Risk loci identified through genome-wide association studies have explained about 25% of the phenotypic variations in nonsyndromic orofacial clefts (nsOFCs) on the liability scale. Despite the notable sex differences in the incidences of the different cleft types, investigation of loci for sex-specific effects has been understudied. To explore the sex-specific effects in genetic etiology of nsOFCs, we conducted a genome-wide gene × sex (GxSex) interaction study in a sub-Saharan African orofacial cleft cohort. The sample included 1,019 nonsyndromic orofacial cleft cases (814 cleft lip with or without cleft palate and 205 cleft palate only) and 2,159 controls recruited from 3 sites (Ethiopia, Ghana, and Nigeria). An additive logistic model was used to examine the joint effects of the genotype and GxSex interaction. Furthermore, we examined loci with suggestive significance (P < 1E-5) in the additive model for the effect of the GxSex interaction only. We identified a novel risk locus on chromosome 8p22 with genome-wide significant joint and GxSex interaction effects (rs2720555, p2df = 1.16E-08, pGxSex = 1.49E-09, odds ratio [OR] = 0.44, 95% CI = 0.34 to 0.57). For males, the risk of cleft lip with or without cleft palate at this locus decreases with additional copies of the minor allele (p < 0.0001, OR = 0.60, 95% CI = 0.48 to 0.74), but the effect is reversed for females (p = 0.0004, OR = 1.36, 95% CI = 1.15 to 1.60). We replicated the female-specific effect of this locus in an independent cohort (p = 0.037, OR = 1.30, 95% CI = 1.02 to 1.65), but no significant effect was found for the males (p = 0.29, OR = 0.86, 95% CI = 0.65 to 1.14). This locus is in topologically associating domain with craniofacially expressed and enriched genes during embryonic development. Rare coding mutations of some of these genes were identified in nsOFC cohorts through whole exome sequencing analysis. Our study is additional proof that genome-wide GxSex interaction analysis provides an opportunity for novel findings of loci and genes that contribute to the risk of nsOFCs.

Objectives: To conduct a systematic review and meta-analysis to assess whether individuals with nonsyndromic orofacial clefts (OCs) display a higher frequency of dental anomalies (DAs) when compared with individuals without OCs. Methods: A literature search of indexed databases (PubMed, Cochrane, Web of Science, Embase, Scopus, and LILACS) was conducted without language restriction up to and including February 1, 2020. Cross-referencing was used to further identify articles. Several cleft teams across the United States and Europe were contacted to obtain unpublished data. The eligibility criteria were observational studies with original data that statistically compared individuals with OC without syndromes and those without OC on any type of DA in primary and/or permanent dentition. Random effects meta-analysis through the Mantel-Haenszel estimator was used to evaluate the association between OC and DA based on odds ratios (ORs) with 95% confidence intervals (CIs). Results: The literature search generated 933 records, and 75 full-text articles were reviewed. Twenty-six studies encompassing 15,213 individuals met the inclusion criteria. The meta-analysis revealed statistically significant associations between OC and agenesis (OR, 14.2; 95% CI, 9.4 to 21.3), supernumerary teeth (OR, 5.7; 95% CI, 3.3 to 9.7), developmental enamel defects (OR, 5.6; 95% CI, 3.5 to 9.0), microdontia (OR, 14.8; 95% CI, 4.0 to 54.6), peg-shaped anterior teeth (OR, 12.2; 95% CI, 3.6 to 41.2), taurodontism (OR, 1.7; 95% CI, 1.0 to 2.7), tooth malposition and/or transposition (OR, 5.6; 95% CI, 2.8 to 11.5), tooth rotation (OR, 3.2; 95% CI, 1.3 to 8.2), and tooth impaction (OR, 3.6; 95% CI, 1.1 to 12.2). The OR estimates of the reviewed studies exhibited significant heterogeneity ( P < 0.0001). No association was observed between OC and fusion and/or gemination. Conclusion: Within the limitations of this study, the available evidence suggests that individuals with OCs are more likely to present with a range of DAs than their unaffected peers. Knowledge Transfer Statement: The findings of the current review suggest that individuals with orofacial clefts (OCs) are more likely to present with a range of dental anomalies than their unaffected peers. Understanding the association between OCs and dental anomalies is essential in guiding clinicians during treatment-planning procedures and is important in raising our awareness of the possible need for future dental treatment for patients with OCs.

The evolution of techniques to manage patients with head injuries has served as the basis for the treatment of other neurosurgical disorders, including brain tumors, intracranial infections, and cerebrovascular disease. In the nineteenth century, advances in anesthesia, asepsis, and cerebral localization slowly took hold and created the groundwork for modern neurosurgery. To better understand the advances in the treatment of brain injuries in the late 1800s and early 1900s, we examine relevant historical literature and, through the courtesy of the Alan Mason Chesney Medical Archives, we review Dr. Harvey Cushing's patient records (1898–1909) in the Johns Hopkins Hospital surgical archives. The original case histories of 10 patients (6 in detail) who suffered head injuries and underwent treatment by Cushing illustrate some of Cushing's early attempts at intracranial surgery. We also examine the influences on Cushing as he developed into a leader in the new era of modern neurosurgery.

BACKGROUND:In 1908, Anton and von Bramann proposed the Balkenstich method, a corpus callosum puncture which created a communication between the ventricle and subarachnoid space. This method offered the benefit of providing continuous CSF diversion without the implantation of cannula or other shunting devices, yet it received only slight reference in the literature of the time. It remained a novel and perhaps underutilized approach at the time Cushing began expanding his neurosurgical practice at the Johns Hopkins Hospital.MATERIALS AND METHODS:Following IRB approval, and through the courtesy of the Alan Mason Chesney Archives, the surgical records of the Johns Hopkins Hospital for the period 1896-1912 were reviewed. Patients operated upon by Harvey Cushing were selected.RESULTS:7 patients underwent puncture of the corpus callosum for treatment of hydrocephalus. 6 patients were treated for obstructive hydrocephalus secondary to presumed intracranial lesions. 1 patient was treated for congenital hydrocephalus.CONCLUSION:The series reported here documents Cushing's early use of the corpus callosum puncture to divert CSF in patients with obstructive hydrocephalus secondary to intracranial tumors, as well as an attempt to use the procedure in a pediatric patient with congenital hydrocephalus. Notably, 3 patients developed new onset left-sided weakness post-operatively, possibly due to retraction injury upon the supplementary motor intra-operative manipulations.

Neurotransplantation remains a much-debated frontier in contemporary neurosurgery and neuroscience, with roots dating to the late 19th century. Contemporary applications are far-reaching, and ongoing laboratory research and clinical trials seek to define the mechanisms at play in neurotransplant engraftment and growth, while advancing the field forward into the 21st century. Neural transplantation therapy remains an attractive idea for treating central nervous system (CNS) and peripheral nervous system (PNS) pathologies. Phase I and phase II clinical trials assessing safety and efficacy are currently underway for various disorders. The remainder of this review will focus on ongoing clinical trials and more recent research advances involving neural transplantation therapy for neuronal death, axonal injury, peripheral nerve lesions, and cancer. The field of neural transplantation, while promising, is not without ethical and scientific dilemmas; this review will conclude with a discussion of the challenges researchers and clinicians face as the field of neural transplantation moves forward.