The impact of court-ordered psychiatric treatment on hospital length of stay: balancing legal and clinical concerns.

Purpose: Psychiatric hospital length of stay (LOS) is not affected solely by socio-clinical factors but also by legal procedures. This study examined the associations between legal procedures and LOS. Methods: Data from 521 patients with psychiatric illnesses hospitalized over 2013-2015 were analyzed. Logistic regression was used to evaluate the predictors of longer (> 14 days) or prolonged (> 30) LOS with socio-clinical factors and legal procedures including court-ordered interventions (assisted outpatient treatment, medication over objection, and retention). Results: Longer LOS occurred in 246 patients and 99 had prolonged LOS. Legal procedures affected 57 patients, with 11 assisted outpatient treatments, 39 cases of medication over objection, and 16 retentions. Longer LOS was significantly associated with six factors including older age, unmarried status, non-Hispanic race, risk of violence, schizophrenia, and legal procedures. Legal procedures had the strongest association. Longer/prolonged LOS yielded qualitatively similar associations. Conclusion: Among 521 psychiatric inpatients, approximately 11% were mandated to receive interventions/procedures by the courts. Court-ordered legal procedures were strongly associated with longer LOS. Mental health providers may consider legal procedures for patients at high treatment/medication noncompliance risk as early as patient admission to inpatient units to prevent, intervene or prepare for a longer or prolonged LOS.

Customized MethylC-Capture Sequencing to Evaluate Variation in the Human Sperm DNA Methylome Representative of Altered Folate Metabolism.

BACKGROUND: The sperm DNA methylation landscape is unique and critical for offspring health. If gamete-derived DNA methylation escapes reprograming in early embryos, epigenetic defects in sperm may be transmitted to the next generation. Current techniques to assess sperm DNA methylation show bias toward CpG-dense regions and do not target areas of dynamic methylation, those predicted to be environmentally sensitive and tunable regulatory elements. OBJECTIVES: Our goal was to assess variation in human sperm DNA methylation and design a targeted capture panel to interrogate the human sperm methylome. METHODS: To characterize variation in sperm DNA methylation, we performed whole genome bisulfite sequencing (WGBS) on an equimolar pool of sperm DNA from a wide cross section of 30 men varying in age, fertility status, methylenetetrahydrofolate reductase (MTHFR) genotype, and exposures. With our targeted capture panel, in individual samples, we examined the effect of MTHFR genotype ([Formula: see text] 677CC, [Formula: see text] 677TT), as well as high-dose folic acid supplementation ([Formula: see text], per genotype, before and after supplementation). RESULTS: Through WGBS we discovered nearly 1 million CpGs possessing intermediate methylation levels (20-80%), termed dynamic sperm CpGs. These dynamic CpGs, along with 2 million commonly assessed CpGs, were used to customize a capture panel for targeted interrogation of the human sperm methylome and test its ability to detect effects of altered folate metabolism. As compared with MTHFR 677CC men, those with the 677TT genotype (50% decreased MTHFR activity) had both hyper- and hypomethylation in their sperm. High-dose folic acid supplement treatment exacerbated hypomethylation in MTHFR 677TT men compared with 677CC. In both cases, [Formula: see text] of altered methylation was found in dynamic sperm CpGs, uniquely measured by our assay. DISCUSSION: Our sperm panel allowed the discovery of differential methylation following conditions affecting folate metabolism in novel dynamic sperm CpGs. Improved ability to examine variation in sperm DNA methylation can facilitate comprehensive studies of environment-epigenome interactions. https://doi.org/10.1289/EHP4812.

A Case of Treatment- resistant Depression and Body Dysmorphic Disorder: The Role of Electroconvulsive Therapy Revisited.

Body dysmorphic disorder is a common, often disabling condition, and is frequently comorbid with major depressive disorder. Selective serotonin reuptake inhibitors constitute first line set of somatic interventions but the management of refractory patients remains challenging. Electroconvulsive therapy, an often highly beneficial treatment for medication resistant-depression, is not considered an effective therapeutic alternative for treatment refractory body dysmorphic disorder. Here we present a 50-year-old woman with body dysmorphic disorder and comorbid major depressive disorder who remained incapacitated and suicidal despite several trials with selective serotonin reuptake inhibitors and antipsychotic medication. Depressive and dysmorphic symptoms appeared to resolve with electroconvulsive therapy, and remission was sustained for two months. Electroconvulsive therapy has an important place in the management of treatment- resistant depression associated with body dysmorphic disorder, and, in select cases, may be effective for dysmorphic symptoms as well.

