Visceral Leishmaniasis (VL) is a potentially fatal disease and may be associated with primary or acquired immunodeficiencies. There are few reports, in the literature, of inborn errors of immunity. Here, we report two cases of VL as a marker of inborn errors of immunity, namely, GATA2 and RAB27A deficiency. Our data suggest that VL patients should be screened for primary immunodeficiency, particularly in cases of VL relapse. Leishmania and transmitted by sandflies. Clinically, VL is characterized by fever, pancytopenia, weight loss and hepatosplenomegaly, but it can be asymptomatic,,Visceral Leishmaniasis (VL) is caused by protozoa of the genus Leishmania. Bone marrow biopsy showed a proportional increase in granulocytes. Liver biopsy was also performed, with immunohistochemistry negative for Leishmania. ELISA immunoassay and rK39 rapid test was positive. Polymerase chain reaction (PCR) was performed on the bone marrow aspirate, with a positive result for Leishmania. Treatment with liposomal amphotericin B (LAB) at a total cumulative dose of 40mg/kg, for 10 days. An HIV test for further immunodeficiencies was negative. Peripheral blood immunophenotyping revealed a CD4+ lymphocyte count of 154 cells/mm³ , absence of B lymphocytes , 8 NK cells/mm3  after the first VL treatment. GATA2 deficiency was detected by dideoxynucleotide sequencing. Due to unresponsive treatment to VL, interferon gamma associated with LAB and meglumine antimoniate at a dose of 10mg/kg, for 16 days . Additionally, empirical treatment for Mycobacterium avium complex (MAC) with rifabutin, clarithromycin and ethambutol was initiated.Male, 37 years old, born in Maranhão (Northeast Brazil), sugarcane cutter, son of consanguineous marriage and occasional drinker. At the age of 21, he presented with inflammatory arthralgia affecting the elbows, wrists, hands, knees and ankles. Rheumatoid arthritis was diagnosed and treatment with non-steroidal anti-inflammatory drugs and prednisone commenced. There was improvement in symptoms, with maintenance of corticosteroid therapy (10 mg/day of prednisone) for 7 years. He and his family did not have a history of recurrent infections. He was admitted to another hospital with a history of daily fever, up to 39°C, for 5 months, asthenia, weight loss of approximately 10 kg and increased abdominal volume. Physical examination revealed pale skin and mucous membranes and splenomegaly  and hepatomegaly . Laboratory tests showed pancytopenia, in addition to hypoalbuminemia . The bonThe patient showed clinical improvement after 5 days of combined treatment for VL and was discharged in good health. We observed resolution of splenomegaly and pancytopenia after 5 months of follow-up. The patient was referred for hematopoietic stem cell transplantation at another institution.Leishmania. He received treatment with LAB at a dose of 35 mg/kg. Four months after hospital discharge, he again presented with fever and thrombocytopenia at the outpatient clinic. A bone marrow aspirate was performed, showing amastigotes of Leishmania that were also detected in his bone marrow culture. He was treated with meglumine antimoniate and intravenous human immunoglobulin, with clinical and laboratory improvement, and was discharged in good health. Three weeks later, with a seven-day history of fever, weakness, pallor and increased abdominal volume, a palpable spleen was detected 23 cm below the left costal margin and a palpable liver 5 cm from the right costal margin. Leishmania ELISA immunoassay and the rK-39 antigen test were negative. Bone marrow biopsy showed a lymphocytic and histiocytic inflammatory reaction with a granulomatous pattern; no amastigotes were observed in the bone marrow aspirate. He was re-treated for VL, on an empirical basis, with LAB. The patient had a phenotype suggestive of Griscelli Syndrome (silvery hair and eyebrows). Next-generation sequencing (NGS) was performed for a panel of genes associated with familial hemophagocytic lymphohistiocytosis, which showed a compound heterozygous mutation in the RAB27A gene . He had fever on alternate days, pallor, increased abdominal volume and unquantified weight loss. He did not have a history of recurrent infections. Anemia and thrombocytopenia were found on admission . Bone ma27A gene , diagnosLeishmania is essentially cell-mediated. Environmental and host factors also contribute to greater susceptibility to the diseaseThe protective immune response against species of the genus GATA-binding protein 2 (GATA2) is one of six GATA-binding factors that act to regulate gene expression for hematopoiesis, allowing hematopoietic stem cells to survive and self-renew. GATA2 deficiency can occur due to gene deletion, mutations in regulatory regions or exonic variations of nucleotides,Infections in patients with GATA2 mutations are predominantly secondary to dysfunction of cell-mediated immunity, with monocytopenia, which leads to profound dysfunction of the cytokine response, absence of IFNγ/IL-12 response, predisposing to atypical mycobacterial infections , aspergillosis (16%), histoplasmosis (9%) and warts by all HPV serotypes (60-70%)Griscelli Syndrome (GS) is commonly diagnosed between 4 months and 7 years of age, unlike our reported patient, with diagnosis made in adolescence. In GS type II, changes in skin and hair color occur, associated with immunological abnormalities and the development of hemophagocytic lymphohistiocytosis (HLH)Leishmania infection depends on an effective cellular response, which does not occur in patients with Griscelli syndrome or with GATA 2 mutations. According to our data, we strongly suggest that VL manifested itself as an opportunistic disease in the two reported cases, as it’s known that control of To our knowledge, these are the first reported cases of an association between VL and GATA2 deficiency and Griscelli syndrome.


Symptoms of levothyroxine overdose may vary depending on age, metabolism, etc. There are no specific guidelines for treating levothyroxine poisoning. Here, we present the case of a 69-year-old man with a history of panhypopituitarism, hypertension, and end-stage renal disease who attempted suicide by ingesting 60 tablets of 150 µg levothyroxine (9 mg). Upon presentation to the emergency room, he was asymptomatic despite the free thyroxine level above the range of the assay. During the hospital stay, he developed sinus tachycardia, which was controlled with propranolol. Mild elevations in liver enzymes were also noted. He received stress-dose steroids; hemodialysis was performed a day earlier, and cholestyramine was administered. Thyroid hormone levels started to improve by day seven and finally normalized in 20 days, after which the home dose of levothyroxine was resumed. The human body has several mechanisms to compensate for levothyroxine toxicity, including the conversion of excess levothyroxine to inactive reverse triiodothyronine, increased binding to thyroid-binding globulin, and hepatic metabolism. This case shows that it is possible to have no symptoms even with an overdose of up to 9 mg a day of levothyroxine. Signs and symptoms of levothyroxine toxicity may not appear for several days after ingestion, and, therefore, close observation preferably on a telemetry floor is recommended until the thyroid hormone levels start to decrease. Effective treatment options include beta-blockers preferably propranolol, early gastric lavage, cholestyramine, and glucocorticoids. While hemodialysis has a limited role, antithyroid drugs and activated charcoal are ineffective. About four in 100 people in the United States have hypothyroidism . MassiveA 69-year-old male with a past medical history of panhypopituitarism due to pituitary resection for a non-secreting pituitary adenoma, hypertension, end-stage renal disease, and depression presented with ingestion of 60 tablets of 150 µg levothyroxine (9 mg) as a suicide attempt. His home medications included levothyroxine 150 µg daily, hydrocortisone 20 mg in the morning and 10 mg in the afternoon, testosterone 200 mg intramuscular injection every two weeks, bupropion 150 mg daily, and enalapril 10 mg daily.The patient presented to the emergency room (ER) four hours after ingestion of levothyroxine pills and was asymptomatic on presentation. The physical examination was negative for any tremors, lid lag, and hyperactive deep tendon reflexes. Vital signs included a blood pressure of 154/90 mmHg and a heart rate of 85 beats/minute. He was afebrile and oxygen saturation was good on room air. An electrocardiogram revealed sinus rhythm. The patient’s laboratory workup was significant for free thyroxine (FT4) of >7.04 ng/dL , total thyroxine (TT4) of >24.9 ng/dL , total triiodothyronine (TT3) of 171 ng/dL , and thyroid-stimulating hormone (TSH) of <0.02 mU/L . Given known hypopituitarism, evaluation and treatment decisions were made based on thyroxine and triiodothyronine levels rather than TSH.The patient received activated charcoal in the ER and was closely monitored with telemetry for the development of any arrhythmia. Upon admission, 100 mg of intravenous (IV) hydrocortisone was administered as a stress dose of steroids which was titrated down to his home dose. Hemodialysis was performed a day earlier than his regular schedule. The following day he developed sinus tachycardia with a heart rate of 110 beats/minute and was started on propranolol 10 mg three times a day. During the hospital course, thyroid function tests (TFT)  in the jejuno-ileum, thus leading to a progressive rise in both TT3 and total T4 levels in the first 24 hours after the ingestion. Moreover, FT4 needs to be converted to the active free T3, thus delaying the onset of symptoms for several days after the ingestion. Peak thyroxine plasma concentration can occur even two to four days after ingestion . Third, Given a long 7.5-day half-life of levothyroxine , all casGiven the rarity of levothyroxine toxicity, this case would help physicians in learning more about the possible presentation and management options of levothyroxine toxicity and help develop management guidelines for levothyroxine toxicity in the future.Patients may remain asymptomatic even with a levothyroxine overdose of up to 9 mg in a day. As no standard guidelines are currently available, the management of levothyroxine overdose should be individualized based on the amount ingested, as well as the clinical symptoms and signs of the patient. Patients should be monitored for cardiac arrhythmias and ideally kept under observation on a telemetry floor until their thyroid hormone levels begin to decrease. Beta-blockers (preferably propranolol) are the preferred treatment modality. Early gastric lavage, glucocorticoids, and cholestyramine are also effective options. Activated charcoal and hemodialysis have no role in levothyroxine overdose.


