Bi-allelic variants in DNA mismatch repair proteins MutS Homolog MSH4 and MSH5 cause infertility in both sexes.

STUDY QUESTION: Do bi-allelic variants in the genes encoding the MSH4/MSH5 heterodimer cause male infertility? SUMMARY ANSWER: We detected biallelic, (likely) pathogenic variants in MSH5 (4 men) and MSH4 (3 men) in six azoospermic men, demonstrating that genetic variants in these genes are a relevant cause of male infertility. WHAT IS KNOWN ALREADY: MSH4 and MSH5 form a heterodimer, which is required for prophase of meiosis I. One variant in MSH5 and two variants in MSH4 have been described as causal for premature ovarian insufficiency (POI) in a total of five women, resulting in infertility. Recently, pathogenic variants in MSH4 have been reported in infertile men. So far, no pathogenic variants in MSH5 had been described in males. STUDY DESIGN, SIZE, DURATION: We utilized exome data from 1305 men included in the Male Reproductive Genomics (MERGE) study, including 90 males with meiotic arrest (MeiA). Independently, exome sequencing was performed in a man with MeiA from a large consanguineous family. PARTICIPANTS/MATERIALS, SETTING, METHODS: Assuming an autosomal-recessive mode of inheritance, we screened the exome data for rare, biallelic coding variants in MSH4 and MSH5. If possible, segregation analysis in the patients' families was performed. The functional consequences of identified loss-of-function (LoF) variants in MSH5 were studied using heterologous expression of the MSH5 protein in HEK293T cells. The point of arrest during meiosis was determined by γH2AX staining. MAIN RESULTS AND THE ROLE OF CHANCE: We report for the first time (likely) pathogenic, homozygous variants in MSH5 causing infertility in 2 out of 90 men with MeiA and overall in 4 out of 902 azoospermic men. Additionally, we detected biallelic variants in MSH4 in two men with MeiA and in the sister of one proband with POI. γH2AX staining revealed an arrest in early prophase of meiosis I in individuals with pathogenic MSH4 or MSH5 variants. Heterologous in vitro expression of the detected LoF variants in MSH5 showed that the variant p.(Ala620GlnTer9) resulted in MSH5 protein truncation and the variant p.(Ser26GlnfsTer42) resulted in a complete loss of MSH5. LARGE SCALE DATA: All variants have been submitted to ClinVar (SCV001468891-SCV001468896 and SCV001591030) and can also be accessed in the Male Fertility Gene Atlas (MFGA). LIMITATIONS, REASONS FOR CAUTION: By selecting for variants in MSH4 and MSH5, we were able to determine the cause of infertility in six men and one woman, leaving most of the examined individuals without a causal diagnosis. WIDER IMPLICATIONS OF THE FINDINGS: Our findings have diagnostic value by increasing the number of genes associated with non-obstructive azoospermia with high clinical validity. The analysis of such genes has prognostic consequences for assessing whether men with azoospermia would benefit from a testicular biopsy. We also provide further evidence that MeiA in men and POI in women share the same genetic causes. STUDY FUNDING/COMPETING INTEREST(S): This study was carried out within the frame of the German Research Foundation sponsored Clinical Research Unit 'Male Germ Cells: from Genes to Function' (DFG, CRU326), and supported by institutional funding of the Research Institute Amsterdam Reproduction and Development and funds from the LucaBella Foundation. The authors declare no conflict of interest.

Skeletal fixation: a review.

While improvements in surgical techniques and recent trends toward early surgery and patient mobilization have led to skeletal traction being utilized more sparingly, it continues to be a basic skill required by the orthopaedic surgeon. The most commonly used anatomical sites for skeletal fixation--distal femur, proximal tibia, distal tibia, calcaneus, and olecranon--are reviewed and illustrated.

Leader-member exchange relationships in health information management.

This article seeks to raise awareness of the leader-member exchange (LMX) theory of leadership and its potential benefit to the health information management (HIM) profession. A literature review that was conducted identified a leadership challenge for HIM practitioners. The review also provides examples of leadership definitions, and potential benefits of LMX to HIM professionals in leading people and influencing leaders in their organizations. The LMX concept may be an avenue to investigate in preparing future and current HIM professionals for leadership.

Childhood lead poisoning and inadequate child care.

Sixteen caretakers of children hospitalized for their first episode of lead poisoning and 16 caretakers of children with normal lead levels were interviewed in their homes to determine if caretakers of children with lead poisoning provided more inadequate child care than the comparison group of caretakers. Children were matched according to age, race, and sex. Correlations were found between children's lead levels and caretakers' scores on the measures of inadequate child care. Differences were evident in the overall physical and cognitive emotional care provided to these children. No differences were found in the caretakers' ages, number of years of education and family monthly income, number of occupants in the household, and family mobility. Implications of the intertwined roles of inadequate child care, subclinical lead poisoning, and later developmental sequelae are discussed.