Turning the corner in fertility: high DNA integrity of boundary-following sperm.

We present a passive microfluidic sperm selection strategy that collects motile sperm based on their preference to follow boundaries and turn corners. Clinical assessment of selected human sperm from the device revealed a strong correlation between high DNA integrity and the tendency for sperm to follow boundaries. Human sperm with preference to follow boundaries on the left- or right-hand sides have higher (>51%) DNA integrity than straight swimmers and significantly higher (>67%) DNA integrity than sperm in raw semen. Boundary following behaviour offers a strategy to selecting sperm with the highest DNA integrity to improve the success rate of assisted reproduction.

Paper-Based Quantification of Male Fertility Potential.

BACKGROUND: More than 70 million couples worldwide are affected by infertility, with male-factor infertility accounting for about half of the cases. Semen analysis is critical for determining male fertility potential, but conventional testing is costly and complex. Here, we demonstrate a paper-based microfluidic approach to quantify male fertility potential, simultaneously measuring 3 critical semen parameters in 10 min: live and motile sperm concentrations and sperm motility. METHODS: The device measures the colorimetric change of yellow tetrazolium dye to purple formazan by the diaphorase flavoprotein enzyme present in metabolically active human sperm to quantify live and motile sperm concentration. Sperm motility was determined as the ratio of motile to live sperm. We assessed the performance of the device by use of clinical semen samples, in parallel with standard clinical approaches. RESULTS: Detection limits of 8.46 and 15.18 million/mL were achieved for live and motile sperm concentrations, respectively. The live and motile sperm concentrations and motility values from our device correlated with those of the standard clinical approaches (R(2) ≥ 0.84). In all cases, our device provided 100% agreement in terms of clinical outcome. The device was also robust and could tolerate conditions of high absolute humidity (22.8 g/m(3)) up to 16 weeks when packaged with desiccant. CONCLUSIONS: Our device outperforms existing commercial paper-based assays by quantitatively measuring live and motile sperm concentrations and motility, in only 10 min. This approach is applicable to current clinical practices as well as self-diagnostic applications.

Direct DNA Analysis with Paper-Based Ion Concentration Polarization.

DNA analysis is essential for diagnosis and monitoring of many diseases. Conventional DNA testing is generally limited to the laboratory. Increasing access to relevant technologies can improve patient care and outcomes in both developed and developing regions. Here, we demonstrate direct DNA analysis in paper-based devices, uniquely enabled by ion concentration polarization at the interface of patterned nanoporous membranes in paper (paper-based ICP). Hepatitis B virus DNA targets in human serum are simultaneously preconcentrated, separated, and detected in a single 10 min operation. A limit of detection of 150 copies/mL is achieved without prior viral load amplification, sufficient for early diagnosis of hepatitis B. We clinically assess the DNA integrity of sperm cells in raw human semen samples. The percent DNA fragmentation results from the paper-based ICP devices strongly correlate (R(2) = 0.98) with the sperm chromatin structure assay. In all cases, agreement was 100% with respect to the clinical decision. Paper-based ICP can provide inexpensive and accessible advanced molecular diagnostics.

High-dose folic acid supplementation alters the human sperm methylome and is influenced by the MTHFR C677T polymorphism.