Teat papillomatosis is reported to be one of the factors causing mastitis and milk losses in dairy cattle. Little is known about bovine papillomavirus (BPV) circulation in the European cattle population, and no reports can yet be found about its prevalence in Polish herds. In this study, 177 BPV-like lesions were collected from teats of 109 slaughtered cows. BPV was identified in 39 of the examined animals, using PCR amplification and Sanger dideoxy sequencing. In total, 10 BPV types were isolated, among which the most common were infections caused by types 8 and 7. Macroscopically, “rice-grain” type lesions dominated (76%) and were mainly found on one teat (57.4%). The diversity of BPV types causing teat papillomatosis in Polish cows seems to be large, with nine already known types isolated and a new putative type found. The spread of new types among the worldwide cattle population can be seen for the first time, as type 25 and so called isolates BPV42 and BPV43 were found in the European cattle population. Papillomaviridae family, widespread among the worldwide population of cattle [Delta-, Epsilon-, Xi-, Dyoxi- and Dyokappapapillomavirus, but fourteen (16–29) persist as non-classified [Bovine papillomaviruses (BPVs) are double-stranded DNA viruses belonging to the f cattle . In genef cattle . In the f cattle ,4. Most assified . Viral Dassified ,6,7,8,9.The course of the disease is usually benign and self-limiting, but severe resistance to treatment lesions may also appear. Up to the present, nine BPV types have been reported to cause teat and udder papillomatosis  ,13. CrosLittle is known about the circulation of BPV in Europe, and no data can yet be found on the prevalence of BPV genotypes that affect the population of Polish cows. This knowledge is valuable as it influences the proper and effective treatment, prophylaxes, and control of the disease. The aim of this study was to genetically evaluate the presence and types of BPV associated with teat papillomatosis in Polish cows. This is also the first report of a new putative type of BPV, type 25, and the so called types BPV42 and BPV43 found in teat papilloma lesions in Europe [The examined samples consisted of skin papillomas collected in the years 2021–2022 from cow teats from the central and western parts of Poland, slaughtered in one of the Polish abattoirs. In total, 177 teat papilloma lesions were sampled from the udder of 109 cows just after slaughter. The lesions were characterized by their morphology, size, and number. The samples for future study were stored directly in a 70% ethanol solution for conservation. DNA was isolated using the Genomic Mini kit  according to the manufacturer’s instructions and stored at −20 °C for further analysis.PCR amplification was provided based on the major capsid protein (L1) nucleotide sequence of the conserved open reading frame (ORF) region . Two paihttp://www.ncbi.nlm.nih.gov/blast/, accessed on 7 March 2023). The isolate with a novel sequence was called a new putative BPV type, since the PCR product was a partial L1 gene nucleotide sequence [The fragment obtained from amplification using FAP59/FAP64 primers was chosen for sequencing due to a markedly higher number of obtained products compared to the second pair of primers. The concentration and quality of the purified DNA samples was determined by the DS-11FX Microvolume Spectrophotometer . Isolated DNA fragments were then sent to the external laboratory for both direction sequencing, using the Sanger dideoxy sequencing method . Sequences were trimmed and aligned using Chromas software , then compared to sequences already registered in GenBank through the blast server . In total, 3200 teats were examined, and 177 possessed warts. The lesions were found in 57.4% of cases only on one teat, in 26.7% on two teats, in 10.9% on three teats and in 5.0% in four teats. The observed skin lesions had a different morphology: 83 of the animals had a “rice-grain” shape consisting of a white elongated protuberance, with the diameter oscillating between 0.1 and 1 cm; 6 had cauliflower-like skin papillomas; one filamentous skin papilloma, 1 pedunculated skin papilloma and 18 were mixed in shape  . The aveUsing FAP59/FAP64 primers, 41 positive results were obtained, which constituted 37.6% of the examined animals. However, in the case of the second pair of primers, this number was five. All positive results for the MY09/MY11 primers were also positive for the FAP59/FAP64 primers. A total of 39 positive results were successfully sequenced for the BPV presence. Ten types of BPV were detected, including types 2, 4, 7, 8, 9, 10, 25, the so called isolates BPV42 and BPV43, and one new putative type (isolate PL-25) . PhylogeLittle is known about the prevalence of BPVs in Europe. It is also unclear which of the BPV types are most common in the worldwide population of cattle. Most research identifies types 1 and 2, mainly from skin lesions, and this tendency seems to be accurate for all anatomical regions except for the skin of teats and udder, where type 6 predominates ,32,33,34In the literature, PCR amplification of BPV DNA is carried out mostly using degenerate FAP59/FAP64 primers, which were primarily designed to find the L1 nucleotide sequence of the conserved ORF region of human papillomavirus ,25. PrimAs proved before, the type of BPV cannot be guessed just by the location and characteristic features of the lesions. In the literature, “rice-grain” shape lesions were thought to be caused by type 5, but new data show that the same types of lesion can also be seen in infections related to other types, such as BPV 7, 9, 8, 25 and so called type 43 confirmed in our study.Xipapillomavirus genus) and BPV43  were found in cows in Europe. Outcomes of these types were only reported before in Brazil from cases of teat papillomatosis of milking cows (GenBank: MG252779.1), with low prevalence [Epsilonpapillomavirus genera . The severity depends on the presence of three oncogenic proteins in the viral genome—E5, E6 and E7, and two of them are usually sufficient to successfully develop malignant tumor lesions [Delta-, Xi-, Dyoxi- and Epsilonpapillomavirus. Only type 2 from Deltapapillomavirus genera could be isolated from teat papillomatosis cases . Among identified viruses, there are two BPV genotypes (type 7 and 8) occurring significantly more frequently in Polish cattle. We can also conclude that morphology of the lesions observed is not correlated with the specific BPV type.Papillomaviridae family to cross inter-species boundaries, and better study of its characterization in addition to the clinical and epidemiological aspects should be conducted [The BPV shows a unique ability for the onducted ,22,23,50onducted ,7,8,9,51


The reaction mechanism of ClO Since first proposed as a selective pathway for the oxidation of primary alcohol groups in polysaccharides , the staldehydes . Finallyhydes [+   , regulat 0.01 M) .After a separated activation stage, the oxoammonium cation can act as a direct oxidant for the Cmolecule ,21,22. Omarkably . For insmarkably  achievedAlthough a ClOIn this section, the ClOBy qualitatively comparing the spectral lines, oxidation at pH 8 proves a lower signal intensity, meaning a more complete conversion of TEMPO. This observation is validated with the quantification of the spin concentration, in which the presence of the radical was reduced in 83.4% when the reaction occurred at pH 8, contrasting with a depletion of 72.1% after TEMPO activation at pH 10. In this sense, the conversion yield is higher at pH 8, even if the oxidative potential of ClOependent .This supports the assertion that a bromide-free nitroxyl oxidation should proceed at almost neutral pH for a more optimal activation , specifi of ClO2 . Indeed,compound . RegardiAs shown in nd ClO3− .The signal sweep period was extended to evaluate the stability of the system. The nitroxyl EPR spectra, taken instantly, then at 3 min and 5 min, are displayed in In detail, for the TEMPO/ClOClOlacement , as seens medium  and the e medium , the genAlternatively, the nitroxyl radical can be recovered by the following chemical routes. Respectively, the main mechanism is the comproportionation reaction between the oxoammonium cation . The test was carried out with a 2:1 molar ratio regarding ClO2 , since Cproducts . At firs pattern . During Then, the spectral line for the TEMPO-ClOery fast  due to to radical, and then the further reaction of Ro with a second molecule of ClODespite the attack by ClOAs byproduct, HOCl represents a selective oxidant that can also react with TEMPO to form an oxoammonium salt , which wFrom the variance in the intensity of the resonance spectrum, a comparable pattern to that without DMSO is observed. Certainly, the decline in the EPR signal intensity is lower when HOCl is trapped: 70.3% of initial TEMPO concentration is achieved. This is also noted when HOCl is added alone (without ClOns (14%) .ClO radical . When anThe EPR technique uses microwave radiation to probe species such as radicals in the presence of an externally static applied magnetic field. EPR is conditioned to the electron spin (ev), there is energy absorption (E). The measurement of absorbed energy, recorded as its first derivative, is the EPR signal [For a molecule with unpaired eR signal .Remark that no signal will be detected if the system does not present unpaired electrons, since there will not be resonant absorption of microwave energy. Precisely, molecules with stable nitroxide radicals, such as TEMPO, can be detected. The TEMPO redox sequence involves the oxoammonium cation oxyl (TEMPO), sodium hypochlorite (NaOCl) (12% Cl), and dimethyl sulfoxide (DMSO) were supplied by Carl Roth. Vanillin (99%) and methyl The ClOed water . The ClOtiovaara , in whiclute HCl .The reactant solutions were prepared in aqueous medium (TEMPO 1 mM, ClOX-band EPR spectra were recorded with a Bruker EMXmicro spectrometer, equipped with a standard ER4102ST Bruker universal cavity. Typical data acquisition parameters were adjusted, operating at X band: data points, 2500; central field, 360 mT; sweep width, 20 mT; total scans, 3; microwave power, 20.5 mW; modulation frequency, 100 kHz; sweep time, 60 s; and modulation amplitude, 2 G . For eacThe relative concentration of the nitroxyl radical in each measurement was subjected to the assumption that TEMPO contains only one nitroxyl radical per molecule . Hence, A medium scan speed system is used to register the absorption spectra of TEMPO, ClOA direct conversion of the TEMPO molecule by ClO


