Occupational therapy practice for post-acute COVID-19 inpatients requiring rehabilitation.

INTRODUCTION: COVID-19 caused significant occupational disruption to people's life roles, with some people requiring an inpatient rehabilitation admission. Occupational therapists assessed and treated these patients using previous knowledge of similar conditions due to limited specificity in available guidelines to inform practice. The aim of this study was to investigate current practice with post-acute COVID-19 (PAC) patients within an inpatient rehabilitation setting in Australia, to better understand the role and impact of occupational therapy. METHODS: A mixed-method study was conducted, including electronic medical record audits (October 2021 October 2022) and descriptive patient interviews at a large metropolitan subacute service. Descriptive statistics and qualitative analysis were used to summarise and interpret data. CONSUMER AND COMMUNITY INVOLVEMENT: No involvement. RESULTS: A total of 24 patient electronic medical records were audited, and 10 patient interviews were completed. Three overarching categories were identified within the 685 occasions of occupational therapy service audited-occupational engagement, education provision and discharge planning. Patients identified the value of occupational therapy by reflecting on their lived experiences of engaging with occupational therapists and associated changes in occupational performance between COVID-19 diagnoses and discharge home. CONCLUSION: Occupational therapists possess a unique skill set that directly addresses the occupational needs and priorities of PAC patients. This study adds to the growing body of evidence supporting the contribution of occupational therapy to the management of COVID-19; however, further research is needed to develop evidence-based practice resources and advocate for system changes that improve quality of life for COVID-19 patients. PLAIN LANGUAGE SUMMARY: During the COVID-19 pandemic, a lot of people got very sick. Some of these people needed more time and support to get better. Occupational therapists were important during this time because they helped these people to do their daily activities again. Because there were not many resources on how to do this, we looked into what occupational therapists were doing to help these people. We looked at patient hospital files and also talked to them to understand this better. We found that occupational therapists focused on three main areas: helping patients do activities that were important to them, teaching them about COVID-19 and helping them plan to leave the hospital. This study shows that occupational therapists are skilled at helping people with COVID-19. But more research is needed to make resources and also help with changing the healthcare system to further help people get better from COVID-19.

Proposed role for COUP-TFII in regulating fetal Leydig cell steroidogenesis, perturbation of which leads to masculinization disorders in rodents.

Reproductive disorders that are common/increasing in prevalence in human males may arise because of deficient androgen production/action during a fetal 'masculinization programming window'. We identify a potentially important role for Chicken Ovalbumin Upstream Promoter-Transcription Factor II (COUP-TFII) in Leydig cell (LC) steroidogenesis that may partly explain this. In rats, fetal LC size and intratesticular testosterone (ITT) increased ~3-fold between e15.5-e21.5 which associated with a progressive decrease in the percentage of LC expressing COUP-TFII. Exposure of fetuses to dibutyl phthalate (DBP), which induces masculinization disorders, dose-dependently prevented the age-related decrease in LC COUP-TFII expression and the normal increases in LC size and ITT. We show that nuclear COUP-TFII expression in fetal rat LC relates inversely to LC expression of steroidogenic factor-1 (SF-1)-dependent genes (StAR, Cyp11a1, Cyp17a1) with overlapping binding sites for SF-1 and COUP-TFII in their promoter regions, but does not affect an SF-1 dependent LC gene (3ß-HSD) without overlapping sites. We also show that once COUP-TFII expression in LC has switched off, it is re-induced by DBP exposure, coincident with suppression of ITT. Furthermore, other treatments that reduce fetal ITT in rats (dexamethasone, diethylstilbestrol (DES)) also maintain/induce LC nuclear expression of COUP-TFII. In contrast to rats, in mice DBP neither causes persistence of fetal LC COUP-TFII nor reduces ITT, whereas DES-exposure of mice maintains COUP-TFII expression in fetal LC and decreases ITT, as in rats. These findings suggest that lifting of repression by COUP-TFII may be an important mechanism that promotes increased testosterone production by fetal LC to drive masculinization. As we also show an age-related decline in expression of COUP-TFII in human fetal LC, this mechanism may also be functional in humans, and its susceptibility to disruption by environmental chemicals, stress and pregnancy hormones could explain the origin of some human male reproductive disorders.

Prenatal plus postnatal exposure to Di(n-Butyl) phthalate and/or flutamide markedly reduces final sertoli cell number in the rat.