Dietary folate is a major source of methyl groups required for DNA methylation, an epigenetic modification that is actively maintained and remodeled during spermatogenesis. While high-dose folic acid supplementation (up to 10 times the daily recommended dose) has been shown to improve sperm parameters in infertile men, the effects of supplementation on the sperm epigenome are unknown. To assess the impact of 6 months of high-dose folic acid supplementation on the sperm epigenome, we studied 30 men with idiopathic infertility. Blood folate concentrations increased significantly after supplementation with no significant improvements in sperm parameters. Methylation levels of the differentially methylated regions of several imprinted loci (H19, DLK1/GTL2, MEST, SNRPN, PLAGL1, KCNQ1OT1) were normal both before and after supplementation. Reduced representation bisulfite sequencing (RRBS) revealed a significant global loss of methylation across different regions of the sperm genome. The most marked loss of DNA methylation was found in sperm from patients homozygous for the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism, a common polymorphism in a key enzyme required for folate metabolism. RRBS analysis also showed that most of the differentially methylated tiles were located in DNA repeats, low CpG-density and intergenic regions. Ingenuity Pathway Analysis revealed that methylation of promoter regions was altered in several genes involved in cancer and neurobehavioral disorders including CBFA2T3, PTPN6, COL18A1, ALDH2, UBE4B, ERBB2, GABRB3, CNTNAP4 and NIPA1. Our data reveal alterations of the human sperm epigenome associated with high-dose folic acid supplementation, effects that were exacerbated by a common polymorphism in MTHFR.

Electroconvulsive in a Schizophrenic Patient With Neuroleptic Malignant Syndrome and Rhabdomyolysis.

We present the case of a middle-aged man with a chronic history of schizoaffective disorder, depressed type, stable on a second-generation antipsychotic. Psychotic symptoms recurred contingent to medication noncompliance necessitating hospitalization. Treatment was complicated by the development of neuroleptic malignant syndrome (NMS). In addition, subsequent medication rechallenges failed because of recurrent rhabdomyolysis and atypical NMS. Electroconvulsive therapy (ECT) treatment was initiated, affording remission of psychotic symptoms and nonrecurrence of NMS and rhabdomyolysis. Our experience confirmed the efficacy of ECT treatment in providing symptom relief of psychosis complicated by recurrent episodes of NMS and atypical NMS. Likewise, it illustrated the efficacy of ECT treatment for rhabdomyolysis.

Seminal hyperviscosity is not associated with semenogelin degradation or sperm deoxyribonucleic acid damage: a prospective study of infertile couples.

OBJECTIVE: To investigate the association between seminal hyperviscosity, the extent of semenogelin degradation, and sperm DNA integrity (DNA fragmentation index [DFI] and high DNA stainability [HDS]) in semen from infertile couples. DESIGN: Prospective study. SETTING: University-affiliated fertility center. PATIENT(S): Twenty-four consecutive infertile couples with moderate or high seminal viscosity (hyperviscosity group) and 25 consecutive infertile couples with normal semen viscosity (control group) undergoing standard IVF. INTERVENTION(S): Semen volume and seminal hyperviscosity, sperm concentration, motility, and morphology, level of semenogelin degradation (by immunoblotting), and sperm chromatin damage (by sperm chromatin structure assay and expressed as %DFI and %HDS) were evaluated. MAIN OUTCOME MEASURES(S): Sperm %DFI and %HDS in the hyperviscosity group and the control group and the relationship between the extent of semenogelin degradation and seminal viscosity. RESULT(S): Semen volume in couples with moderate and high seminal viscosity was significantly lower as compared with the control group. In addition, total motility and normal morphology were significantly lower in the couples with high seminal viscosity as compared with the control group; however, there were no significant differences in sperm %DFI and %HDS between the hyperviscosity group and the control group. In addition, there was no relationship between the extent of semenogelin degradation and seminal viscosity. CONCLUSION(S): Our data suggest that seminal hyperviscosity (a posttesticular factor) is not an important cause of sperm DNA damage. Moreover, seminal hyperviscosity is not related to the degree of semenogelin degradation.

Rapid selection of sperm with high DNA integrity.

Sperm selection is essential to assisted reproductive technology (ART), influencing treatment outcomes and the health of offspring. The fundamental challenge of sperm selection is dictated by biology: a heterogeneous population of ~10(8) sperm per milliliter with a short lifetime in vitro. However, conventional sperm selection approaches result in less than 50% improvement in DNA integrity. Here, a clinically applicable microfluidic device is presented that selects sperm based on the progressive motility in 500 parallel microchannels. The result is a one-step procedure for semen purification and high DNA integrity sperm selection from 1 mL of raw semen in under 20 minutes. Experiments with bull sperm indicate more than 89% improvement in selected sperm vitality. Clinical tests with human sperm show more than 80% improvement in human DNA integrity, significantly outperforming the best current practices. These results demonstrate the presence of a sub-population of sperm with nearly intact chromatin and DNA integrity, and a simple clinically-applicable lab-on-a-chip method to select this population.