Rare tumor-induced osteomalacia (TIO) usually resulted in bone pain, fragility fractures and muscle weakness in clinical, which is caused by the reduced phosphate reabsorption, thus impaired mineralization of the bone matrix and free energy transfer. The specific problems in postsurgical patients are obscure although surgical removal of the tumor is the only definitive treatment. Here, we documented a female TIO patient who suffered more severe bone pain and muscle spasms post-operation. Further, we presented and discussed our explanation for the unexpected symptoms.The main symptoms were whole-body pain and muscle weakness. The patient also presented with osteoporosis and multiple fractures.Elevated serum fibroblast growth factor 23 (FGF23) level and hypophosphatemia indicated the diagnosis of TIO. Positron emission tomography (PET)/computed tomography (CT) with 68 Ga-DOTATATE located the tumor in the dorsolateral part of the left foot. Histopathological examinations confirmed the diagnosis.The tumor was surgically removed immediately after the diagnosis of TIO and localization of the tumor. Postoperatively, calcium carbonate supplement treatment was continued.Two days after surgery, the serum FGF23 level was decreased to the normal range. Five days after surgery, N-terminal propeptide of type I procollagen and β-CrossLaps (β-CTx) had a remarkable increase. A month after surgery, the patient N-terminal propeptide of type I procollagen and β-CTx levels were decreased obviously, and serum FGF23, phosphate and 24h urinary phosphate were in the normal range.We report a female patient who presented with osteoporosis and fractures. She was found with an elevation of FGF23 and diagnosis with TIO after PET/CT scanning. After surgically removing the tumor, the patient experienced more severe bone pain and muscle spasms. Active bone remodeling might be the reason for the symptoms. Further study will reveal the specific mechanism for this abnormal bone metabolism. The overproduced FGF23 acts on the proximal renal tubule to decrease the level of sodium phosphate cotransporters NaPi-2a and NaPi-2c, resulting in reduced phosphate reabsorption. Furthermore, 25-hydroxyvitamin D3 1-alpha-hydroxylase in the proximal tubules is also can be suppressed by FGF23, which could cause the reduction of 1,25(OH)2D and consequently reduce the intestinal absorption of phosphate and calcium.,3Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by autonomous excessive secretion of fibroblast growth factor 23 (FGF23). With similar clinical symptoms and the age of onset to primary osteoporosis, as well as the extremely low incidence of the disease, the diagnosis of TIO is challenging.–7 The previous investigations noted that the duration from the onset of symptoms to the diagnosis of it was a median of 2.9 years in China and 2.4 years in Japan. Here, we document a TIO patient who was considered as having primary osteoporosis for nearly 2 years and had an ineffective treatment. After the diagnosis of TIO and surgical removal of the tumor, the patient presented unexpectedly increased bone resorption, as well as more severe bone pain and muscle spasms. Although intensive care during the surgery was mentioned, the specific problems associated with bone metabolism disorders in postsurgical patients are poorly described in the literature.The main clinical features of TIO include bone pain, muscle weakness and fractures.The patient is a 43-year-old female who was suffering from 2 years of whole-body pain and muscle weakness. Her medical history included controlled type 2 diabetes (HbA1c 7.2%) for 2 years and well-controlled hypertension (SBP < 140 mm Hg or DBP < 90 mm Hg) for 6 years. She was on acarbose, sitagliptin, and amlodipine. She had no history of smoking, alcohol, or illicit drug use. Skeletal growth had been normal and her menstrual cycles were regular. She had not previously suffered from bone fractures or abnormal skeletal pains. She did not have a family history of skeletal, metabolic or hormonal disorders.Two years prior to diagnosis, the patient visited a local hospital due to back pain and was diagnosed with primary osteoporosis. However, with 1-year calcium and vitamin D supplements treatment , the back pain was worse and followed by hip pain and muscle weakness. Thus, the patient went to the hospital again in 1 year later and found vertebral compression fractures in T11 to L1 vertebras. To ease the back pain, she experienced vertebroplasty with bone cement augmentation . Despite this, the back pain could not effectively treat and the patient gradually became unable to stand and move. Therefore, the patient visited the orthopedics outpatient clinic of our hospital 4 months before the correct diagnosis of TIO. The bone scanning indicated multiple rib fractures, bilateral sacral fractures, bilateral femoral neck fractures, and ilium fractures, with bone bruises in main joints such as the knee, elbows, wrists and intertarsal joints. Thought of the possibility of metabolic bone disease, the patient was referred to us by the orthopedic surgeon. At this point, the patient was bedridden and required continuous administration of pain drugs including various nonsteroidal anti-inflammatory drugs or oral tramadol.Considering that the patient presented with severe osteoporosis, we measured the patient bone metabolism and calcium-phosphorus homeostasis at first. Then, parathyroid hormone (PTH) and creatinine in serum were tested due to hypophosphatemia. The results shown in Table TIO is the most prevalent form of acquired hypophosphatemic osteomalacia. To test this, we further measured the serum FGF23 level and found it remarkably elevated Table B and C, After the diagnosis was confirmed, the surgical removal of the tumor was operated. Histopathological examination of formalin-fixed and paraffin-embedded slides demonstrated a 16 × 14 mm phosphaturic mesenchymal tumor with multinucleated, osteoclast-like cells, with minimum tumor-free resection margins of 0.5 mm. Immunohistochemical staining showed a positive FGF23 staining  was warranted to correct for severe hypophosphatemia. Administration of calcium carbonate 600 mg and alfacalcidol 0.5 μg daily was continued. Two days after surgery, the serum FGF23 concentration of the patient was decreased to 15.7 pg/mL (reference range 23.3–95.4 pg/mL). The serum phosphate and 24 h urinary phosphate were 1.07 mmol/L and 2.62 mmol/24 h, respectively  also had a remarkable increase compared to the pre-operation Table . We usedHere, we report a 43-year-old female with TIO, who presented with back pain at the beginning and rapidly progressed to multiple fractures and muscle weakness. There was little benefit from calcium and vitamin D supplements treatment before the removal of the tumor, and neither got remission from vertebroplasty. After the patient was delivered to us, we found the patient had hypophosphatemia with normal serum calcium, PTH and creatinine level. Then, we measured the serum FGF23 level, and the elevated of it assisted us to diagnose TIO. Further, PET/CT with 68 Ga-DOTATATE helped us to locate the tumor. Interestingly, after the removal of the tumor in the dorsolateral part of the left foot, the patient emerged with severe bone pain and muscle spasms, which could be alleviated with the treatment of calcium. A Japanese study documented that the average age of the TIO patients for the first visit to treating physicians was 52 ± 17 years, which is similar to the perimenopausal age. Therefore, TIO is easily be misdiagnosed as primary osteoporosis and missed. In our case, the patient was first considered as having primary osteoporosis and experienced ineffective calcium and vitamin D supplements treatment for a year. More importantly, the calcium and vitamin D treatment without the supplement of inorganic phosphorus possibly increased the risk of kidney stones and renal impairment.TIO is a rare paraneoplastic syndrome, which could stimulate urine phosphorus excretion, leading to the gradual resorption of bone, and resulting in secondary osteoporosis, osteomalacia and fractures.,13 However, TIO is a rare disease with an approximate annual incidence of 0.04 per hundred thousand people. The low prevalence of TIO and the low awareness of it makes the measurement of FGF23 still not accessible in many areas. During the early treatment, our patient presented an unexpected acceleration in bone degradation, which led us to suspect the diagnosis of primary osteoporosis. Luckily, serum FGF23 could be measured in our hospital, and the elevated level of it helps us distinguish TIO from other secondary osteoporosis as Fanconi syndrome or vitamin D deficiency. Next, the tumor location is the second bottleneck in the diagnosis of TIO. Previous research indicated PET/CT with 68 Ga-DOTATATE as the first recommendation,,15 which showed very high sensitivity (87.5%) to detect tumors regardless of tumor size. Nevertheless, we have received 3 adults presented as high FGF23 related hypophosphatemic osteomalacia with no mutation in the dmp-1, enpp1, fgf23, phex, and slc34a3 genes in the past 2 years. This patient is the only one who successfully detected the tumor by 68 Ga-DOTATATE PET/CT.The autonomous secretion of FGF23 by tumor is the key modulator that causes urine phosphorus excretion. Thus, the elevation of FGF23 level in serum is a central role in the diagnosis of TIO.Two days after the removal of the tumor, the patient serum FGF23 level was back to normal and hypophosphatemia was corrected. However, 5 days after the surgery, the patient appeared severe muscle spasms in all of her limbs. At this point, the patient was on calcium, vitamin D, and phosphate supplement therapy. Her serum calcium, phosphate, and albumin-corrected serum calcium were all in normal range. It seems that she was developing hypocalcemic muscle cramps except the serum calcium level did not decrease. Besides, she was also suffering a heavier bone pain in the whole body staring on the fifth postoperative day, and we found a significantly elevation of her serum β-CTx level. Surprisedly, the results indicates increased bone resorption after the removal of the tumor. To alleviate the spasms, we used calcium gluconate intravenously and it turned out to be effective on both spasms and bone pain. To explain this, we had a speculation. At the initial stage of TIO, the patient bone resorption was active due to hypophosphatemia. With the process of the disease, the persistence of bone resorption finally caused bone depletion and bone homeostasis sustained at a low background level. However, after the removal of the tumor, bone formation was active because of the over-reduced bone mass, fracture healing, calcium, and vitamin D supplementation therapy or the protective effect of estrogen. During the active bone remodeling process, the bone requires calcium eagerly. Thus, more serum calcium was used for bone formation and less calcium is available in the tissue fluid. Therefore, the patient was present a kind of hypocalcemic muscle cramps that can be alleviated by calcium supplements. Furthermore, bone resorption was also enhanced as a result of active bone remodeling, causing the elevation of β-CTx level and temporary bone pain. To treat the muscle cramps and promote bone formation, we double the dose of calcium carbonate daily to 1200 mg. As we expected, the symptoms were attenuated 3 days after adjusting and recovered well during the 1-month follow-up.Conclusively, we report a TIO patient presented with osteoporosis with multiple fractures and appeared unexpected muscle cramps and bone pain post-operation. An explanation for the unexpected symptoms was also presented and discussed by us. Though we seem effectively treated the symptoms, the specific mechanism of it still unknown and worth to be further exploring.Conceptualization: Lingfeng Shi, Mengjia Tang, Yuping Zhang, Jiongyu Hu.Data curation: Lingfeng Shi, Mengjia Tang, Jiongyu Hu.Formal analysis: Lingfeng Shi, Mengjia Tang, Fang Deng, Jiongyu Hu.Funding acquisition: Jiongyu Hu.Investigation: Lingfeng Shi, Shanshan Duan, Yuping Zhang.Methodology: Lingfeng Shi, Shanshan Duan, Fang Deng, Jing Yang.Project administration: Lingfeng Shi.Resources: Lingfeng Shi, Fang Deng.Software: Lingfeng Shi, Jing Yang.Supervision: Lingfeng Shi.Validation: Lingfeng Shi.Visualization: Lingfeng Shi.Writing – original draft: Lingfeng Shi, Mengjia Tang, Jiongyu Hu.Writing – review & editing: Lingfeng Shi.


