Yasuhiro Nakano

Background: The clinical features and recovery of patients with obesity and Long COVID remain incompletely understood. Methods: We retrospectively analyzed 903 patients attending a COVID-19 aftercare clinic during the Omicron period. Biomarkers were compared across body mass index (BMI) categories. Recovery was defined as physician-determined conclusion of outpatient follow-up following sufficient symptom improvement, not necessarily complete resolution. Recovery analyses were exploratory; 572 patients comprised a sensitivity cohort clinically compatible with the World Health Organization (WHO) post-COVID-19 condition definition. Results: Serum ferritin levels were higher in overweight and obese men than in normal-weight men. Cortisol/adrenocorticotropic hormone (ACTH) ratios in women and free thyroxine (FT4) levels in men differed across BMI categories. Recovery analysis from symptom onset included 565 participants and 186 events. Men with obesity had a lower recovery hazard than normal-weight men, with consistent direction across sensitivity analyses (age-adjusted pooled model, n = 565; hazard ratio: 0.390; 95% CI: 0.170–0.894), based on six recovery events among men with obesity. The main sex-by-obesity interaction was nonsignificant; additional interaction results varied by model. The WHO-compatible recovery analysis was limited by sparse events. Conclusions: Obesity was associated with a longer time to clinically defined recovery among men, alongside BMI-related endocrine–metabolic differences. These exploratory findings warrant confirmation; sparse events and residual confounding preclude causal or definitive sex-specific conclusions.

Background: Although several risk factors have been reported for long COVID (LC), reliable biomarkers for this illness remain lacking. Insulin-like growth factor (IGF)-I, a major mediator of growth hormones, plays an important role in metabolism, neuroprotection, and systemic homeostasis, and therefore may be useful in predicting the severity and prognosis of LC. Methods: This study included patients who visited a specialized clinic for long COVID between 2022 and 2025 during the Omicron period and had serum IGF-I measurements taken. IGF-I levels were expressed as age- and sex-adjusted standard deviation scores (IGF-I SD), and patients were classified into low (SD < −1.0), normal (−1.0 ≤ SD < 1.0), and high (SD ≥ 1.0) groups. Clinical characteristics, patient-reported outcomes, laboratory data, and follow-up duration were analyzed. Results: A total of 811 patients were included (median 42 years; 52.5% female). Compared with the normal group, the low-IGF-I group exhibited higher fatigue (FAS: 37.0 vs. 34.0; p < 0.05) and depressive (SDS: 50.0 vs. 49.0; p < 0.05) status. Multivariable linear regression analyses identified lower IGF-I SD as independently associated with higher scores of both FAS and SDS. IGF-I SD values showed negative correlations with ferritin (ρ = −0.125, p < 0.05) and TSH (ρ = −0.202, p < 0.01) and positive correlations with albumin (ρ = 0.227, p < 0.01) and FT4 (ρ = 0.165, p < 0.01). Among the 237 patients who completed follow-up, the median duration from the initial visit to recovery tended to be longer in the low-IGF-I group (221 days) compared with the normal (191 days) and high (109 days) groups, although these differences were not statistically significant overall. In patients aged < 50 years, the low-IGF-I group showed a relatively longer follow-up duration (p < 0.05). Furthermore, the low-IGF-I group had a longer time to recovery compared to the high-IGF-I group (p < 0.05), and this difference was more pronounced in patients under 50 years of age, with significant differences observed among the three IGF-I groups. Conclusions: Lower IGF-I levels in LC may be associated with greater fatigue and depressive symptoms and longer recovery time, particularly in younger patients. Further studies are needed to clarify the clinical significance of these findings.