Sperm DNA and chromatin integrity in semen samples used for intrauterine insemination.

BACKGROUND: Sperm DNA damage is associated with male infertility but whether normozoospermic infertile men also have DNA damage is unknown. OBJECTIVE: To evaluate sperm DNA and chromatin integrity in men with mild male factor infertility. DESIGN, SETTING AND PARTICIPANTS: Prospective study of 102 consecutive men (78 normozoospermic, 15 asthenozoospermic, 9 oligozoospermic) enrolled for intrauterine insemination (IUI) and 15 fertile controls. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Standard semen parameters and sperm chromatin and DNA integrity were assessed and compared between groups. Sperm chromatin quality was assessed by (1) aniline blue staining (AB is specific to histone lysines), (2) iodoacetamide fluorescein fluorescence (IAF targets free protamine sulfhydryl groups) and (3) sperm chromatin structure assay (SCSA) with the results expressed as % DNA fragmentation index (%DFI). RESULTS AND LIMITATIONS: The mean (±SD) percentage of spermatozoa with positive IAF fluorescence was significantly higher in the IUI population compared to fertile controls (17 % ± 10 % vs. 8 % ± 6 %, P = 0.0011) and also in the normozoospermic subset (n = 78) compared to controls (16 % ± 9 % vs. 8 % ± 6 %, P < 0.0001, ANOVA). We also observed a trend toward lower %progressive motility, and higher %AB staining and %DFI in the IUI group compared to controls. We observed significant relationships between sperm %DFI and progressive motility (r = -0.40, P < 0.0001) and between positive AB staining and IAF fluorescence (r = 0.58, P < 0.0001). CONCLUSIONS: The data indicate that sperm chromatin integrity may be abnormal in men enrolled in IUI treatment cycles, despite the fact that most of these men are normozoospermic.

High prevalence of isolated sperm DNA damage in infertile men with advanced paternal age.

BACKGROUND: Sperm DNA damage is associated with male infertility, lower pregnancy rates and pregnancy loss. OBJECTIVE: The primary aim of our study was to evaluate the prevalence of sperm DNA damage in younger and older men with normozoospermia. DESIGN, SETTING AND PARTICIPANTS: We obtained semen from 277 consecutive non-azoospermic men presenting for sperm DNA testing. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The main outcome measures included sperm % DNA fragmentation index (%DFI, using sperm chromatin structure assay), sperm concentration, motility and morphology, and, paternal age. RESULTS AND LIMITATIONS: Sperm % DFI was positively correlated with paternal age (r = 0.20, P < 0.001) and inversely correlated % progressive motility (r = -0.16, P = 0.01). Sperm %DFI was significantly higher in older (≥40 years) compared to younger (<40 years) normozoospermic men (17 ± 13 vs. 12 ± 8, respectively P = 0.008), whereas, sperm concentration, progressive motility and morphology were not significantly different in these two groups. Moreover, the prevalence of high levels of sperm DNA damage (>30 % DFI) was significantly higher in older compared to younger normozoospermic men (17 % vs. 3 %, respectively, P < 0.001). CONCLUSION: The data indicate that a conventional semen analysis can often fail to detect a defect in spermatogenesis (high %DFI) in older men and suggest that infertile couples with advanced paternal age, including those with normal semen parameters, should consider sperm DNA testing as part of the couple evaluation.

Low amounts and high thiol oxidation of peroxiredoxins in spermatozoa from infertile men.