The postacute care for cerebrovascular disease (PAC-CVD) program was launched in Taiwan nearly a decade ago. However, no clear regulations regarding length of stay (LOS) in the program and extension standards exist. Thus, the allocation of limited medical resources such as hospital beds is a major issue.This novel study retrospectively investigated the effects of functional performance and national health insurance (NHI) costs on PAC-CVD LOS. Data for 263 patients with stroke who participated in the PAC-CVD program were analysed. Hierarchical multiple regression was used to estimate the effects of functional performance and NHI costs on LOS at three time points: weeks 3, 6, and 9.At week 3, age, NHI costs, modified Rankin scale score, and Barthel index significantly affected LOS, whereas at week 6, age and NHI costs were significant factors. However, functional performance and NHI costs were not significant factors at week 9.The study provides crucial insights into the factors affecting LOS in the PAC-CVD program, and the results can enable medical decision-makers and health care teams to develop inpatient rehabilitation plans or provide transfer arrangements tailored to patients. Specifically, this study highlights the importance of early functional recovery and consideration of NHI costs when managing LOS in the PAC-CVD program. According to the World Health Organization, stroke is the second leading cause of death worldwide and the third leading cause of disability . In the Regarding treatment to recover function or reduce disability and alleviate the economic burden incurred by stroke, the National Health Insurance Administration (NHIA) of Taiwan launched a nationwide postacute care for cerebrovascular disease (PAC-CVD) program in 2014. This program gives patients high-intensity inpatient rehabilitation and integrated care implemented by a multidisciplinary PAC-CVD stroke team . StudiesThis study was a retrospective observational study based on medical record review. Data were collected for patients with stroke who participated in the PAC-CVD program at a regional hospital in southern Taiwan from January 2017 to June 2021. The exclusion criteria were unexpected termination of the PAC-CVD program for the patient due to a change in their medical condition  or personal reasons and the inability to continue the program. The study protocol was approved by the Research Ethics Committee of Taiwan Municipal An-Nan Hospital—China Medical University (TMANH110-REC007). The requirement for informed consent was waived because of the retrospective design of the study. Data on patients’ demographics , LOS, NHI costs, functional performance, clinical attributes , and common risk factors  were collected from electronic medical records. To retain patients’ privacy, the data were kept confidential and protected, and patients were anonymized. Once data collection was complete, statistical analysis was conducted.The PAC-CVD program is the first structured PAC program implemented in Taiwan. When experiencing an acute stroke, a patient receives acute medical intervention at a medical centre or large-scale hospital. Within 1 month of their medical condition stabilizing, the patient is transferred to a community hospital  for the inpatient PAC program. The inclusion criteria for the PAC-CVD program are: (1) experiencing an acute stroke within the preceding 30 days; (2) having stable vital signs and a stable neurological status for at least 72 h without uncontrolled complications; (3) having moderate-to-moderately severe functional impairment with a modified Rankin scale (mRS) score of 3 to 4; (4) demonstrating sufficient physical ability to sit in a wheelchair or at the bedside for at least 1 h; (5) possessing basic cognitive ability to understand rehabilitation activities and actively participate in rehabilitation therapy; and (6) having good family support.The services provided by the PAC-CVD program include: (1) tailored treatment plans; (2) integrated care from a multidisciplinary team of clinicians, nurses, physical therapists, occupational therapists, speech therapists, social workers, dietitians, and case managers; (3) high-intensity rehabilitation (3–5 sessions per day); (4) lessons on homecare skills to prepare for discharge; (5) prevention and treatment of comorbidities and complications; and (6) regular assessments  to facilitate the development of a care plan.The LOS is generally 3–6 weeks. If a patient requires hospitalization for > 6 weeks, the multidisciplinary team’s conference records are sent to the NHIA, which decides whether and for how long the extension can be permitted. The LOS can be extended to be 12 weeks maximum. If an extension request is rejected, the multidisciplinary team must inform the patient and plan for their discharge or a transfer of services.mRS and Barthel index (BI) scores were collected to reflect general physical activity. The mRS is widely used by clinical professionals as a general disability assessment to evaluate the degree of required daily living assistance of patients with stroke and their walking ability. The scores range from 0 to 6, with 0, 1, 2, 3, 4, 5, and 6 corresponding to no symptoms, no significant disability, slight disability, moderate disability, moderately severe disability, severe disability, and death, respectively. The higher the score, the more severe is the degree of disability . The BI Regarding walking ability, data were collected using the 5-m walking speed (5MWS) and the 6-min walking distance (6MWD) tests. The 5MWS is the time it takes for a patient with stroke to walk 5 m at a comfortable high speed (in m/s) on a flat surface without assistance. The 5MWS is used to evaluate both walking speed and ability . The 6MWPatients’ gender, clinical factors , and common risk factors  were coded as categorical variables. Age, LOS, mRS score, BI, 5MWS, 6MWD, and NHI costs  were coded as continuous variables and are presented as the mean and standard deviation (SD).Hierarchical multiple regression was conducted to investigate the effect of functional performance and NHI costs on LOS in the PAC-CVD program at different time points . Because individual factors and differences in recovery may lead to different prognoses for functional performance, patient demographics , clinical factors, and common risk factors were set as control variables. Each regression model consisted of the following four components, which were added in sequence: (1) age and gender; (2) clinical and common risk factors; (3) NHI costs; and (4) functional performance. The dependent variable was LOS in the PAC-CVD program. Normality was examined before each regression was conducted; the absolute value of skewness should be below 2, and the absolute value of kurtosis should be below 7 . To verip of < 0.05 indicated statistical significance.Statistical analyses were conducted using SPSS . All tests were two-sided, and a During the period of data collection, 286 patients with stroke participated in the PAC-CVD program, and participation in the program was terminated for 23 due to changes in their medical conditions or personal factors. A total of 263 patients were thus enrolled in this study. Functional performance measurement and NHI cost data were collected at weeks 3, 6, 9, and 12 of hospitalization for 263, 152, 26, and 6 patients, respectively . Of the 263 patients, 89 patients (33.8%) had an mRS score of 3, and 174 (66.2%) had an mRS score of 4. Thus, more than half of the participants had moderate-to-severe disability and required assistance with walking and daily activities. The mean BI was 44.56 (SD: 22.23), indicating that many patients had considerable dependence for daily activities. Regarding walking speed, the mean 5MWS was 0.1 (SD: 0.24) m/s. Regarding cardiorespiratory endurance and walking ability, the mean 6MWD was 25.67 (SD: 67.64) m  = 20.372, p < 0.001). The results of the hierarchical multiple regression analysis regarding the effects of functional performance and NHI costs on PAC-CVD LOS revealed that age, NHI costs, mRS score, and BI had significant effects; they contributed to 14.2% , p = 0.006), 38.6% , 25.9% , and 20.8%  of the regression model, respectively. Thus, the results revealed that old age was associated with a short LOS, whereas high NHI costs were associated with a long LOS. Moreover, a high mRS score, indicating severe disability, was linked to a long LOS, whereas a high BI, indicating high functional independence, was associated with a short LOS  = 5.501, p < 0.001). Age  and NHI costs  had significant power to explain LOS in the PAC-CVD program. Thus, as age increases, LOS in the PAC-CVD program decreases; however, as NHI costs increase, this LOS increases  = 1.295, p = 0.346). Therefore, the regression model had no significant power to explain LOS in the PAC-CVD program.At week 9 of the PAC-CVD program, the hierarchical multiple regression analysis demonstrated no significant effects on LOS in the PAC-CVD program  on how long patients with stroke remain in the PAC-CVD program. The results indicated that in week 3 of hospitalization, age, NHI costs, mRS score, and BI were significant predictors of LOS. In week 6 of hospitalization, age and NHI costs remained significant predictors of LOS. However, in week 9 of hospitalization, patient demographics , clinical attributes , common risk factors (smoking and drinking), NHI costs, and functional performance  were not found to significantly predict LOS.When an individual experiences a stroke in Taiwan, they are typically sent to either a medical centre or regional hospital for acute medical treatment. Once their condition stabilizes, they are discharged and must continue their recovery through outpatient rehabilitation at a small-scale hospital or clinic. However, an inability to continue rehabilitation at a medical centre often causes patients to feel helpless, and some may choose to transfer to another medical centre or large hospital for inpatient rehabilitation. Consequently, a high number of patients with stroke remain in large-scale hospitals for treatment, which leads to high NHI expenditure and consumes emergency and intensive care hospital beds and resources . AccordiThe results of this study indicate that mRS score and BI have significant power to explain LOS at week 3 of hospitalization. These two functional assessments evaluate a patient’s general disability level and independence in performing activities of daily living , 16. TypRegarding NHI costs, under the per-diem reimbursement system, the PAC-CVD program can effectively restore physical function without the patient incurring additional medical expenses . The preSeveral studies have found that age is a factor influencing LOS in the PAC-CVD program, and our study yielded a similar finding; specifically, we discovered that LOS tends to be shorter for older patients than for younger patients , 30, 31.Although this study obtained valuable findings, it has some limitations. First, the sample was drawn from a single centre, which may limit the study’s generalizability. Future studies should recruit more patients across several centres. Second, to provide a tailored rehabilitation plan, different types of training were administered