Androgens may be important regulators of Sertoli cell (SC) proliferation perinatally, with implications for the testicular dysgenesis syndrome (TDS) hypothesis. Fetal exposure of rats to 500 mg/kg . d di(n-butyl) phthalate (DBP) reduces fetal testosterone production and SC number at birth, but SC number recovers to normal by postnatal d (Pnd)25. It is unclear when and how SC proliferation is affected prenatally by DBP exposure or when and how postnatal compensation occurs. This study addressed these questions and investigated whether continued maternal exposure to DBP or to flutamide from Pnd1-Pnd15 could prevent SC number compensation, because this would have implications for how sperm counts might be lowered in TDS. DBP exposure attenuated SC proliferation by 7-18% throughout embryonic d (e)15.5-e21.5 (P < 0.05 at e21.5). After birth, SC proliferation increased significantly (>1.5-fold) between Pnd6 and Pnd10 in prenatally DBP-exposed animals, explaining the compensation. Continued maternal administration of DBP after birth attenuated (19% reduction) SC number compensation at Pnd25 and maternal administration of flutamide (100 mg/kg . d) to prenatally DBP-exposed animals was even more effective (42% reduction), suggesting the postnatal compensatory increase in SC proliferation after prenatal DBP exposure is androgen dependent. SC maturation (Pnd25) was unaffected, based on analysis of expression of key proteins, but lumen formation/expansion was attenuated in parallel with treatment-induced reduction in SC number. Our results provide further evidence that perinatal SC proliferation is androgen dependent and, importantly, show that similar exposure of mothers to antiandrogenic chemicals before birth and during lactation reduces final SC number, with implications for the origin of low sperm counts in TDS.

Steroidogenesis in the fetal testis and its susceptibility to disruption by exogenous compounds.

Masculinization depends on adequate production of testosterone by the fetal testis within a specific "masculinization programming window." Disorders resulting from subtle deficiencies in this process are common in humans, and environmental exposures/lifestyle could contribute causally because common therapeutic and environmental compounds can affect steroidogenesis. This evidence derives mainly from rodent studies, but because there are major species differences in regulation of steroidogenesis in the fetal testis, this may not always be a guide to potential effects in the human. In addition to direct study of the effects of compounds on steroidogenesis, information also derives from study of masculinization disorders that result from mutations in genes in pathways regulating steroidogenesis. This review addresses this issue by critically reviewing the comparative timing of production and regulation of steroidogenesis in the fetal testis of humans and of rodents and its susceptibility to disruption; where there is limited information for the fetus, evidence from effects on steroidogenesis in the adult testis is considered. There are a number of fundamental regulatory differences between the human and rodent fetal testis, most notably in the importance of paracrine vs. endocrine drives during masculinization such that inactivating LH receptor mutations block masculinization in humans but not in rodents. Other large differences involve the steroidogenic response to estrogens and GnRH analogs and possibly phthalates, whereas for other compounds there may be differences in sensitivity to disruption (ketoconazole). This comparison identifies steroidogenic targets that are either vulnerable (mitochondrial cholesterol transport, CYP11A, CYP17) or not (cholesterol uptake) to chemical interference.

Glucocorticoids amplify dibutyl phthalate-induced disruption of testosterone production and male reproductive development.

Common male reproductive abnormalities including cryptorchidism, hypospadias, and low sperm counts may comprise a testicular dysgenesis syndrome (TDS), resulting from fetal testis dysfunction during a critical developmental period involving reduced androgen production/action. The recent increase in TDS prevalence suggests environmental/lifestyle factors may be etiologically important. The developing fetus is exposed to multimodal challenges, and we hypothesized that exposure to a combination of factors rather than single agents may be important in the pathogenesis of TDS. We experimentally induced fetal testis dysfunction in rats via treatment of pregnant females daily from embryonic day (e) 13.5 to e21.5 with vehicle, 100 or 500 mg/kg . d dibutyl phthalate (DBP), 0.1 mg/kg . d dexamethasone (Dex), or a combination of DBP + Dex. In adulthood, penile length/normality, testis weight/descent, prostate weight, and plasma testosterone levels were measured plus anogenital distance (AGD) as a measure of androgen action within the masculinization programming window. Intratesticular testosterone and steroidogenic enzyme gene expression were measured in fetal testes at e17.5. High-dose DBP reduced fetal intratesticular testosterone and steroidogenic gene expression; induced mild hypospadias (31%) and cryptorchidism (53%); and reduced penile length, AGD, and testis and prostate weight in adulthood. Dex alone had no effect except to reduce birth weight but amplified the adverse effects of 500 mg/kg . d DBP and exacerbated the effects of 100 mg/kg . d DBP. All adverse effects were highly correlated to AGD, emphasizing the etiological importance of the masculinization programming window. These findings suggest that exposure to common environmental chemicals in combination with, for example, maternal stress, may increase the risk of common male reproductive abnormalities, with implications for human populations.

Relationship between androgen action in the "male programming window," fetal sertoli cell number, and adult testis size in the rat.

