-mm screw, the 40° derotational K-wire also led to a statistically significant smaller gap closure when compared with 0°, 15°, and 30° derotational K-wires. CONCLUSIONS: A derotational K-wire placed in parallel to the planned trajectory of a headless compression screw does not affect fracture gap closure. With greater angulation of the derotational K-wire, the fracture gap is still closed, but less tightly. CLINICAL RELEVANCE: Derotational K-wires can help prevent fracture fragment rotation during headless compression screw insertion. At small deviations from parallel (≤30°), fracture gap closure achieved by the screw is minimally affected. At greater angles (ie, 40°), fracture gap closure may be substantially reduced, preventing fracture compression.

Hyperperfusion syndrome after superficial temporal artery-middle cerebral artery bypass for non-moyamoya steno-occlusive disease.

BACKGROUND AND OBJECTIVES: Stroke is a major cause of morbidity and mortality worldwide, and intracranial stenoses increase the risk for stroke. Superficial temporal artery to middle cerebral artery bypass can be beneficial in selected patients with non-moyamoya steno-occlusive disease, however data is limited regarding the postoperative occurrence of hyperperfusion syndrome in this population. This case series describes the outcomes and complications, including hyperperfusion, in these patients who underwent bypass. METHODS: This is a retrospective review of bypass procedures done for medically refractory intracranial stenosis at a single institution by a single surgeon between 2014 and 2021. RESULTS: 30 patients underwent 33 bypass procedures for unequivocal non-moyamoya steno-occlusive disease. All patients had immediate bypass patency on post-operative day one. Major perioperative complications (9%) included one stroke and two cases of hyperperfusion syndrome. Minor perioperative complications (12%) included two seizures, one superficial wound infection and one deep vein thrombosis. Modified Rankin Score improved in 20 patients (74%), worsened in one patient (4%), and remained stable in seven patients (22%) at the last follow up. Twenty-three patients (85%) had scores ≤ 2. The recurrent stroke rate was 3% at 30 days and 7% at two years. The bypass patency rate at one year was 87.5%. CONCLUSION: In this series, bypass for patients with medically refractory non-moyamoya steno-occlusive disease was well tolerated and effective, with overall favorable outcomes. The occurrence of hyperperfusion syndrome is rare but significant and should be considered in post-operative management of this population.

Individual Placement and Support for People with Autism Spectrum Disorders: A Pilot Program.

Young adults with autism spectrum disorder (ASD) experience significant rates of unemployment and underemployment, and the field needs an inexpensive, evidence-based vocational intervention. We examined an approach developed for people with serious mental illness, IPS supported employment, for young adults with ASD. We described a pilot IPS program for young adults with ASD and evaluated the first five participants over 1 year. The first five IPS participants succeeded in competitive employment, expanded independence, and achieved broad psychosocial gains. IPS could help young adults with ASD succeed in competitive employment at a relatively low cost.

Business Associations, Conservative Networks, and the Ongoing Republican War over Medicaid Expansion.

A major component of the Affordable Care Act involves the expansion of state Medicaid programs to cover the uninsured poor. In the wake of the 2012 Supreme Court decision upholding and modifying reform legislation, states can decide whether to expand Medicaid-and twenty states are still not proceeding as of August 2015. What explains state choices about participation in expansion, including governors' decisions to endorse expansion or not as well as final state decisions? We tackle this puzzle, focusing closely on outcomes and battles in predominantly Republican-led states. Like earlier scholars, we find that partisan differences between Democrats and Republicans are central, but we go beyond earlier analyses to measure added effects from two dueling factions within the Republican coalition: statewide business associations and cross-state networks of ideologically conservative organizations. Using both statistical modeling and case studies, we show that GOP-leaning or GOP-dominated states have been most likely to embrace the expansion when organized business support outweighs pressures from conservative networks. Our findings help make sense of ongoing state-level debates over a core part of health reform and shed new light on mounting policy tensions within the Republican Party.

Group housing and nest building only slightly ameliorate the cold stress of typical housing in female C57BL/6J mice.