Seminal oxidative stress occurs when there is an increased production of reactive oxygen species (ROS) and/or a decrease of antioxidant activity, promoting impaired sperm function. Peroxiredoxins (PRDX) are abundant in human semen and are important antioxidant enzymes, which act as ROS scavengers and modulators in ROS-dependent signaling. Our aim was to determine whether the levels of PRDX1 and PRDX6 and their oxidation on thiol groups are associated with a decrease in sperm motility and DNA integrity. We evaluated the sperm and seminal PRDX level in men (13 healthy controls, 15 men with clinical varicocele, and 17 men with idiopathic infertility). We assessed conventional semen parameters, sperm DNA integrity (by the sperm chromatin structure assay), lipid peroxidation in seminal plasma and spermatozoa (by the thiobarbituric acid reactive substances assay), and the amount and thiol oxidation of PRDX1 and PRDX6 (by immunoblotting). PRDXs were affected in seminal plasma (lower amounts) and in sperm samples (lower amounts and higher levels of thiol oxidation) characterized by lower sperm motility, higher lipid peroxidation, and sperm DNA damage. The thioloxidation ratio of PRDXs (thiol-oxidized PRDX/total PRDX) correlated negatively with sperm motility (total and progressive) and positively with sperm DNA damage and sperm lipid peroxidation. In conclusion, because of the lower amount of total PRDX1 and PRDX6 and the high thiol oxidation of these PRDXs, very little (less than 20%) protection due to PRDXs remains, and this is associated with impaired sperm function and poor DNA integrity and suggests an important role of PRDXs in the protection of human spermatozoa against oxidative stress.

Lycopene supplementation in vitro can protect human sperm deoxyribonucleic acid from oxidative damage.

OBJECTIVES: To examine the effects of lycopene on human sperm motility and DNA damage. DESIGN: Prospective study. SETTING: Andrology research laboratory. PATIENT(S): Twelve fertile donors. INTERVENTION(S): Preincubation of washed sperm suspensions with or without lycopene (2 or 5 micromol/L) followed by a 2-hour incubation with or without hydrogen peroxide (H2O2, 50 micromol/L). Assessments of sperm motility (percentage) and DNA fragmentation index (percent DNA fragmentation index) before and after incubation. MAIN OUTCOME MEASURE(S): Sperm motility (percentage) and sperm percent DNA fragmentation index. RESULT(S): Incubation of spermatozoa with H2O2 resulted in a significant decline in mean (+/-SD) percent sperm motility (28%+/-13% vs. 73%+/-4%, respectively) and a significant increase in percent DNA fragmentation index compared with samples incubated without H2O2 (29.8%+/-39.4% vs. 11.1%+/-14.6%, respectively). Pretreatment of samples with 5 micromol/L lycopene resulted in a significantly lower percent DNA fragmentation index than samples incubated without lycopene (8.0%+/-7.9% vs. 29.8%+/-39.4%, respectively). However, lycopene did not protect spermatozoa from the decline in motility after H2O2 treatment. CONCLUSION(S): The data suggest that preincubation of spermatozoa with lycopene offers protection against oxidative DNA damage in vitro. These data also highlight the differential protective effects of lycopene on sperm motility and sperm DNA integrity.

Antioxidants and sperm DNA damage: a clinical perspective.

PURPOSE: Infertile men possess substantially more sperm DNA damage than do fertile men, damage that may impact negatively on reproductive outcomes. In this era of assisted reproductive technologies there is mounting concern regarding the safety of utilizing DNA-damaged spermatozoa in this setting. Therefore, it is important to identify strategies that may reduce sperm DNA damage. The purpose of this review is to discuss the rationale for antioxidant therapy in men with sperm DNA damage and to evaluate the data on the efficacy of dietary and in vitro antioxidant preparations on sperm DNA damage. METHODS: We reviewed the literature on antioxidants and sperm DNA damage. RESULTS: To date, the data suggest that dietary antioxidants may be beneficial in reducing sperm DNA damage, particularly, in men with high levels of DNA fragmentation. However, the mechanism of action of dietary antioxidants has not been established and most of the clinical studies are small. A beneficial effect of in vitro antioxidant supplements in protecting sperm DNA from exogenous oxidants has been demonstrated, however, the effect of these antioxidants in protecting sperm from endogenous ROS, gentle sperm processing and cryopreservation has not been established.

Sperm head morphology is related to high deoxyribonucleic acid stainability assessed by sperm chromatin structure assay.