Fetal androgen action is an important determinant of Sertoli cell (SC) number at birth. Androgens "program" reproductive tract development in rats between embryonic d (e) 15.5 and e17.5 ("male programming window"), and this is reflected for life by anogenital distance (AGD). We investigated if androgen regulation of SC number/proliferation was also programmed by androgens in this window. Pregnant rats were treated in various fetal time windows with vehicle (control) or 500 mg/kg.d di(n-butyl) phthalate (DBP), which suppresses fetal intratesticular testosterone (ITT). ITT and SC number/proliferation index were determined at e17.5 or e21.5; AGD was also determined at e21.5. In controls, SC number increased 11-fold and ITT by 10-fold from e17.5-e21.5. In animals exposed daily to DBP from e13.5, SC number was reduced by approximately 50% at e21.5, but increased 6-fold, as did ITT, from e17.5-e21.5; DBP had no effect on ITT at e15.5, reduced ITT by 50% at e17.5, and by more than 75% at e19.5-21.5. DBP exposure just in the male programming window did not alter SC number at e17.5 or 21.5 but reduced AGD. DBP treatment beyond e19.5 caused major reductions in SC number/proliferation index and ITT at e21.5. Only DBP treatments that included the male programming window led to reduced AGD at e21.5, but SC number was clearly not programmed in this window. Nevertheless, testis weight correlated highly (P<0.001) with AGD at e21.5, and postnatal d 25 and 90 in animals exposed in utero to vehicle or DBP (e13.5-e21.5). Thus, AGD may predict adult testis size but probably not through a direct relationship with SC number.

Identification in rats of a programming window for reproductive tract masculinization, disruption of which leads to hypospadias and cryptorchidism.

Becoming a phenotypic male is ultimately determined by androgen-induced masculinization. Disorders of fetal masculinization, resulting in hypospadias or cryptorchidism, are common, but their cause remains unclear. Together with the adult-onset disorders low sperm count and testicular cancer, they can constitute a testicular dysgenesis syndrome (TDS). Although masculinization is well studied, no unifying concept explains normal male reproductive development and its abnormalities, including TDS. We exposed rat fetuses to either anti-androgens or androgens and showed that masculinization of all reproductive tract tissues was programmed by androgen action during a common fetal programming window. This preceded morphological differentiation, when androgen action was, surprisingly, unnecessary. Only within the programming window did blocking androgen action induce hypospadias and cryptorchidism and altered penile length in male rats, all of which correlated with anogenital distance (AGD). Androgen-driven masculinization of females was also confined to the same programming window. This work has identified in rats a common programming window in which androgen action is essential for normal reproductive tract masculinization and has highlighted that measuring AGD in neonatal humans could provide a noninvasive method to predict neonatal and adult reproductive disorders. Based on the timings in rats, we believe the programming window in humans is likely to be 8-14 weeks of gestation.

Sertoli cell development and function in an animal model of testicular dysgenesis syndrome.

Pregnancy exposure to di(n-butyl) phthalate (DBP) in rats induces a testicular dysgenesislike syndrome (TDS) in male offspring. Earlier studies suggested altered Sertoli cell development/maturation may result, especially in testes that become cryptorchid. This study quantitatively assessed Sertoli cell numerical and functional development in DBP-exposed rats and compared (unilaterally) cryptorchid and scrotal testes. Pregnant rats were gavaged with 500 mg/kg/day DBP or corn oil from embryonic (E) Days 13.5 to 21.5. Male offspring were sampled on E21.5 or Postnatal Day 6, 10, 15, 25, or 90. Sertoli cell number in DBP-exposed males was reduced by approximately 50% at E21.5 but recovered to normal by Days 25-90, accompanied by significant changes in plasma inhibin B and testosterone levels. Sertoli cell maturational development in DBP-exposed males, assessed using five protein markers (anti-müllerian hormone, cytokeratin, androgen receptor, CDKN1B, and Nestin), was largely normal, with some evidence of delayed maturation. However, in adulthood, Sertoli cells (SC) in areas lacking germ cells (Sertoli cell-only [SCO] tubules) often exhibited immature features, especially in cryptorchid testes. Sertoli cells in DBP-exposed animals supported fewer germ cells during puberty, but this normalized in scrotal testes by adulthood. Scrotal and especially cryptorchid testes from DBP-exposed animals exhibited abnormalities (SCO tubules, focal dysgenetic areas) at all postnatal ages. Cryptorchid testes from DBP-exposed animals exhibited more Sertoli cell abnormalities at Day 25 compared with scrotal testes, perhaps indicating more severe underlying Sertoli cell malfunction in these testes. Our findings support the concept of altered Sertoli cell development in TDS, especially in cryptorchid testes, but show that maturational defects in Sertoli cells in adulthood most commonly reflect secondary dedifferentiation in absence of germ cells.