Long COVID (LC) may involve endocrine dysfunction; however, the underlying mechanism remains unclear. To examine hypothalamic–pituitary responses in patients with LC, we conducted a single-center retrospective study of patients with refractory LC referred to our University Hospital who underwent anterior pituitary stimulation tests. Between February 2021 and November 2025, 1251 patients with long COVID were evaluated, of whom 207 (19%) had relatively low random ACTH or cortisol levels. Ultimately, 16 underwent anterior pituitary stimulation tests and were included. All tests were performed in an inpatient setting without exogenous steroids. Fifteen patients (six women, mean age 35.6 years) underwent corticotropin-releasing hormone (CRH), thyrotropin-releasing hormone (TRH), and gonadotropin-releasing hormone (GnRH) tests. All patients had mild acute COVID-19, eight had ≥2 vaccinations, and the mean interval from infection was 343 days. Frequent symptoms included fatigue (100%), insomnia (66.7%), headache (60.0%), anorexia/nausea (40.0%), and brain fog (40.0%). Mean early-morning cortisol and 24 h urinary free cortisol were 7.5 μg/dL and 41.0 μg/day, respectively. MRI showed an empty sella in one case. Peak hormonal responses were preserved (ΔACTH 247%, ΔTSH 918%, ΔPRL 820%, ΔFSH 187%, ΔLH 1150%); however, peaks were delayed beyond 60 min in ACTH (13%), LH (33%), and FSH (87%). Notably, significantly delayed elevations remained at 120 min in the responses of TSH (4.1-fold), PRL (1.8-fold), LH (9.3-fold), and FSH (2.8-fold), suggesting possible hypothalamic involvement, particularly in the gonadotropin responses. Additionally, serum IGF-I was lowered (−0.70 SD), while GH response (mean peak 35.5 ng/mL) was preserved by growth hormone-releasing peptide (GHRP)-2 stimulation. Low-dose hydrocortisone and testosterone were initiated for three patients. Although direct viral effects and secondary suppression have been proposed, our findings may suggest that, at least in part, the observed response characteristics are consistent with functional secondary hypothalamic dysfunction rather than irreversible primary injury. These findings highlight the need for objective endocrine evaluation before initiating hormone replacements.

Background: Candidemia is a life-threatening infection with high mortality, and appropriate management is essential to improve patient outcomes. The Candida Care Bundle aims to standardize hospital management for patients with candidemia and reduce mortality. Methods: This retrospective multicenter cohort study included candidemia cases from 9 hospitals in Japan between 2016 and 2023. Compliance to the Candida Care Bundle was evaluated based on 5 elements: central venous catheter removal within 24 hours, appropriate antifungal therapy, ophthalmologic examination, follow-up blood cultures, and antifungal treatment for ≥2 weeks after clearance. Patients were categorized into high (4–5 items) and low (0–3 items) compliance groups. The primary and secondary outcomes were defined as 30-day survival and the development of endophthalmitis, with propensity score matching used to adjust for potential confounders. Results: Among 230 patients, 160 (69.5%) were classified into the high compliance group, which exhibited significantly lower 30-day mortality than the low compliance group (8.8% vs 57.1%, P < .01). Even after matching, the high compliance group remained independently associated with improved survival (hazard ratio [HR]: 0.15; 95% confidence interval [CI]: .08–.30). C. albicans (HR: 1.95; 95% CI: 1.01–3.52) and central line-associated bloodstream infection (HR: 2.63; 95% CI: 1.35–5.12) were associated with the fatal outcome. Endophthalmitis involved 23.6% of the patients, being associated with C. albicans (odds ratio [OR]: 8.18; 4.46–19.30) and central line-associated bloodstream infection (OR: 2.69; 1.08–6.70). Conclusions: Strict compliance to the Candida Care Bundle significantly improves survival, underscoring its importance in candidemia management.

Thyroid hormones are fundamental regulators of cellular differentiation, development, and metabolism. Their receptors are expressed in reproductive tissues, including the ovary, and dysregulation of thyroid hormone homeostasis has been associated with menstrual disturbances, infertility, and adverse pregnancy outcomes. Bone morphogenetic protein (BMP) ligands and their receptors are functionally involved in gonadotropin-induced ovarian steroidogenesis in an autocrine or paracrine manner. In this study, we examined the effects of thyroid hormones on steroidogenesis and their interplay with BMP signaling by using human granulosa-like KGN cells and primary rat granulosa cells (GCs). In KGN cells, triiodothyronine (T3) enhanced forskolin-induced expression of key steroidogenic enzymes involved in both estradiol biosynthesis and progesterone synthesis/metabolism, whereas thyroxine (T4) exerted minimal effects. In rat GCs, T3 treatment increased follicle-stimulating hormone (FSH)-stimulated estradiol production without altering progesterone output. T3 pretreatment attenuated BMP-6-induced phosphorylation of Smad1/5/9 in KGN cells, accompanied by upregulation of inhibitory Smad6 and downregulation of the BMP type II receptor. Conversely, BMP-6 stimulation elevated thyroid hormone receptor β expression, indicating reciprocal regulatory interactions between thyroid hormone and BMP pathways. Collectively, these findings suggest that thyroid hormones modulate steroidogenesis, at least in part, through suppression of endogenous BMP-6 signaling in granulosa cells.