OBJECTIVE: To examine the relationship between sperm strict morphology and sperm chromatin integrity. DESIGN: Prospective study. SETTING: Infertility clinic. PATIENT(S): Eighty-seven consecutive semen samples from non-azoospermic men presenting for infertility evaluation and 6 samples from fertile donors. INTERVENTION(S): Assessment of standard semen parameters and sperm chromatin structure assay (SCSA) parameters (%DFI [DNA fragmentation index] and %HDS [high DNA stainability]). Evaluation of %HDS and %DFI after treatment with dithiothreitol (a thiol-reducing agent used to decondense sperm nuclei) was also undertaken. MAIN OUTCOME MEASURE(S): Relationship between sperm strict morphology defects and SCSA parameters (%DFI and %HDS). RESULT(S): We observed significant relationships between the percentage of normal sperm forms and both %HDS (r = -0.40) and sperm motility (r = 0.32). We also found significant relationships between sperm head defects and both %HDS (r = 0.40) and sperm concentration (r = -0.39). Sperm tail, midpiece, and neck defects were not significantly related to the SCSA parameters. Treatment of spermatozoa with dithiothreitol (to induce decondensation) resulted in a substantial increase in %HDS but no measurable change in %DFI. CONCLUSION(S): The observed relationship between sperm head defects and %HDS suggests that sperm head abnormalities may, in part, be due to incomplete sperm chromatin condensation.

Sperm nuclear histone H2B: correlation with sperm DNA denaturation and DNA stainability.

AIM: To examine the relationship between sperm DNA damage and sperm nuclear histone (H2B) staining. METHODS: We evaluated sperm samples from 14 consecutive asthenoteratozoospermic infertile men and six consecutive fertile controls. Sperm nuclear histone (H2B) staining and sperm chromatin integrity (assessed by sperm chromatin structure assay and expressed using the percentage of (i) DNA fragmentation index [% DFI] and (ii) high DNA stainability [% HDS)]) were evaluated. RESULTS: Histone H2B immunocytochemistry demonstrated two nuclear staining patterns: (i) focal punctate staining; and (ii) diffuse staining. Infertile men had a higher mean percentage of spermatozoa exhibiting diffuse H2B staining than did fertile men (7.7% +/- 4.6% vs. 1.6% +/- 1.2%, respectively, P < 0.01). We observed significant relationships between the proportion of spermatozoa with diffuse nuclear histone staining and both sperm % DFI (r = 0.63, P < 0.01) and sperm %HDS (r = 0.63, P < 0.01). CONCLUSION: The data demonstrate that infertile men have a higher proportion of spermatozoa with diffuse histone H2B than do fertile men and suggest that sperm DNA damage might, at least in part, be due to abnormally high histone H2B levels.

Localization of single-stranded DNA in human sperm nuclei.

OBJECTIVE: To localize foci of single-stranded (ss) DNA in sperm nuclei of fertile and infertile men. DESIGN: Prospective, observational study. SETTING: University infertility clinic. PATIENT(S): Semen samples from 12 consecutive asthenoteratospermic men presenting for infertility evaluation and 5 consecutive fertile men presenting for vasectomy. INTERVENTION(S): Semen analysis, semen processing, and immunocytochemistry using an antibody targeting ssDNA. MAIN OUTCOME MEASURE(S): Sperm nuclear ssDNA immunostaining pattern in whole and processed semen samples. RESULT(S): Immunocytochemistry (using ssDNA antibody) demonstrated one of two sperm nuclear staining patterns: [1] faint punctated staining, and [2] diffuse nuclear staining. Infertile men had a higher proportion of spermatozoa exhibiting diffuse ssDNA staining than did fertile men (52 +/- 19 vs. 14 +/- 13, respectively). The proportion of spermatozoa exhibiting diffuse ssDNA staining was significantly higher in whole compared with processed semen. Positive (DNAse-treated nuclei) and negative controls (S1 nuclease-treated nuclei) were obtained to validate the specificity of the antibody. CONCLUSION(S): Human sperm nuclei generally exhibit discrete (presumably peripheral) foci of ssDNA. The data also show that infertile men have a higher proportion of sperm nuclei with diffuse areas of ssDNA than do fertile men, and suggest that spermatozoa with diffuse nuclear staining are abnormal.

Estimation of human sperm gene-specific deoxyribonucleic acid damage by real-time polymerase chain reaction analysis.

It has been reported that spermatozoa of infertile men have poorer DNA integrity than that of fertile men. Using analyses based on real-time polymerase chain reaction, we have estimated the relative gene-specific DNA damage in human spermatozoa and have observed that the spermatozoa of infertile men possess measurably more DNA damage than that of fertile men.