The origins and time of appearance of focal testicular dysgenesis in an animal model of testicular dysgenesis syndrome: evidence for delayed testis development?

A testicular dysgenesis-like syndrome is induced in rats by fetal exposure to di(n-butyl) phthalate (DBP). A key feature of this is the formation of focal dysgenetic areas comprising malformed seminiferous cords/tubules and intratubular Leydig cells (ITLC), but how and why these arise remains unclear. The present study has used combinations of cell-specific markers and immunohistochemistry to address this. The results show that focal dysgenetic areas and ITLC first appear postnatally at 4-10 days of age, but this only occurs in treatment groups in which formation of fetal Leydig cell aggregation is induced between e17.5 and e21.5. Extreme variability in the formation and size of the Leydig cell aggregates probably accounts for the equally extreme variation in occurrence and size of focal dysgenetic areas postnatally. DBP-induced fetal Leydig cell aggregation traps Sertoli and other cells within the aggregates, but it is unclear why this happens nor why cords fail to form prenatally in these cell mixtures but do elsewhere in the fetal testis. The present studies show that differentiation of the fetal Leydig cells is drastically delayed at e15.5 after DBP exposure, which may be indicative of a wider delay in testis cell development and organisation, and this might account for some of the unexplained findings.

Role of androgens in fetal testis development and dysgenesis.

This study sought to establish whether reduced androgen levels/action in the fetal rat testis induced by di(n-butyl) phthalate (DBP) contributes to dysgenetic features, namely reduced Sertoli cell number, occurrence of multinucleated gonocytes (MNG), and Leydig cell aggregation. Pregnant rats were administered treatments or cotreatments designed to manipulate testosterone levels [DBP, testosterone propionate (TP)] or action [flutamide, 7,12-dimethyl-benz[a]anthracene (DMBA)]. The aforementioned end points were analyzed and related to intratesticular testosterone (ITT) levels and peripheral androgen action (anogenital distance). Dysgenetic features were also evaluated in mice with inactivation of the androgen receptor (testicular feminized or ARKO mice). Exposure to DBP alone, or combined with flutamide, DMBA, or TP, resulted in reduced Sertoli cell number and ITT levels, as did exposure to TP alone; coadministration of DBP + TP caused the most severe reduction in both parameters. A positive correlation between ITT levels and Sertoli cell number was found (r = 0.791; P = 0.019). Similarly, exposure to DBP alone, or as a cotreatment, significantly increased occurrence of MNG and Leydig cell aggregation, and these were negatively correlated with ITT levels. Exposure to flutamide or DMBA alone had no significant effect on these dysgenetic end points. These findings suggest that reduced ITT decreases fetal Sertoli cell numbers and might be involved in Leydig cell aggregation and MNG. However, of these three end points, only Sertoli cell number was affected significantly in ARKO/testicular feminized mice with absent androgen action. Therefore, induction of MNG and Leydig cell aggregation might result from DBP-induced effects other than suppression of ITT levels.

In utero exposure to di(n-butyl) phthalate and testicular dysgenesis: comparison of fetal and adult end points and their dose sensitivity.

BACKGROUND: Fetal exposure of male rats to di(n-butyl) phthalate (DBP) induces reproductive disorders similar to those in human testicular dysgenesis syndrome (TDS), including infertility, cryptorchidism, focal "dysgenetic areas," and Sertoli cell-only tubules in the adult testis. Humans are widely exposed to DBP, but at much lower levels than those causing adverse effects in rats. OBJECTIVES: The objective of this study was to evaluate end points affected by DBP action in rats in fetal and adult life that are relevant to human TDS, and to compare their dose sensitivity. METHODS: Pregnant rats were gavaged daily with corn oil (control) or with 4, 20, 100, or 500 mg/kg DBP. We examined adult end points of TDS (infertility, cryptorchidism) and indicators within the fetal testis of dysgenesis [abnormal Leydig cell (LC) aggregation, multinucleated gonocytes (MNGs)], as well as conditions that may result from these indicators in adulthood (occurrence of focal dysgenetic areas). Fetal testis weight and testicular testosterone levels were also evaluated. RESULTS: The fetal end points analyzed (testicular testosterone levels, abnormal LC aggregation, occurrence of MNGs) were most sensitive to disruption by DBP, as all were significantly affected at a dose of 100 mg/kg/day DBP, with a trend toward effects occurring at 20 mg/kg/day DBP; adult end points were affected consistently only by 500 mg/kg/day DBP. CONCLUSIONS: The fetal end points we evaluated can be objectively quantified and may prove helpful in evaluating the health risk of exposure to DBP and other phthalates, as well as identifying DBP-sensitive fetal events that have adult consequences/end points that are identifiable in human TDS.