To characterize changes in markers of oxidative stress for the clinical evaluation of patients with long COVID, we assessed oxidative stress and antioxidant activity based on serum samples from patients who visited our clinic between May and November 2024. Seventy-seven patients with long COVID (41 [53%] females and 36 [47%] males; median age, 44 years) were included. Median [interquartile range] serum levels of diacron-reactive oxygen metabolites (d-ROM; CARR Unit), biological antioxidant potential (BAP; μmol/L), and oxidative stress index (OSI) were 533.8 [454.9–627.6], 2385.8 [2169.2–2558.1] and 2.0 [1.7–2.5], respectively. Levels of d-ROMs (579.8 vs. 462.2) and OSI (2.3 vs. 1.8), but not BAP (2403.4 vs. 2352.6), were significantly higher in females than in males. OSI levels positively correlated with age and body mass index, whereas BAP levels negatively correlated with these parameters. d-ROM and OSI levels were significantly associated with inflammatory markers, including C-reactive protein (CRP) and fibrinogen, whereas BAP levels were inversely correlated with CRP and ferritin levels. Notably, serum free thyroxine levels were negatively correlated with d-ROMs and OSI, whereas cortisol levels were positively correlated with d-ROMs. Among long COVID symptoms, patients reporting brain fog exhibited significantly higher OSI levels (2.2 vs. 1.8), particularly among females (d-ROMs: 625.6 vs. 513.0; OSI: 2.4 vs. 2.0). The optimal OSI cut-off values were determined to be 1.32 for distinguishing long COVID from healthy controls and 1.92 for identifying brain fog among patients with long COVID. These findings suggest that oxidative stress markers may serve as indicators for the presence or prediction of psycho-neurological symptoms associated with long COVID in a gender-dependent manner.

Background: Since the pathophysiology of long COVID is not yet fully understood, there are no specific methods for its treatment; however, its individual symptoms can currently be treated. Long COVID is characterized by symptoms that persist at least 2 to 3 months after contracting COVID-19, although it is difficult to predict how long such symptoms may persist. Methods: In the present study, 774 patients who first visited our outpatient clinic during the Omicron period from February 2022 to October 2024 were divided into two groups: the early recovery (ER) group (370 cases; 47.8%), who recovered in less than 180 days (median 33 days), and the persistent-symptom (PS) group (404 cases; 52.2%), who had symptoms that persisted for more than 180 days (median 437 days). The differences in clinical characteristics between these two groups were evaluated. Results: Although the median age of the two groups did not significantly differ (40 and 42 in ER and PS groups, respectively), the ratio of female patients was significantly higher in the PS group than the ER group (59.4% vs. 47.3%). There were no significant differences between the two groups in terms of the period after infection, habits, BMI, severity of COVID-19, and vaccination history. Notably, at the first visit, female patients in the PS group had a significantly higher rate of complaints of fatigue, insomnia, memory disturbance, and paresthesia, while male patients in the PS group showed significantly higher rates of fatigue and headache complaints. Patients with more than three symptoms at the first visit were predominant in the PS groups in both genders. Notably, one to two symptoms were predominant in the male ER group, while two to three symptoms were mostly reported in the female PS group. Moreover, the patients in the PS group had significantly higher scores for physical and mental fatigue and for depressive symptoms. Conclusions: Collectively, these results suggest that long-lasting long COVID is related to the number of symptoms and presents gender-dependent differences.

Background: To characterize the clinical significance of vitamin D deficiency (VDD) detected in long COVID, a retrospective observational study was performed for outpatients who visited our clinic during the period from May 2024 to November 2024. Methods: Clinical trends in long COVID patients diagnosed with VDD who showed serum concentrations of 25-hydroxyvitamin D (25-OHD) lower than 20 ng/mL were compared with those in long COVID patients in a non-deficient vitamin D (NDD) group. Results: Of 126 patients with long COVID, 97 patients (female: 50) who had been infected during the Omicron phase were included. Sixty-six patients (68%) were classified in the VDD group. The median serum concentrations of 25-OHD were 14.8 ng/mL in the VDD group and 22.9 ng/mL in the NDD group. There were no significant differences between the two groups in terms of age, gender, BMI, severity of COVID-19, period after infection and vaccination history. Although the levels of serum calcium and phosphate were not significantly different between the two groups, the percentages of patients in the VDD group who complained of dizziness, memory impairment, palpitation and appetite loss were larger than those in the NDD group. Of note, the patients who complained of palpitation showed significantly lower concentrations of serum 25-OHD than those in the patients without palpitation (median: 11.9 vs. 17.3 ng/mL). Moreover, patients in the VDD group had significantly higher scores for physical and mental fatigue as well as higher scores for depressive symptoms. Conclusions: Collectively, VDD is involved in clinical manifestations of long COVID, particularly symptoms of palpitation, fatigue and depression.