to individual patients. This may result in varying recovery durations that subsequently impact the LOS. Consequently, this can have implications for the overall cost of hospitalization within the NHI per diem reimbursement system. Third, psychological factors may have affected rehabilitation and LOS. Qualitative methods and a deeper exploration of the psychological factors are warranted. Finally, the statistical methods used in this study analysed the effect of functional performance and NHI costs on LOS at three assessment time points; however, because healthcare is patient-centred, individual patients could be assessed repeatedly to yield longitudinal data for investigating the effects on LOS. Despite these limitations, this study contributes to the literature by highlighting the effects of functional performance and medical costs on LOS in the PAC-CVD program.This study analysed the effects of functional performance and NHI costs on LOS in the PAC-CVD program for patients with stroke. At week 3, mRS score and BI significantly influenced this LOS, indicating that the degree of disability and independence in daily living activities during the early stage of hospitalization greatly affects the LOS. Clinical rehabilitation personnel can develop individualized treatment plans with such scores in mind. At week 6 and 9, functional performance did not significantly affect LOS in the PAC-CVD program. However, clinical personnel can devise inpatient rehabilitation plans or assist with transferring patients to outpatient care on the basis of their functional abilities such as walking speed. If hospitalization lasts less than 6 weeks, higher NHI expenditure corresponds to a longer LOS. If hospitalization is extended (> 6 weeks), NHI expenditure does not significantly affect the LOS. The NHIA’s policy of controlling hospitalization through extension applications may also be used to control medical expenses. However, the older the patient is, the shorter is their LOS. Although NHI expenditure is well-controlled, extended hospitalization for patients with declines in all functional measures may be discouraged in order to efficiently utilize limited PAC-CVD beds. Home-based rehabilitation can be an alternative to inpatient rehabilitation that improves patients’ activities of daily living would facilitate the return of individuals to their homes and help control NHI costs. Under the PAC-CVD policy, LOS is affected by various factors. The present study can be a valuable resource for medical decision-makers and clinical practitioners who devise medical care plans and arrange postdischarge referrals.


Background: Breast cancer (BC) is a prevalent form of cancer and a leading cause of death among women worldwide. In Saudi Arabia, it accounted for 31.8% among females of all new cancer cases reported in 2018. Following the declaration of COVID-19 as a global pandemic, there was a complete redistribution of healthcare resources to face this crisis, which caused a significant delay in the management of various diseases, including BC. There is currently a lack of research in our region on the facility time interval in BC management. Therefore, this study aimed to fill this gap by determining the timelines of diagnosis, management, and factors influencing the delay.Methods: This observational retrospective study included all female patients diagnosed with BC at or referred to King Abdullah Medical City (KAMC) in Makkah, Saudi Arabia, between January 2020 and August 2021. The data for this study were obtained from a centralized electronic chart review of all included patients at the KAMC center.Results: A total of 76 patients were included in the study, with a mean age of 50 ± 11 years. In terms of the disease management duration, 20 patients (26.3%) completed their management within 30 days, 28 patients (36.8%) had a management duration between 31 and 60 days, and the management duration of 28 patients (36.8%) exceeded 60 days. Patient deposition showed a significant association with delay (p = 0.033). A higher incidence of delays at the initiation of treatment was observed in patients who failed to attend appointments (p < 0.001). Among patients who skipped two or more appointments, 12 individuals (80%) experienced a delay of more than 60 days. Moreover, appointment cancellation was associated with delayed treatment initiation (p = 0.03). Patients' age and comorbidity showed no significant association .Conclusion: Our findings highlight the significant impact of patient deposition and canceled or skipped appointments on delayed initiation of therapy for BC patients. Further research should be conducted to evaluate the impact of COVID-19 on other malignancies. Breast cancer (BC) is the predominant form of cancer and a primary contributor to female mortality worldwide. According to the Saudi Cancer Registry, In Saudi Arabia, it accounted for 31.8% among females of all new cancer cases reported in 2018 .The emergence of the new coronavirus disease in 2019 (COVID-19) has led to the implementation of several measures to minimize the transmission of the disease. Here in Saudi Arabia, all educational institutions, social gatherings, sporting events, domestic travel, and international flights were suspended following the disclosure of the first case. Before the first 100 confirmed COVID-19 cases, restrictions on social gatherings, travel, companies, and other activities were put in place . PatientTime to surgery (TTS) serves as an important metric in evaluating the quality of care in BC treatment. Prolonged delays in surgeries have been associated with reduced therapy response rates, as evidenced in previous research . TherefoStudy design, settings, and participantsThis observational retrospective study included female patients diagnosed with BC (confirmed by histopathology) at or referred to King Abdullah Medical City (KAMC) in Makkah, Saudi Arabia, between January 2020 and August 2021. Patients who had received chemotherapy before referral to our center, as well as patients who were scheduled for palliative care, were excluded from this study.This study was conducted after receiving ethical approval from the Institutional Review Board (IRB) of KAMC (IRB number: 21-871 and registration number: H-02-K-001). All data were safely maintained at the principal investigator's workstation, and all analyses were carried out on-site according to the Declaration of Helsinki, 2013.Objective of the studyThe primary objective of the study was to track the timeline of patients with BC, specifically focusing on three key time intervals, including the duration from the first visit to KAMC, the investigation period, and the time of initiation of individualized treatment plans. Subsequently, we aimed to examine the factors contributing to the delay of patient and/or facility procedures encountered during the COVID-19 era.Data source and measurementsThe study data were obtained through a centralized electronic chart review of all patients included in this study, conducted at the KAMC center. Data on demographic characteristics and comorbidities were collected in accordance with the defined outcome variables. A comprehensive collection of patient records included information on referral type, work-up management , and biopsy specimen), diagnosis, and histopathology reports, as well as subsequent management plans . A tracking model for clinic appointments was applied to determine the number of canceled/skipped appointments. Timeline counts for the duration of the investigation and management were calculated in days for each patient. In the context of this research, we established the first visit to our center as the time when patients initially sought evaluation or were referred to our clinic  to address breast-related complaints.Statistical analysisMicrosoft Excel  was used to gather, manage, and visualize the data. It was then transferred to the statistical software, IBM Corp. Released 2017. IBM SPSS Statistics for Windows, Version 25.0. Armonk, NY: IBM Corp., for data analysis. Frequencies and percentages were used to describe categorical data. For continuous data (including age and duration of investigation), mean and standard deviation (SD) were used for normally distributed data, while median and interquartile range (IQR) were used for skewed data.The Pearson Chi-square test was applied to evaluate the factors associated with delay in treatment . A p-value of less than 0.05 was considered statistically significant.Seventy-six patients, with an average age of 50 ± 11 years, were included in this study. A total of 47 patients (61.8%) were referred from other centers. Approximately one-third of the patients were hypertensive, and 17 (22.4%) of them had diabetes. Regarding the tumor, node, and metastasis (TNM) stage of the patients, the majority were classified as T2, N1, and M0, accounting for 27 (35.5%), 28 (36.8%), and 74 (97.4%) patients, respectively. The surgical approaches employed in this study included a modified radical mastectomy, partial mastectomy, simple mastectomy, and skin-sparing mastectomy performed on 41 (54%), 23 (30.3%), 11 (14.5%), and one (1.3%) patients, respectively (Table The duration of the diagnostic workup was measured in days. The study found that non-referred patients or those referred based on suspicion (without biopsy) had a median time of 19 days (IQR: 14 to 29) until the final diagnosis. However, in the referred patients, the median time from the referral to the final diagnosis was 10 days (IQR: 7 to 16). While performing a breast ultrasound and MRI, the median time was 14 days (IQR: 8.25 to 21.5) and 31 days (IQR: 21 to 150)  received treatment within 30 days, while for 28 patients (36.8%), the duration of treatment ranged between 31 and 60 days; additionally, for 28 patients (36.8%), the duration exceeded 60 days. However, when considering the time duration between the initial hospital visit and surgical management, 17 patients (56.7%) underwent breast surgery after more than 60 days. In addition, neoadjuvant chemotherapy was initiated within 30 days for 16 patients (41%) from the initial hospital visit and within 31-60 days for 16 patients (41%) (Table % receiveWe found no significant association between age and delayed initiation of the first BC treatment p = 0.49). On the other hand, the patients' deposition (referred versus non-referred) was significantly associated with the delay. Among the non-referred patients, 14 individuals (48.3%) had their treatment initiated 60 days after the diagnosis, whereas among the referred patients, 17 individuals (36.2%) had their treatment initiated within 30 days of the diagnosis (p = 0.033). The patients who skipped appointments experienced a significant delay in the initiation of their treatment (p < 0.001). Among patients who skipped two or more appointments, 12 individuals (80%) experienced a delay of more than 60 days. Additionally, the cancellation of appointments was found to be associated with delayed treatment initiation (p = 0.03) (Table 9. On theDuring the COVID-19 pandemic, healthcare resources were extensively utilized to manage the escalating number of COVID cases. However, resource-demanding diseases, including BC, encountered