Huddling and nest building are two methods of behavioral thermoregulation used by mice under cold stress. In the laboratory, mice are typically housed at an ambient temperature (Ta) of 20°C, well below the lower end of their thermoneutral zone. We tested the hypothesis that the thermoregulatory benefits of huddling and nest building at a Ta of 20°C would ameliorate this cold stress compared with being singly housed at 20°C as assessed by heart rate (HR), blood pressure (BP), triiodothyronine (T3), brown adipose (BAT) expression of Elovl3 mRNA, and BAT lipid content. A series of experiments using C57BL/6J female mice exposed to 20°C in the presence or absence of nesting material and/or cage mates was used to test this hypothesis. Mice showed large differences in HR, BP, shivering, and core body temperature (Tb) when comparing singly housed mice at 20°C and 30°C, but only a modest reduction in HR with the inclusion of cage mates or bedding. However, group housing and/or nesting at 20°C decreased T3 levels compared with singly housed mice at 20°C. Singly housed mice at 20°C had a 22-fold higher level of BAT Elovl3 mRNA expression and a significantly lower triacylglycerol (TAG) content of BAT compared with singly housed mice at 30°C. Group housing at 20°C led to blunted changes in both Elovl3 mRNA and TAG levels. These findings suggest that huddling and nest building have a limited effect to ameliorate the cold stress associated with housing at 20°C.

Crystal structures and hydrogen bonding in the co-crystalline adducts of 3,5-di-nitro-benzoic acid with 4-amino-salicylic acid and 2-hy-droxy-3-(1H-indol-3-yl)propenoic acid.

The structures of the co-crystalline adducts of 3,5-di-nitro-benzoic acid (3,5-DNBA) with 4-amino-salicylic acid (PASA), the 1:1 partial hydrate, C7H4N2O6·C7H7NO3·0.2H2O, (I), and with 2-hy-droxy-3-(1H-indol-3-yl)propenoic acid (HIPA), the 1:1:1 d (6)-dimethyl sulfoxide solvate, C7H4N2O6·C11H9NO3·C2D6OS, (II), are reported. The crystal substructure of (I) comprises two centrosymmetric hydrogen-bonded R 2 (2)(8) homodimers, one with 3,5-DNBA, the other with PASA, and an R 2 (2)(8) 3,5-DNBA-PASA heterodimer. In the crystal, inter-unit amine N-H⋯O and water O-H⋯O hydrogen bonds generate a three-dimensional supra-molecular structure. In (II), the asymmetric unit consists of the three constituent mol-ecules, which form an essentially planar cyclic hydrogen-bonded heterotrimer unit [graph set R 3 (2)(17)] through carboxyl, hy-droxy and amino groups. These units associate across a crystallographic inversion centre through the HIPA carb-oxy-lic acid group in an R 2 (2)(8) hydrogen-bonding association, giving a zero-dimensional structure lying parallel to (100). In both structures, π-π inter-actions are present [minimum ring-centroid separations = 3.6471 (18) Šin (I) and 3.5819 (10) Šin (II)].

Crystal structures of the co-crystalline adduct 5-(4-bromo-phen-yl)-1,3,4-thia-diazol-2-amine-4-nitro-benzoic acid (1/1) and the salt 2-amino-5-(4-bromo-phen-yl)-1,3,4-thia-diazol-3-ium 2-carb-oxy-4,6-di-nitro-phenolate.

The structures of the 1:1 co-crystalline adduct C8H6BrN3S·C7H5NO4, (I), and the salt C8H7BrN3S(+)·C7H3N2O7 (-), (II), obtained from the inter-action of 5-(4-bromo-phen-yl)-1,3,4-thia-diazol-2-amine with 4-nitro-benzoic acid and 3,5-di-nitro-salicylic acid, respectively, have been determined. The primary inter-species association in both (I) and (II) is through duplex R (2) 2(8) (N-H⋯O/O-H⋯O) or (N-H⋯O/N-H⋯O) hydrogen bonds, respectively, giving heterodimers. In (II), these are close to planar [the dihedral angles between the thia-diazole ring and the two phenyl rings are 2.1 (3) (intra) and 9.8 (2)° (inter)], while in (I) these angles are 22.11 (15) and 26.08 (18)°, respectively. In the crystal of (I), the heterodimers are extended into a chain along b through an amine N-H⋯Nthia-diazole hydrogen bond but in (II), a centrosymmetric cyclic hetero-tetra-mer structure is generated through N-H⋯O hydrogen bonds to phenol and nitro O-atom acceptors and features, together with the primary R (2) 2(8) inter-action, conjoined R (4) 6(12), R (2) 1(6) and S(6) ring motifs. Also present in (I) are π-π inter-actions between thia-diazole rings [minimum ring-centroid separation = 3.4624 (16) Å], as well as short Br⋯Onitro inter-actions in both (I) and (II) [3.296 (3) and 3.104 (3) Å, respectively].