Lipid adsorption onto hydrogel contact lens materials. Advantages of Nile red over oil red O in visualization of lipids.

An artificial tear solution containing the major types of proteins, glycoproteins, and lipids represented in human tears has been developed. The adsorption of lipids onto various hydrogel lens materials (polymacon, lidofilcon A, phemfilcon A, etafilcon A) was examined by exposing the lenses to our artificial tear solution for 18 h. The adsorbed lipids were detected using Nile red stain. The patterns of deposits obtained in vitro were similar to those obtained with human worn lenses. The Nile red stain appeared far more sensitive in detecting lipids adsorbed to hydrogel lenses than the oil red O stain. It was found that lipids adsorb to hydrogel materials quite readily either in a pure state or combined with mucin or other proteins. In view of this work more attention should be given to the role of lipids in the etiology of various contact lens wear complications.

Evaluating the potential effectiveness of using computerized information systems to prevent adverse drug events.

In this study a dynamic computer simulation model is used to estimate the effectiveness of various information systems applications designed to detect and prevent medication errors that result in adverse drug events (ADEs). The model simulates the four stages of the drug ordering and delivery system: prescribing, transcribing, dispensing and administering drugs. In this study we simulated interventions that have been demonstrated in prior studies to decrease error rates. The results demonstrated that a computerized information system that detected 26% of medication errors and prevented associated ADEs could save 1,226 days of excess hospitalization and $1.4 million in hospital costs annually. Those results suggest that such systems are potentially a cost-effective means of preventing ADEs in hospitals. The results demonstrated the importance of viewing adverse drug events from a systems perspective. Prevention efforts that focus on a single stage of the process had limited impact on the overall error rate. This study suggests that system-wide changes to the drug-ordering and delivery system are required to significantly reduce adverse drug events in a hospital setting.

Multiquadrant digital analysis of shoulder capsular thickness.

PURPOSE: Nonablative thermal capsular shrinkage has been developed in an attempt to address the plastic capsule deformation thought to cause increased rates of recurrent instability following arthroscopic stabilization procedures. Although the temperature required to optimize collagen shrinkage is known, a safe depth of thermal penetration, in various locations about the shoulder capsule, has not been defined. The purpose of this study was to measure shoulder capsule thickness by quadrant and circumferentially from the glenoid to the humerus so that thermal energy in shoulder procedures can be more precisely applied to limit possible injury to pericapsular structures. TYPE OF STUDY: This is an anatomic study using a cadaveric shoulder specimens. MATERIALS AND METHODS: Soft tissue was dissected from 8 fresh cadaveric shoulders to isolate intact glenohumeral joint capsules. The humeral insertion was released and the capsule was cut into 6 longitudinal quadrants around the glenoid. The capsule specimens were then flash frozen and stored at -80 degrees C. Quadrant tissue was cut into longitudinal sections 14 to 16 microm wide and stained with hematoxylin and eosin. The specimens were then digitized under a dissecting microscope and measured using computer imaging software at approximately 4-mm intervals. Two-way analysis of variance (ANOVA) was performed on the measurements of the intact capsule specimens 2.5 cm off the glenoid. Humeral insertion data were recorded separately. RESULTS: A total of 248 separate measurements were made throughout the capsule in 8 specimens. Capsular thickness increased from an average of 2.42 mm anteriorly to 2.80 mm in the inferior capsular pouch and again thinned to 2.22 mm posteriorly. Global shoulder capsule thickness ranged from 1.32 to 4.47 mm. When analyzed by position, from glenoid to humerus, a general thinning was noted with a mean thickness of 3. 03 mm at the glenoid to 2.17 mm at the humeral insertion. Two-way ANOVA showed a significant thickness variation along the specimen (P <.05), a nearly significant thickness variation with regard to quadrant (P <.03), and no significant interaction (P >.07) when applied to specimen measurements approximately 2.5 cm off the glenoid. CONCLUSIONS: The thickness of the shoulder capsule ranges from 1.32 to 4.47 mm, with a significant thinning laterally from the glenoid to the humerus. Further, capsule thickness ranges from 2.76 to 3.18 mm in the regions in closest proximity to the axillary nerve. These data may help determine the proper amount of thermal penetration necessary when performing shrinkage procedures and provide safety guidelines to limit the depth of thermal penetration to avoid possible injury to pericapsular structures.