significant challenges. Consequently, many hospitals during the pandemic were compelled to temporarily suspend routine breast screening and follow-up appointments for patients receiving adjuvant therapy to conserve hospital resources and prevent the spread of infection -16. As pThe treatment delay issue among patients with BC has been impacted by changes in hospital policies, priorities, and capacity to accommodate patients. According to Papautsky’s report, approximately half of BC patients experienced delays in their care during the pandemic . The stuFurthermore, it is important to note that the delay in management is not solely attributable to hospitals. For instance, the national cancer database has identified delays in low-income patients . MoreoveIn our cohort, the median time from the first hospital visit to the final diagnosis was 10 and 19 days for referred patients and non-referred patients, respectively. These results indicate a shorter duration compared to Kapp's report, where the time from symptom onset to diagnosis was more than 25 days . AdditioIn this study, the majority of patients received their initial management, including surgery, chemotherapy, hormonal therapy, or radiation, within an average period of 31 days after their first hospital visit. Specifically, with regard to surgical resection, more than half of the patients underwent surgery within 60 days of their initial presentation. This is in contrast to Mooghal’s study, which reported an average of 69 days from presentation to surgery . AdditioA significant association was found between the delay in initiating the first management and various factors, including patient deposition and skipping and canceling appointments. This observation sheds light on the potential impact of COVID-19 on both patient- and facility-related management delays. Furthermore, these two factors could help explain the differences in patient presentations before and after the COVID-19 pandemic, as reported in the literature ,21. HoweTo the best of our knowledge, this is the first study to examine BC timeline management in tertiary hospitals during the COVID-19 pandemic in Saudi Arabia. However, there are certain limitations to consider. First, the study design is retrospective, which may restrict the available information and introduce potential biases. Second, the small cohort size could have influenced the results, and a larger sample size would provide more reliable conclusions. Third, the study did not include information on the COVID-19 status of the participants or specific histopathological subtypes. Fourth, we included breast cancer patients who visited KAMC institutions during the COVID-19 era, which is a small group of patients that cannot give a reliable conclusion about factors that contribute to delayed management in KAMC institutions. Further studies should aim to address the impact of COVID-19 on other malignancies and consider a prospective design to gather more comprehensive data.In conclusion, this study provides valuable insights into the impact of COVID-19 on the timeline management of BC. Our findings indicate that the delay in initiating therapy for patients with BC was significantly associated with 40 patient depositions, appointment cancellations, and skipped appointments. However, further research is needed to validate these findings on a larger scale, preferably through a nationwide study involving multiple centers, and further studies are needed to address the reasons for delayed management. Additionally, future studies to assess the extent of cancer up-staging caused by these delays should be conducted. These efforts will contribute to a better understanding of the challenges faced by BC management during the COVID-19 pandemic and help guide the development of strategies to mitigate these delays.


Glioblastoma (GB) is characterized by a high level of resistance to radiotherapy. Recent studies focused attention on the importance of cancer stem cells (CSC) as elements that influence not only the growth of GB but also its resistance to available treatments. Therefore, stem cells’ radiosensitivity has become an important area of investigation. In this context, biomarkers of stemness  seem to play an important role. The aim of this review is to summarize findings both on stem cells’ radiosensitivity and on biomarkers of stemness, in order to evaluate their relevance in this field.Despite countless papers in the field of radioresistance, researchers are still far from clearly understanding the mechanisms triggered in glioblastoma. Cancer stem cells (CSC) are important to the growth and spread of cancer, according to many studies. In addition, more recently, it has been suggested that CSCs have an impact on glioblastoma patients’ prognosis, tumor aggressiveness, and treatment outcomes. In reviewing this new area of biology, we will provide a summary of the most recent research on CSCs and their role in the response to radio-chemotherapy in GB. In this review, we will examine the radiosensitivity of stem cells. Moreover, we summarize the current knowledge of the biomarkers of stemness and evaluate their potential function in the study of radiosensitivity. Glioblastomas (GB) are the most common primary malignant tumors of the central nervous system (CNS) . Due to Cancer stem cells (CSCs) are derived from normal stem cells and/or progenitor cells through genetic mutations and epigenetic changes. They represent a distinct subpopulation of cancer cells with unique characteristics including self-renewal, unlimited division potential, and the ability to differentiate in multiple directions. Initial detection of CSCs was reported in leukemia in 1997 and, subsequently, in various solid tumors such as brain, breast, colon, liver, and lung cancer ,13,14,15Extracellular vesicles, including exosomes, as well as soluble factors such as interleukins, cytokines, and other metabolites are found in the tumor microenvironment (TME) ,22,23. TCurrently, the study of the role of CSCs in the radioresistance of gliomas is mainly limited to preclinical investigations. Moreover, with due limitations related to patient selection, static data, and partial representation of the tumor as a whole, to date, the translational development of biomarkers of CSCs in GB is linked to tumor tissue collected during surgery . There iRadiotherapy (RT) induces DNA damage, either directly or indirectly, through the generation of water-derived radicals and reactive oxygen species (ROS), which interact with macromolecules, lipids, and proteins ,37,38. DIn recent years, several stem cell-related biomarkers have been identified in various solid and hematological tumors, although clinical translation has not yet been achieved for the treatment of glioblastomas. Moreover, to make the development of stem cell-related clinical biomarkers even more difficult, similar transcription factors and signaling pathways are shared between CSCs and healthy stem cells. Listed below are reported the most important CSCs biomarkers that could play a role in radio-resistance in glioblastoma .Membrane proteins known as the cluster of differentiation antigens (CD) play numerous roles in cell adhesion, communication, and differentiation.CD 133, also known as prominin-1, is a glycoprotein with five transmembrane regions first discovered as a hemopoietic cell biomarker. Chemoresistance has also been associated with the presence of CD133+ CSCs in oral cancer, lung cancer, and glioma (GB) (oma (GB) . AngelasBao et al. showed that the activation checkpoint kinases Chk1 and Chk2 help CD133+ glioma CSCs make gliomas less sensitive to radiation . TherefoCD44 is involved in cell adhesion, migration, and interaction [The cell surface glycoprotein eraction . CD44 pleraction . Accordieraction ,97. The eraction . Liu et eraction .TIM-3 (T-cell immunoglobulin mucin-3) is a type 1 cell-surface glycoprotein known to be expressed on the surface of leukemic stem cells and in more than 70% of patients with GB [p 0.05). Patients with no or low Tim-3 expression experienced a median survival of 16.9 and 16.4 months, respectively, but those with high Tim-3 expression and MGMT promoter nonmethylation had a median survival of 7.6 months. The average survival time for patients with low Tim-3 expression and methylation of the MGMT promoter was 21.8 months. with GB . Through with GB . Zhang e with GB . ThereinNestin  is an important intermediate filament constituent that the cellular cytoskeleton usually presents in neuronal stem cells [p < 0.05) [p < 0.05). Patients with Nestin+/CD133+ expression had the lowest survival rate (p < 0.01). This finding was also confirmed at multivariate analysis (p < 0.01). In 2016, Guadagno et al. obtained the same results [em cells . Increasem cells . Inhibitem cells . In 2008 < 0.05) . The low results . Further results . Calabre results . HambardNotch pathway controls cell division, differentiation, proliferation, and death and plays a fundamental role in central nervous system development. Protein convertases at site 1 (S1) cleave Notch receptors after they are synthesized, controlling their trafficking and signaling function. The intensity and timing of Notch activity are regulated by posttranslational changes of the receptors and ligands to generate context-specific signals [The  signals . The exp signals . On the  signals . Multivap < 0.001 for TC, p < 0.001 for TC) and OS . Lastly, there is evidence that JAG1 is also implicated in radioresistance. Kim et al. irradiated JAG1-depleted LN18 cells with 3 and 5 Gy. The results showed colony survival was significantly reduced compared to LN18 cells that normally expressed JAG1 [There is evidence that JAG-1 is implicated in radioresistance. KIM et al. irradiated JAG1-depleted LN18 cells with 3 and 5 Gy. The results showed colony survival was significantly reduced compared to LN18 cells that normally expressed JAG1 . Anothersed JAG1 .Aldehyde dehydrogenase (ALDH) is a class of NAD(P)+-dependent enzymes that play an important role in the detoxification process catalyzing the oxidation of aldehyde substrates [p = 0.000315), compared with PN GSCs (p < 0.01) [n = 30) collected from adult patients with histopathologically confirmed diagnosis of GB. High ALDH mRNA expression was associated with the poorer OS  and higher grade of peritumoral edema compared to the low expression group. In addition, Wang et al. demonstrated that ALDH3B1 and ALDH16A1 affect proliferation and migration of HGG cells by inducing cell-cycle arrest and the epithelial–mesenchymal transition [bstrates . ALDH isbstrates . Furtherbstrates . In HGG  < 0.01) . ALDH exansition .Research into DNA repair pathways, particularly involving RAD51 and BRCA1/2, has shed light on their critical roles in glioblastoma. These pathways are central to maintaining genome stability and influencing the behavior of CSCs. A pivotal investigation conducted by Balbous et al. assessed the expression of RAD51 within glioblastoma stem-like cells and its consequential association with resistance to radiation . This unSTAT3  has been reported to be permanently activated in a variety of tumors, including GB, resulting in raised radio-resistance [sistance . Masliansistance . In addisistance . STAT3 gSox2 (SRY-Box Transcription Factor 2) is responsible for the maintenance of an undifferentiated cellular phenotype [Transcriptional regulator henotype . SOX 2 ihenotype . Accordihenotype . Other shenotype .The HIF-1  pathway plays an important and nuanced function in glioblastoma, particularly in response to the neoplasm’s hypoxic condition . Under hEZH2 (Enhancer of zeste 2 polycomb repressive complex 2 subunit) is a part of a multimeric proteic complex called PRC2 consisting of three other subunits termed EED, SUZ12, and RbAp46/4. EZH2 has also been implicated in radio-resistance. Kim et al. assessed the impact of ionizing radiation on three glioma sphere samples  and detected a significant increase in both mRNA expression and protein levels of the EZH2/MELK–FOXM1 axis [XM1 axis . The effXM1 axis . EZH2 caXM1 axis . A possiXM1 axis . EZH2 alXM1 axis . FurtherXM1 axis .Exosomes are extracellular vesicles (30–160 nm in size) released from different type of cells, including GB cells, and are one of the main cell-to-cell communication tools. In recent years, thanks to the development of bioinformatics and, thus, the possibility of studying the content of the exosomes produced by tumor cells using a computational approach, these vesicles have assumed an increasingly important role in the study of glioblastomas. Their contents in terms of DNA, mRNA, miRNA, other non-coding RNA, proteins, lipids, and metabolites play critical functions in cancer progression ,89,90 reOne of the most important weapons in the treatment of glioblastomas (as well as other solid tumors) is represented by radiotherapy. Unfortunately, due to a series of aspects that are still poorly understood, the radio-sensitivity of these tumors is not satisfactory, and, to date, we have few biomarkers that can help identify the most appropriate approach able to overcome the radioresistance of GB. Over the past 20 years, despite the development of new radiotherapy techniques and several successes achieved in the treatment of various solid tumors, the survival of glioblastoma patients has remained essentially the same, just a little more than a year. In order to break the impasse, increasing evidence is showing that CSCs, a limited proportion of tumor cells, may play an important role in the failure of cancer therapies and, above all, in tumor progression following radiotherapy treatment. For that reason, the study of CSCs to fight the radioresistance exhibited by GB represents a pivotal research frontier with profound potential implications. Research conducted in preclinical models has demonstrated that radiation therapy has a selective effect on eliminating differentiated tumor cells while preserving cancer stem cells. Furthermore, it has been observed that radiation exposure induces the upregulation of certain genes, including SOX2, OCT4, and NANOG. These genes encode transcription factors that play a crucial role in the acquisition of a cancer stem cell phenotype by differentiated tumor cells.As we reported in this review, there are several biomarkers related to CSCs that have been associated with an increased radio- and chemoresistance of glioblastoma cells. However, unfortunately, to date, there are few translational studies conducted on glioblastoma patients, and the available literature consists mainly of in vitro studies. Translational studies conducted on glioblastoma patients might be more useful in the real world, where GBs have a lot of genetic and phenotype variation. These studies could also look at the connection between cancer stem cells and the tumor microenvironment, which is becoming more and more important in discussions about why some therapies do not work. Further impulse for the characterization of stemness biomarkers will come from the introduction of bioinformatics in translational research. Studying the individual gene may give insight into its potential to limit the effectiveness of ionizing radiation; however, each gene must be embedded in a network of genes that are activated or suppressed in response to a stimulus or insult, making the application of bioinformatics essential to characterizing the role that multiple biomarkers of stemness may play together. In the end, the study of CSCs and the numerous biomarkers associated with them may enable researchers in the near future to plan prospective translational studies and identify radioresistance factors. This approach could provide researchers with targets we need to improve the activity of ionizing radiation and, at the same time, to be able to develop an innovative personalized therapy for each GB patient.


The transient receptor potential channel (TRP channel) family is a kind of non- specific cation channel widely distributed in various tissues and organs of the human body, including the respiratory system, cardiovascular system, immune system, etc. It has been reported that various TRP channels are expressed in mammalian macrophages. TRP channels may be involved in various signaling pathways in the development of various systemic diseases through changes in intracellular concentrations of cations such as calcium and magnesium. These TRP channels may also intermingle with macrophage activation signals to jointly regulate the occurrence and development of diseases. Here, we summarize recent findings on the expression and function of TRP channels in macrophages and discuss their role as modulators of macrophage activation and function. As research on TRP channels in health and disease progresses, it is anticipated that positive or negative modulators of TRP channels for treating specific diseases may be promising therapeutic options for the prevention and/or treatment of disease. Macrophages are widely found in various tissues and organs of the human body and are also known as the mononuclear phagocyte system(MPS). Macrophages in the body come from a wide range of sources, including monocytes in the blood, hematopoietic stem cells in the bone marrow and early T lymphocytes in the thymus. The most important way is that monocytes in the blood penetrate the blood vessels and enter the connective tissue to differentiate and form macrophages . It is aTRP channels are ubiquitously expressed multimodal ion channels with six transmembranes S1-S6) domains and intracellular N- and C-termini. Fragments between S5 and S6 are embedded to form ion passages, which are especially permeable to Ca2+ and Na+ . At pres domains Mature macrophages undergo dynamic phenotypic/functional switching in response to microenvironmental signals, known as macrophage polarization. Macrophages are mainly activated into two phenotypes, M1 and M2, depending on their response to environmental stimuli . M1 macrUp-regulation of TRPA1 in atherosclerotic plaques can regulate the development of macrophages to the M1 inflammatory phenotype, thereby promoting the progression of atherosclerosis . It has In vitro, LPS- induced TNF-α release was increased, but IL-10 release was attenuated in TRPM8 KO PM, suggesting that TRPM8 contributes to the expression of anti-inflammatory cytokines. In vivo, menthol (TRPM8 agonist) enema increased in the anti- inflammatory cytokine profile of M2 macrophages, which had a protective effect on mice with experimental colitis. TRPM8-deficient mice exhibit increased susceptibility to colitis, a phenotype rescued by systemic IL-10 expression  is the pathological basis of various cardiovascular diseases, characterized by high morbidity, disability, and high mortality. It is a major cause ofhealth and death, with an increasing trend in morbidity and mortality in recent years . As immuTRPA1 channel expression in the normal and atherosclerotic aorta. TRPA1 can regulate the development of macrophages to M1 inflammatory phenotype, thereby promoting the progression of atherosclerosis . TRPA1 dThe activation of TRPV4 also intensifies the development of AS. TRPV4 channels function in primary normal BMDMs, and in RAW264.7 cells. As a mechanical sensor, TRPV4 can regulate macrophage phagocytosis through matrix stiffness, among which oxLDL phagocytosis uptake is a key process in atherogenesis. Knockout of TRPV4 prevents foam cell formation induced by oxLDL uptake after stromal stiffness or scratching . In addiin vitro, impaired survival signaling and increased apoptosis , et al. The expression of TRPC6 mRNA was significantly increased in alveolar macrophages from COPD patients, and the patch clamp showed that TRPC6 was functionally active on smaller macrophages . In pulm2 infection of PBAM promotes Ca2+ influx, further activating the NF-κB p65 signaling pathway and enhancing cytokine secretion. We can reduce the inflammatory response in the lung by reducing the release of cytokines that drive the inflammatory response by knockdown or antagonist of TRPV2 . The lit2+ signaling pathway could be potential therapeutic targets in respiratory disease.The role of TRPV4 in lung tissue is controversial.TRPV4 significantly increases calcium, superoxide, and nitric oxide production in response to high PIP activation, with increased filtration coefficient K(f), ultimately leading to acute lung injury , 75. It Persistent, low-grade inflammation may be a potentially modifiable risk factor in inherited metabolic diseases such as diabetes and obesity . Obesity2+ signaling in microglia mitochondria, production of mtROS, activation of MAPK, and increased chemotaxis activity in microglia, inducing immune and neurological diseases , and TRP-related genes are closely related to the infiltration of immune cells. TRPM5 was differentially expressed in different samples, its related gene ADCY6 was negatively correlated with macrophage M1, HRH1 was positively correlated with macrophage M2, and HTR2B was positively correlated with macrophage M2 . These rSepsis refers to systemic and injurious inflammatory response syndrome caused by severe infection, a common critical disease in clinical practice. The key to sepsis is the imbalance of proinflammatory/anti-inflammatory mechanisms: in the early stage, systemic inflammation is predominant, manifested as SIRS; Later, severe immunosuppression predominates, namely CARS, leading to severe systemic infections and organ damage that are difficult to control , 95, 96.in vitro phagocytosis of LPS-treated peritoneal macrophages  expression on macrophages . Decreasrophages . This imrophages . Both ofrophages .This review highlights the possible functions of macrophage TRP channels in different systems, including the regulation of macrophage activation and their role in disease. In general, it plays an important role in physiological and pathological states. Due to the wide distribution of macrophages and the differential expression of TRP in different organs and tissues, targeting and selective activation and inhibition of macrophage TRP is the key to preventing and treating diseases. Currently, many drugs use TRP channels as therapeutic targets to treat diseases , for exaJW and ZL wrote the manuscript. YD, XL, CL, XM, TZ, ST, JL, QA, DF, YX, XW, YH, and QD collect the literature. JX primarily revised and finalized manuscript. RX revised the manuscript for clarity and style. All authors contributed to the article and approved the submitted version.