MRI order appropriateness for chronic neck pain: Comparison of ordering practices and treatment outcomes for primary care physicians and specialists.

Chronic neck pain is a common reason for doctor visits in the United States. This diagnosis can be evaluated through patient history, physical examination, and judicious use of radiographs. However, possible inappropriate magnetic resonance imaging (MRI) ordering persists. We hypothesized that no difference in ordering practices, ordering appropriateness, and subsequent intervention would be appreciated regarding physician specialty, location, patient characteristics, and history and physical exam findings. A multisite retrospective review of cervical spine MRI between 2014 and 2018 was performed. A total of 332 patients were included. Statistical analysis was used to assess MRI order appropriateness, detail of history and physical exam findings, and intervention decision-making among different specialties. If significant differences were found, multiple linear regression was performed to evaluate the association of MRI order appropriateness regarding physician specialty, location, patient characteristics and history, and physical exam findings. The significance level for all tests was set at <0.05 Orthopedic surgeons ordered MRIs most appropriately with an average American College of Radiology (ACR) score of 8.4 (p < 0.005). Orthopedic surgeons had more comprehensive physical exams as compared to the remaining specialties. The decision for intervention did not vary by physician specialty or ACR score, except for patients of pain medicine physicians who received pain management (p = 0.000). Orthopedic surgeons utilize MRI most appropriately and have more comprehensive physical exams. These findings suggest a need for increased physician education on what indicates an appropriate MRI order to improve the use of resources and further protect patient risk-benefit profiles. Further research elucidating factors to minimize negative findings in "appropriate" MRIs is indicated. Clinical significance: More detailed physical exams may lead to more appropriately ordered MRIs, subsequently resulting in surgery or procedures being performed when appropriately indicated. This suggests the need for increased physician education on when MRI ordering is appropriate for chronic neck pain to improve the use of resources and further protect patient risk-benefit profiles.

A Quantitative Assessment of ChatGPT as a Neurosurgical Triaging Tool.

BACKGROUND AND OBJECTIVES: ChatGPT is a natural language processing chatbot with increasing applicability to the medical workflow. Although ChatGPT has been shown to be capable of passing the American Board of Neurological Surgery board examination, there has never been an evaluation of the chatbot in triaging and diagnosing novel neurosurgical scenarios without defined answer choices. In this study, we assess ChatGPT's capability to determine the emergent nature of neurosurgical scenarios and make diagnoses based on information one would find in a neurosurgical consult. METHODS: Thirty clinical scenarios were given to 3 attendings, 4 residents, 2 physician assistants, and 2 subinterns. Participants were asked to determine if the scenario constituted an urgent neurosurgical consultation and what the most likely diagnosis was. Attending responses provided a consensus to use as the answer key. Generative pretraining transformer (GPT) 3.5 and GPT 4 were given the same questions, and their responses were compared with the other participants. RESULTS: GPT 4 was 100% accurate in both diagnosis and triage of the scenarios. GPT 3.5 had an accuracy of 92.59%, slightly below that of a PGY1 (96.3%), an 88.24% sensitivity, 100% specificity, 100% positive predictive value, and 83.3% negative predicative value in triaging each situation. When making a diagnosis, GPT 3.5 had an accuracy of 92.59%, which was higher than the subinterns and similar to resident responders. CONCLUSION: GPT 4 is able to diagnose and triage neurosurgical scenarios at the level of a senior neurosurgical resident. There has been a clear improvement between GPT 3.5 and 4. It is likely that the recent updates in internet access and directing the functionality of ChatGPT will further improve its utility in neurosurgical triage.

Single-center outcomes of Onyx Frontier™ and Resolute Onyx™ drug-eluting balloon-mounted stents for rescue stenting for acute large vessel occlusion.

BACKGROUND: In cases where mechanical thrombectomy (MT) fails, rescue stenting may be necessary to achieve reperfusion; however, the lack of standardized techniques or devices poses a challenge. This series aims to present our early experience with the Onyx Frontier™ and Resolute Onyx™ balloon-mounted drug-eluting stents for rescue stenting. METHODS: A retrospective chart review was performed of all patients who underwent rescue stenting, in the setting of failed MT, using Onyx Frontier™ or Resolute Onyx™ stents at a single institution. Technical details, procedural complications, and patient outcomes were recorded for each case. RESULTS: Twenty-two Onyx Frontier™ and Resolute Onyx™ stents were deployed in 18 patients undergoing rescue stenting. Stent locations included the middle cerebral artery (36.4%), internal carotid artery (18.2%), vertebral artery (22.7%), and basilar artery (22.7%). The average National Institutes of Health Stroke Scale score before MT was 13.8 (range 0-31). The median initial modified Rankin Scale (mRS) score was zero, while the median mRS score at follow-up was three. Successful reperfusion, as assessed by TICI scores, was achieved in 43.8% of patients for TICI 3, 43.8% for TICI 2C, and 12.5% for TICI 2B. Post-revascularization, 16.7% of patients experienced hemorrhage, of which one patient (5.6%) had symptomatic hemorrhage. CONCLUSIONS: Onyx Frontier™ and Resolute Onyx™ stents are well suited for rescue stenting in cases of failed MT. These balloon-mounted drug-eluting stents exhibit excellent navigability, rendering them appropriate for rescue revascularization procedures. Our findings demonstrate that these stents confer a high degree of technical success.

The origins and genetic distinctiveness of the Chamorros of the Marianas Islands: an mtDNA perspective.

BACKGROUND: Archaeological and linguistic evidence suggests the Marianas Islands were settled around 3,600 years before present (ybp) from Island Southeast Asia (ISEA). Around 1,000 ybp latte stone pillars and the first evidence of rice cultivation appear in the Marianas. Both traditions are absent in the rest of prehistoric Oceania. OBJECTIVE: To examine the genetic origins and postsettlement gene flow of Chamorros of the Marianas Islands. METHODS: To infer the origins of the Chamorros we analyzed ∼360 base pairs of the hypervariable-region 1 (HVS1) of mitochondrial DNA from 105 Chamorros from Guam, Rota, and Saipan, and the complete mitochondrial genome of 32 Guamanian Chamorros, and compared them to lineages from ISEA and neighboring Pacific archipelagoes from the database. RESULTS: Results reveal that 92% of Chamorros belong to haplogroup E, also found in ISEA but rare in Oceania. The two most numerous E lineages were identical to lineages currently found in Indonesia, while the remaining E lineages differed by only one or two mutations and all were unique to the Marianas. Seven percent of the lineages belonged to a single Chamorro-specific lineage within haplogroup B4, common to ISEA as well as Micronesia and Polynesia. CONCLUSIONS: These patterns suggest a small founding population had reached and settled the Marianas from ISEA by 4,000 ybp, and developed unique mutations in isolation. A second migration from ISEA may have arrived around 1,000 ybp, introducing the latte pillars, rice agriculture and the homogeneous minority B4 lineage.

Molecular cocrystals of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine: hydrogen bonding in the structures of the 1:1 adduct with 2-(naphthalen-2-yloxy)acetic acid and the salt with 3,5-dinitrobenzoic acid.

The crystal structures of the anhydrous products from the interaction of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine with 2-(naphthalen-2-yloxy)acetic acid, viz. the 1:1 adduct C8H6BrN3S·C12H10O3, (I), and with 3,5-dinitrobenzoic acid, viz. the salt 2-amino-5-(4-bromophenyl)-1,2,4-thiadiazol-3-ium 3,5-dinitrobenzoate, C8H7BrN3S(+)·C7H3N2O6(-), (II), have been determined. In adduct (I), a heterodimer is formed through a cyclic hydrogen-bonding motif [graph set R2(2)(8)], involving carboxylic acid-heteroatom O-H···N and amine-carboxylic acid N-H···O interactions. The heterodimers are essentially planar, with a thiadiazole-to-naphthalene ring dihedral angle of 15.9 (2)° and an intramolecular thiadiazole-to-benzene ring angle of 4.7 (2)°. An amine-heteroatom N-H···N hydrogen bond between the heterodimers generates a one-dimensional chain structure extending down [001]. Also present are weak benzene-benzene and naphthalene-naphthalene π-π stacking interactions down the b axis [minimum ring-centroid separation = 3.936 (3) Å]. With salt (II), the cation-anion association is also through a cyclic R2(2)(8) motif but involving duplex N-H···O(carboxylate) hydrogen bonds, giving a heterodimer that is close to planar [dihedral angles between the thiadiazole ring and the two benzene rings = 5.00 (16) (intra) and 7.23 (15)° (inter)]. A secondary centrosymmetric cyclic RR4(2)(8) N-H···O(carboxylate) hydrogen-bonding association involving the second amino H atom generates a heterotetramer. Also present in the crystal structure are weak π-π interactions between thiadiazolium rings [minimum ring-centroid separation = 3.9466 (18) Å], as well as a short Br···O(nitro) interaction [3.314 (4) Å]. The two structures reported here now provide a total of three crystallographically characterized examples of cocrystalline products from the interaction of 5-(4-bromophenyl)-1,3,4-thiadiazol-2-amine with carboxylic acids, of which only one involves proton transfer.