In Brazil, new leprosy cases with grade-2 disability (G2D) have been increasing. Physical disability has been associated with experienced stigmatization, psychological distress, and social restriction.To identify factors associated with leprosy disability in an endemic area of Brazil focusing on occupational and other sociodemographic factors.Between July and December 2015, adult patients with multibacillary leprosy who attended a clinic in Belo Horizonte, Brazil were enrolled. Social, clinical, and demographic factors were collected from an administered questionnaire and medical charts. Occupations were categorized as manual vs non-manual. Descriptive statistics and multivariable logistic regression were performed to study associated factors with disability (Grade 1 disability (G1D) and G2D combined).Seventy-three patients were enrolled with 48 (65.8%) presenting with either G1D or G2D at the time of enrollment. Twenty-nine (39.7%) had G2D. About half of the patients  reported a manual labor occupation and reactions were common . On univariate analyses, older age (p = 0.048) and low education (p = 0.007) were associated with disability. On multivariable analyses, only low education (primary or less) was associated with disability . Greater distance from clinic, income, smoking, marital status, and occupation were not associated.Low education was associated with leprosy disability, consistent with prior studies, and therefore should be a focus for disability reduction programs. While the sample size of this study may have limited detection of associations between disability and social determinants tested, half of the patients reported a manual job, highlighting the need for more extensive studies on associations between occupation, disability, and related injuries. Mycobacterium leprae infection, which affects the skin and peripheral nerves. On occasion, leprosy may even develop in the form of silent neuropathy, allowing M. leprae bacilli to cause damage long before skin lesions and sensory impairment is noticed. Nerve damage can be irreversible and increases in severity when the infection is left untreated. However, early diagnosis and treatment can prevent permanent nerve damage, consequent disability, and stigmatization that may affect individuals’ health and productivity [Leprosy is a result of uctivity .The World Health Organization (WHO) has reported an increasing number of cases of leprosy with grade-2 disabilities (G2D) and global leprosy strategies have been focused on reducing the number of new cases with visible deformities since 2005 . In 2019Brazil has the second highest number of new cases with G2D, accounting for 89% of the new cases with G2D in the Americas , 5, 6. BG2D is usually permanent, leading to noticeable disability, increased stigma, and associated social isolation. Stigma can then significantly impact the patients affecting their physical, psychological, social, and economic well-being . In a hyThe WHO Global Leprosy Strategy 2016–2020 emphasized new cases with G2D targeting new cases among high-risk and marginalized groups to reduce G2D at diagnosis with the objective to decrease the G2D case rate to <1 per million population , 21, 22.Prior studies have evaluated factors such as education, rural residency, medical adherence, marital status, and illiteracy , 24–28. Between July and December 2015, adult cases (18 years and older) of multibacillary (MB) leprosy who presented for care to a dermatologic reference center in Belo Horizonte, Minas Gerais, Brazil, were enrolled in a study to study risk factors for leprosy reactions . EligiblAn in-person questionnaire was administered by study staff, and included questions on demographic topics such as race, marital status, occupation, socioeconomic status, residence , education level, and smoking status. Data abstracted from the medical records included the leprosy type per Ridley Jopling categorization , date ofManual labor was defined as occupations that rely heavily on physical work and intense strength such as farmers, day laborers, bricklayers, handymen, and fishermen. Those who worked in a less intensive physical environment were grouped as non-manual laborers and included office clerks, housekeepers, and taxi drivers. These assignments follow the standard form of occupational segmentations in current literature and in the Brazilian National Classification of Economic Activities , 32, 33.th grade or less), marital status, age, sex, and race. The model was evaluated for collinearity (by measuring condition indexes), interactions, and confounding. Interactions between the main exposure, hard labor, and each of the other variables were assessed by the chunk test. A change in estimates approach was utilized to determine confounding and variables were dropped from the model if the inclusion of them did not change the point estimate of the main exposure by more than 10% or did not improve the primary measure’s precision. All analyses were done using SAS v9.4 , Tableau 10.3 , and ESRI ArcMap 10.6 .Descriptive statistics and univariate analyses were performed on the main study variables and p-values were calculated to compare those patients with or without disability (Grade 1 or Grade 2 combined) using chi-square, Fisher’s exact test, or t-test where appropriate. A p-value of <0.05 was taken as statistically significant. For this paper, we performed a post-hoc analysis to look at this research question of disability, understanding that the original question was looking at risk factors for leprosy reactions . The samEthical approval was obtained from the institutional review boards of Emory University and Faculdade da Saúde e Ecologia Humana (FASEH). Ethical approval was also granted by the Institutional Review Board at Hospital Eduardo de Menezes. All participants provided written informed consent.Additional information regarding the ethical, cultural, and scientific considerations specific to inclusivity in global research is included in the Supporting Information .Of the seventy-three patients enrolled, 65.8% (n = 48) had evidence of disability at the time of either diagnosis or first clinic visit with 39.7% (n = 29) presenting with G2D, 26% (n = 19) with G1D, and 34.2% (n = 25) without disability. About a quarter was female . The mean age was 51.2 years (±14.3) and a quarter of them were above the age of 60 . Of the total study population, the majority were nonwhite  of study participants had objective evidence of nerve impairment at the time of the study. Of those with apparent neuropathy, 60% (n = 29) had the most severe, G2D . This isThe most significant finding in our study was the association between low education (primary or less) and higher occurrence of Grade 1 or 2 disability, with an adjusted odds ratio of 6.34 , consistent with other studies , 38, 39.While our study did not show an association of disability with manual labor, those with such occupation may be at greater risk of accidental damage while working with disability . Of all Distance to reference clinic as a measure of access to care was also not associated with disability. Access to care was a hard measure to define and absolute distance may not have been an adequate measurement of access. A drive-time area map and a more detailed investigation of transportation barriers may provide a deeper understanding of accessibility. Access to care is likely an under-recognized social determinant of health in regard to leprosy leading to potential treatment delays and further disability.Lastly, other studies have found that certain age groups are associated with disability , 28, 38 Limitations of this analysis are the cross-sectional nature of the analysis and small sample size, which is often the case with leprosy given the overall rarity of the disease even in endemic areas. Since the analysis is one-point in time, causation is not possible to assess. The original scope of the study was to investigate the association of leprosy reactions with co-infections  but giveHowever, our most important finding of educational links to disability supports the need for increased awareness and health campaigns to bring people to care and ensure they understand how to lessen their risk of permanent nerve damage. Also, the high proportion of low education, manual labor, and low socioeconomic status of these patients point to potential health disparities of people with leprosy in Brazil and call for more research and program implementation to address these issues.S1 Text(DOCX)Click here for additional data file.S2 Text(DOCX)Click here for additional data file.