2-[(3,3-Di-methyl-indolin-2-yl-idene)meth-yl]-4-[(3,3-dimethyl-3H-indol-1-ium-2-yl)methyl-idene]-3-oxo-cyclo-but-1-en-1-olate chloro-form disolvate.

In the title squaraine dye solvate, C26H24N2O2·2CHCl3, the dye mol-ecule is essentially planar, except for the methyl groups, having a maximum deviation over the 26-membered delocalized bond system of 0.060 (2) Å. It possesses crystallographic twofold rotational symmetry with the indole ring systems adopting a syn conformation. The mol-ecular structure features intra-molecular N-H⋯O hydrogen bonds enclosing conjoint S7 ring motifs about one of the dioxo-cyclo-butene O atoms, while the two chloro-form solvent mol-ecules are linked to the second O atom through C-H⋯O hydrogen bonds.

4-Hy-droxy-1,2,6-tri-methyl-pyridinium chloride monohydrate.

In the crystal of the title hydrated mol-ecular salt, C8H12NO(+)·Cl(-)·H2O, the water mol-ecule makes two O-H⋯Cl hydrogen bonds, generating [010] zigzag chains of alternating water mol-ecules and chloride ions. The cation is bonded to the chain by an O-H⋯O hydrogen bond and two weak C-H⋯Cl inter-actions. Weak aromatic π-π stacking [centroid-centroid separation = 3.5175 (15) Å] occurs between the chains.

1-Allyl-2-amino-pyridin-1-ium bromide.

In the cation of the title salt, C8H11N2 (+)·Br(-), the dihedral angle between the planes of the pyridinium ring and the allyl group is 79.4 (3)°. In the crystal, N-H⋯Br and weak C-H⋯Br hydrogen bonds link the cations and anions, forming chains of alternating R 2 (1)(7) and R 4 (2)(8) rings, which run parallel to the c-axis direction. The crystal studied was an inversion twin with components in a 0.753 (12):0.247 (12) ratio.

4-Hy-droxy-1,2,6-tri-methyl-pyridinium bromide monohydrate.

The title salt, C8H12NO(+)·Br(-)·H2O, is isomorphous with the chloride analogue [Seethalakshmi et al. (2013). Acta Cryst. E69, o835-o836]. In the solid state, the cations, anions and water mol-ecules are inter-linked by a network of O-H⋯O, O-H⋯Br and C-H⋯Br inter-actions. The water mol-ecule makes two O-H⋯Br hydrogen bonds, generating [010] zigzag chains of alternating water mol-ecules and bromide anions. The cation is involved in two inter-molecular C-H⋯Cl inter-actions in the chloride salt, whereas three inter-molecular C-H⋯Br inter-actions are observed in the title bromide salt. This additional inter-molecular C-H⋯Br inter-action links the adjacent water and bromide zigzag chains via cationic mol-ecules. In addition, weak π-π stacking inter-actions are observed between pyridinium rings [centroid-centroid distance = 3.5664 (13) Å].

Multi-Mechanistic Approaches to the Treatment of Traumatic Brain Injury: A Review.

Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Despite extensive research efforts, the majority of trialed monotherapies to date have failed to demonstrate significant benefit. It has been suggested that this is due to the complex pathophysiology of TBI, which may possibly be addressed by a combination of therapeutic interventions. In this article, we have reviewed combinations of different pharmacologic treatments, combinations of non-pharmacologic interventions, and combined pharmacologic and non-pharmacologic interventions for TBI. Both preclinical and clinical studies have been included. While promising results have been found in animal models, clinical trials of combination therapies have not yet shown clear benefit. This may possibly be due to their application without consideration of the evolving pathophysiology of TBI. Improvements of this paradigm may come from novel interventions guided by multimodal neuromonitoring and multimodal imaging techniques, as well as the application of multi-targeted non-pharmacologic and endogenous therapies. There also needs to be a greater representation of female subjects in preclinical and clinical studies.